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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Selective Efflux Inhibition of ATP-binding Cassette Sub-family G Member 2 - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
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<meta name="citation_title" content="Selective Efflux Inhibition of ATP-binding Cassette Sub-family G Member 2">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2013/02/25">
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<meta name="citation_author" content="J. Jacob Strouse">
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<meta name="citation_author" content="Irena Ivnitski-Steele">
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<meta name="citation_author" content="Hadya M. Njus">
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<meta name="citation_author" content="Terry D. Foutz">
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<meta name="citation_author" content="Tuanli Yao">
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<meta name="citation_author" content="Warren S. Weiner">
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<meta name="citation_author" content="Chad E. Schroeder">
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<meta name="citation_author" content="Denise S. Simpson">
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<meta name="citation_author" content="Brooks E. Maki">
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<meta name="citation_author" content="Kelin Li">
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<meta name="citation_author" content="Jennifer E. Golden">
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<meta name="citation_author" content="Anna Waller">
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<meta name="citation_author" content="Annette M. Evangelisti">
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<meta name="citation_author" content="Susan M. Young">
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<meta name="citation_author" content="Dominique Perez">
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<meta name="citation_author" content="Stephanie E. Chavez">
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<meta name="citation_author" content="Mathew J. Garcia">
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<meta name="citation_author" content="Oleg Ursu">
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<meta name="citation_author" content="Dan C. Fara">
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<meta name="citation_author" content="Cristian G. Bologa">
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<meta name="citation_author" content="Mark B. Carter">
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<meta name="citation_author" content="Virginia M. Salas">
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<meta name="citation_author" content="George P. Tegos">
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<meta name="citation_author" content="Tudor I. Oprea">
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<meta name="citation_author" content="Bruce S. Edwards">
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<meta name="citation_author" content="Richard S. Larson">
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<meta name="citation_author" content="Jeffrey Aubé">
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<meta name="citation_author" content="Larry A. Sklar">
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<meta name="citation_pmid" content="23658968">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK133425/">
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<link rel="schema.DC" href="http://purl.org/DC/elements/1.0/">
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<meta name="DC.Title" content="Selective Efflux Inhibition of ATP-binding Cassette Sub-family G Member 2">
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<meta name="DC.Type" content="Text">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="J. Jacob Strouse">
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<meta name="DC.Contributor" content="Irena Ivnitski-Steele">
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<meta name="DC.Contributor" content="Hadya M. Njus">
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<meta name="DC.Contributor" content="Terry D. Foutz">
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<meta name="DC.Contributor" content="Tuanli Yao">
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<meta name="DC.Contributor" content="Warren S. Weiner">
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<meta name="DC.Contributor" content="Chad E. Schroeder">
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<meta name="DC.Contributor" content="Denise S. Simpson">
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<meta name="DC.Contributor" content="Brooks E. Maki">
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<meta name="DC.Contributor" content="Kelin Li">
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<meta name="DC.Contributor" content="Jennifer E. Golden">
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<meta name="DC.Contributor" content="Anna Waller">
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<meta name="DC.Contributor" content="Annette M. Evangelisti">
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<meta name="DC.Contributor" content="Susan M. Young">
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<meta name="DC.Contributor" content="Dominique Perez">
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<meta name="DC.Contributor" content="Stephanie E. Chavez">
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<meta name="DC.Contributor" content="Mathew J. Garcia">
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<meta name="DC.Contributor" content="Oleg Ursu">
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<meta name="DC.Contributor" content="Dan C. Fara">
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<meta name="DC.Contributor" content="Cristian G. Bologa">
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<meta name="DC.Contributor" content="Mark B. Carter">
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<meta name="DC.Contributor" content="Virginia M. Salas">
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<meta name="DC.Contributor" content="George P. Tegos">
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<meta name="DC.Contributor" content="Tudor I. Oprea">
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<meta name="DC.Contributor" content="Bruce S. Edwards">
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<meta name="DC.Contributor" content="Richard S. Larson">
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<meta name="DC.Contributor" content="Jeffrey Aubé">
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<meta name="DC.Contributor" content="Larry A. Sklar">
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<meta name="DC.Date" content="2013/02/25">
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<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK133425/">
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<meta name="description" content="Although many mechanisms exist, resistance of tumors to cancer therapy drugs is the principal reason for treatment failure and the majority of clinical and experimental data indicates that multidrug transporters such ABCB1 (a.k.a. Pgp, MDR1) and ABCG2 (a.k.a. BCRP, MRP1) play a leading role by preventing cytotoxic intracellular drug concentrations. Inhibition of the function of these drug efflux pumps presents a promising approach to treat cancer using existing drugs. To date, clinical trials with such adjuvant therapies have been relatively unsuccessful. One likely contributing factor to these failed clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We propose that searching for selective efflux inhibitors by profiling multiple ABC transporter efflux pumps against a library of small molecules could result in molecular probes that could further explore such interactions. Using the mitochondrial membrane potential dye JC-1 as a dual-pump fluorescent reporter substrate in our primary screening protocol we observed a piperazine substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused structure activity relationship (SAR) driven chemistry effort we describe herein a selective ABCG2 efflux inhibitor (SID 88095709) with a 36 fold preference over ABCB1 with increased activity over prior art for ABCG2. The probe has low in vitro cellular toxicity, as well as adequate solubility and stability under appropriate experimental conditions. The probe also appears to have an IP landscape with space to operate. In vitro chemotherapeutic potentiation further illustrates the utility of the probe compound and related members. A related scaffold (SID 97301789) also shows promise for further development and optimization.">
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<meta name="og:title" content="Selective Efflux Inhibition of ATP-binding Cassette Sub-family G Member 2">
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<meta name="og:type" content="book">
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<meta name="og:description" content="Although many mechanisms exist, resistance of tumors to cancer therapy drugs is the principal reason for treatment failure and the majority of clinical and experimental data indicates that multidrug transporters such ABCB1 (a.k.a. Pgp, MDR1) and ABCG2 (a.k.a. BCRP, MRP1) play a leading role by preventing cytotoxic intracellular drug concentrations. Inhibition of the function of these drug efflux pumps presents a promising approach to treat cancer using existing drugs. To date, clinical trials with such adjuvant therapies have been relatively unsuccessful. One likely contributing factor to these failed clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We propose that searching for selective efflux inhibitors by profiling multiple ABC transporter efflux pumps against a library of small molecules could result in molecular probes that could further explore such interactions. Using the mitochondrial membrane potential dye JC-1 as a dual-pump fluorescent reporter substrate in our primary screening protocol we observed a piperazine substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused structure activity relationship (SAR) driven chemistry effort we describe herein a selective ABCG2 efflux inhibitor (SID 88095709) with a 36 fold preference over ABCB1 with increased activity over prior art for ABCG2. The probe has low in vitro cellular toxicity, as well as adequate solubility and stability under appropriate experimental conditions. The probe also appears to have an IP landscape with space to operate. In vitro chemotherapeutic potentiation further illustrates the utility of the probe compound and related members. A related scaffold (SID 97301789) also shows promise for further development and optimization.">
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id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK133425_"><span class="title" itemprop="name">Selective Efflux Inhibition of ATP-binding Cassette Sub-family G Member 2</span></h1><p class="contribs">Strouse JJ, Ivnitski-Steele I, Njus HM, et al.</p><p class="fm-aai"><a href="#_NBK133425_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Although many mechanisms exist, resistance of tumors to cancer therapy drugs is the
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principal reason for treatment failure and the majority of clinical and experimental
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data indicates that multidrug transporters such ABCB1 (a.k.a. Pgp, MDR1) and ABCG2
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(a.k.a. BCRP, MRP1) play a leading role by preventing cytotoxic intracellular drug
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concentrations. Inhibition of the function of these drug efflux pumps presents a
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promising approach to treat cancer using existing drugs. To date, clinical trials
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with such adjuvant therapies have been relatively unsuccessful. One likely
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contributing factor to these failed clinical applications is limited understanding
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of specific substrate/inhibitor/pump interactions. We propose that searching for
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selective efflux inhibitors by profiling multiple ABC transporter efflux pumps
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against a library of small molecules could result in molecular probes that could
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further explore such interactions. Using the mitochondrial membrane potential dye
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JC-1 as a dual-pump fluorescent reporter substrate in our primary screening protocol
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we observed a piperazine substituted pyrazolo[1,5-a]pyrimidine
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substructure with promise for selective efflux inhibition. As a result of a focused
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structure activity relationship (SAR) driven chemistry effort we describe herein a
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selective ABCG2 efflux inhibitor (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=abstract&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>) with a 36 fold
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preference over ABCB1 with increased activity over prior art for ABCG2. The probe
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has low <i>in vitro</i> cellular toxicity, as well as adequate solubility
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and stability under appropriate experimental conditions. The probe also appears to
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have an IP landscape with space to operate. <i>In vitro</i>
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chemotherapeutic potentiation further illustrates the utility of the probe compound
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and related members. A related scaffold (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=abstract&targetsite=entrez&targetcat=link&targettype=pubchem">SID 97301789</a>) also shows
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promise for further development and optimization.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1 R03 MH081228-01A1</p><p><b>Screening Center Name & PI:</b> University of New Mexico Center for
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Molecular Discovery (UNMCMD) formerly NM Molecular Libraries Screening Center (NMMLSC),
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Larry Sklar</p><p><b>Chemistry Center Name & PI:</b> University of Kansas Specialized
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Chemistry Center (KU SCC), Jeffrey Aubé</p><p><b>Assay Submitter & Institution:</b> Richard Larson, University of New
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Mexico</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1818" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1818</a></p><div id="ml230.s1"><h2 id="_ml230_s1_">Probe Structure & Characteristics</h2><div id="ml230.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK133425/bin/ml230fu1.jpg" alt="ML230." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML230[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML230</a></span></h3></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml230tu1"><a href="/books/NBK133425/table/ml230.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml230tu1" rid-ob="figobml230tu1"><img class="small-thumb" src="/books/NBK133425/table/ml230.tu1/?report=thumb" src-large="/books/NBK133425/table/ml230.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml230.tu1"><a href="/books/NBK133425/table/ml230.tu1/?report=objectonly" target="object" rid-ob="figobml230tu1">Table</a></h4></div></div></div><div id="ml230.s2"><h2 id="_ml230_s2_">Recommendations for Scientific Use of the Probe</h2><p>The intrinsic or acquired resistance of tumors to current drugs is the principal
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reason for failure of cancer therapy. Although many mechanisms of resistance exist,
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the majority of clinical and experimental data indicate that multidrug
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|
transporters--principally ABCB1 (a.k.a. Pgp, MDR1) and ABCG2 (a.k.a. BCRP,
|
|
MRP1)--play a leading role in treatment failure by preventing intracellular drug
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|
concentrations from increasing. Thus, inhibition of the function of these drug
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|
efflux pumps in tumor cells presents one of the most promising approaches to cure
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cancer using existing drugs.</p><p>In general, ABCB1, ABCC1, and ABCG2 transporters are known to significantly influence
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the efficacy of drugs, and although a large number of compounds have been identified
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possessing ABC transporter inhibitory properties, only a few of these agents are
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appropriate candidates for clinical use as MDR reversing agents.<sup><a class="bibr" href="#ml230.r1" rid="ml230.r1">1</a>–<a class="bibr" href="#ml230.r2" rid="ml230.r2">2</a></sup> The characterization of the
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transporter/substrate/inhibitor interactions might provide further clues about their
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structure and toxicology effects prior to <i>in vivo</i> use, as well as
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aid in predicting potential drug interactions among different therapeutic
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agents.</p><p>The project was originally proposed to simultaneously screen a transporter triplex
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including ABCC1. However, a prior MLSCN project by the Southern Research Institute
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screened against ABCC1 and identified sulindac sulfide as a probe. As JC-1 proved
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not to be a convenient substrate for a cell triplex, our project focused on the
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ABCB1/ABCG2 duplex. It was originally envisioned that the project would identify a
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scaffold selective for individual targets in which medicinal chemistry could
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optimize three important elements: 1) selectivity in the transporter efflux assay;
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2) selectivity in the chemoreversal assay; and 3) selectivity in off-target toxicity
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. The probe has been identified primarily on the basis of a distinct efflux
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inhibition preference for ABCG2. However, ABCG2 potentiation is also slightly
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preferred, particularly in the context of <i>in vitro</i> toxicity
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profiles. Individual analogs in the SAR series may be selected on the basis of any
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or all of these properties to fit given test situations, where for example, optimal
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therapeutic index or minimal off-target toxicity may be desired over selectivity.
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Structural clustering based on Partial Least Squares (PLS) analysis in the molecular
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descriptors’ space (normalized percent response and EC<sub>50</sub> values
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in primary and secondary assays for both ABCB1 and ABCG2 transporters, and also the
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associated toxicity data for these two targets) demonstrates that our scaffold
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occupies a unique chemical space as compared to several compounds in current or past
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clinical trials (i.e. Cyclosporin, Biricodar, Tariquidar, Zosuquidar, etc.) as well
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as the selective efflux inhibitors depicted in <a class="figpopup" href="/books/NBK133425/figure/ml230.f1/?report=objectonly" target="object" rid-figpopup="figml230f1" rid-ob="figobml230f1">Figure 1</a>. Thus, the scaffold and analogs within the series have the
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potential to serve as probes for members of the ABC family individually, or
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selectively under a variety of <i>in vitro</i> tests as well as showing
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promise for extension of the scaffold into <i>in vitro</i> animal models.
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In fact, preliminary studies in our ABCG2 over-expressing tumor model (data not
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shown, available upon request) indicate that the probe significantly reduces tumor
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size in combination with the chemotherapeutic topotecan. Tumors that were grown for
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4 weeks effectively disappeared by the fourth day of treatment.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f1" co-legend-rid="figlgndml230f1"><a href="/books/NBK133425/figure/ml230.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml230f1" rid-ob="figobml230f1"><img class="small-thumb" src="/books/NBK133425/bin/ml230f1.gif" src-large="/books/NBK133425/bin/ml230f1.jpg" alt="Figure 1. Structures of small molecules chosen for direct experimental comparison." /></a><div class="icnblk_cntnt" id="figlgndml230f1"><h4 id="ml230.f1"><a href="/books/NBK133425/figure/ml230.f1/?report=objectonly" target="object" rid-ob="figobml230f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Structures of small molecules chosen for direct experimental
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comparison. </p></div></div></div><div id="ml230.s3"><h2 id="_ml230_s3_">1. Introduction</h2><p>The three major subfamilies of human multidrug resistance (MDR) proteins (ABCB, ABCC,
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and ABCG) influence oral absorption and disposition of a wide variety of drugs, and
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as a result their expression levels have important consequences for susceptibility
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to drug-induced side effects, interactions, and treatment efficacy. Dual treatment
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with ABC transporter inhibitors in conjunction with chemotherapeutics is a common
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treatment strategy to circumvent MDR in cancers.<sup><a class="bibr" href="#ml230.r3" rid="ml230.r3">3</a>–<a class="bibr" href="#ml230.r4" rid="ml230.r4">4</a></sup> However, the failure of current classes provide ample
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justification for identifying new classes of modulators and exploring the biology
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around them. More than 48 members of the ABC transporter superfamily have been
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identified and three of these members, MDR1/Pgp (ABCB1), MRP1 (ABCC1), and BCRP
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(ABCG2), have unambiguously been shown to contribute to cancer multidrug
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resistance.<sup><a class="bibr" href="#ml230.r5" rid="ml230.r5">5</a>–<a class="bibr" href="#ml230.r6" rid="ml230.r6">6</a></sup> These efflux pumps are
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expressed in many human tumors where they likely contribute to resistance to
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chemotherapy treatment. ABCB1, ABCC1, and ABCG2 are highly expressed in the gut,
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liver, and kidneys and they may restrict the oral bioavailability of administered
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drugs. ABCB1 and ABCG2 are also expressed in the epithelia of the brain and placenta
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and also in stem cells, where they perform a barrier function.<sup><a class="bibr" href="#ml230.r7" rid="ml230.r7">7</a></sup></p><p>Early clinical failures with ABCB1 inhibitors initially resulted in diminished
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enthusiasm. However, progress over the last decade has renewed activity in the field
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and a variety of modulators have been identified. ABC efflux transporter inhibition
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is now in its third generation with the majority of focus still on ABCB1. It has
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been observed that a large number of structurally and functionally diverse compounds
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act as substrates or modulators of these pumps with numerous publications dedicated
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to the subject.<sup><a class="bibr" href="#ml230.r8" rid="ml230.r8">8</a>–<a class="bibr" href="#ml230.r11" rid="ml230.r11">11</a></sup> A subset of these compounds
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will be discussed here. The first-generation of chemosensitizers were discovered
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from already approved drugs and included the calcium channel blocker verapamil (as
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well as nicardipine), cyclosporin A, and progesterone but dose-related toxicity and
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other adverse effects (i.e. solubility limitations) prevented progress into the
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clinic.<sup><a class="bibr" href="#ml230.r12" rid="ml230.r12">12</a>–<a class="bibr" href="#ml230.r19" rid="ml230.r19">19</a></sup> Second and third generation
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inhibitors were drawn predominantly from the derivatization of first-generation
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molecules as well as from combinatorial chemistry targeted primarily at ABCB1. Some
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of the higher profile examples include: the cyclosporin A derivative valspodar
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(PSC-833)<sup><a class="bibr" href="#ml230.r20" rid="ml230.r20">20</a></sup>; Vertex
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Pharmaceuticals’ biricodar (VX-710)<sup><a class="bibr" href="#ml230.r21" rid="ml230.r21">21</a>–<a class="bibr" href="#ml230.r23" rid="ml230.r23">23</a></sup>; the anthranilamide based modulators XR9051<sup><a class="bibr" href="#ml230.r24" rid="ml230.r24">24</a></sup>, tariquidar
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(XR9576)<sup><a class="bibr" href="#ml230.r25" rid="ml230.r25">25</a>–<a class="bibr" href="#ml230.r27" rid="ml230.r27">27</a></sup>, XR9577<sup><a class="bibr" href="#ml230.r28" rid="ml230.r28">28</a>–<a class="bibr" href="#ml230.r29" rid="ml230.r29">29</a></sup>, and WK-X-34<sup><a class="bibr" href="#ml230.r29" rid="ml230.r29">29</a>–<a class="bibr" href="#ml230.r30" rid="ml230.r30">30</a></sup>; the acridone carboxamide derivative elacridar
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(GF120918)<sup><a class="bibr" href="#ml230.r31" rid="ml230.r31">31</a></sup>; the
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heteroaryloxypropanolamines zosuquidar (<a href="/nuccore/1257451115" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">LY335979</a>)<sup><a class="bibr" href="#ml230.r32" rid="ml230.r32">32</a>–<a class="bibr" href="#ml230.r34" rid="ml230.r34">34</a></sup> and dofequidar (MS-209)<sup><a class="bibr" href="#ml230.r35" rid="ml230.r35">35</a>–<a class="bibr" href="#ml230.r36" rid="ml230.r36">36</a></sup> (and the structurally related laniquidar (R101933)<sup><a class="bibr" href="#ml230.r37" rid="ml230.r37">37</a>–<a class="bibr" href="#ml230.r38" rid="ml230.r38">38</a></sup>), and diarylimidazole ontogen (OC144-093,
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ONT-093)<sup><a class="bibr" href="#ml230.r39" rid="ml230.r39">39</a>–<a class="bibr" href="#ml230.r42" rid="ml230.r42">42</a></sup>. The late generation
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inhibitors tended to be more potent and less toxic than the first-generation
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compounds, however, multiple issues remain.</p><p>Although much of the work to date is targeted at ABCB1, the selectivity profile of
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these inhibitors is significantly varied. Valspodar, tariquidar, elacridar,
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zosuquidar and ontogen have been reported to be selective (though not necessarily
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specific) for ABCB1.<sup><a class="bibr" href="#ml230.r20" rid="ml230.r20">20</a>–<a class="bibr" href="#ml230.r23" rid="ml230.r23">23</a>,<a class="bibr" href="#ml230.r25" rid="ml230.r25">25</a>–<a class="bibr" href="#ml230.r26" rid="ml230.r26">26</a>,<a class="bibr" href="#ml230.r35" rid="ml230.r35">35</a></sup> Those specific for ABCC1 include the quinoline based MK 571 and
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the uricosuric drug probenecide.<sup><a class="bibr" href="#ml230.r43" rid="ml230.r43">43</a>–<a class="bibr" href="#ml230.r44" rid="ml230.r44">44</a></sup>
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Although there has been significant progress with ABCB1 inhibitors, similar progress
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has not been made with ABCG2 inhibitors. The <i>Aspergillus fumigatus</i>
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|
mycotoxin fumitremorgin C (FTC) and its analogs Ko 132, Ko 134, and Ko 143 have been
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demonstrated to be selective inhibitors for ABCG2.<sup><a class="bibr" href="#ml230.r45" rid="ml230.r45">45</a>–<a class="bibr" href="#ml230.r48" rid="ml230.r48">48</a></sup> Other imidazoline and β–carboline amino
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|
acid benzyl ester conjugates analogous to FTC were labeled
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|
‘dual-acting’ due to a cytotoxicity that was coupled to their
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resistance reversing activity.<sup><a class="bibr" href="#ml230.r49" rid="ml230.r49">49</a></sup> Examples of cross pump inhibitors include verapamil,
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cyclosporin A, dofequidar, and reversan for ABCB1/ABCC1 and biricodar and
|
|
nicardipine for ABCB1/ABCC1/ABCG2.<sup><a class="bibr" href="#ml230.r23" rid="ml230.r23">23</a>,<a class="bibr" href="#ml230.r50" rid="ml230.r50">50</a>–<a class="bibr" href="#ml230.r52" rid="ml230.r52">52</a></sup></p><p>Structural information for all mammalian ABC transporter family members is relatively
|
|
sparse, with ABCB1 being the most extensively studied. The presence of multiple,
|
|
potentially overlapping, binding sites and possible interactions between them may
|
|
account for diverse specificity of structurally and functionally unrelated
|
|
modulators and substrates. This polyspecificity also raises questions as to which
|
|
substrate should be used to demonstrate inhibitory potential of a new chemical
|
|
probe. In order to understand the mechanism and to design more effective modulators,
|
|
great effort has been made to study the interaction of substrates and modulators
|
|
with these transporters.<sup><a class="bibr" href="#ml230.r53" rid="ml230.r53">53</a></sup>
|
|
It was shown that most ABCB1 inhibitors are additionally substrates of the efflux
|
|
pump.<sup><a class="bibr" href="#ml230.r54" rid="ml230.r54">54</a></sup> It is
|
|
important to not only evaluate inhibitor potency in a given transporter, but also to
|
|
profile its activity with other transporters as well as its interrelationship with
|
|
substrate drugs. For instance, strong inhibition of ABCB1 by drugs like cyclosporine
|
|
or verapamil in <i>in vitro</i> models proved to be limited in <i>in
|
|
vivo</i> studies due to toxic pharmacological effects of the
|
|
inhibitors.<sup><a class="bibr" href="#ml230.r6" rid="ml230.r6">6</a></sup> Our
|
|
recent work further demonstrated differential cross-reactivity of inhibitors across
|
|
ABCB1, ABCC1, and ABCG2 transporters and we demonstrated cross-reactivity of both
|
|
these inhibitors across all three transporters, which could help explain such severe
|
|
toxicity effects.<sup><a class="bibr" href="#ml230.r52" rid="ml230.r52">52</a></sup> The
|
|
focus of this report further the discussion of substrate/inhibitor/pump interactions
|
|
in the context of the probe compound and scaffold related compounds in ABCB1 and
|
|
ABCG2 rather than to address current physiological limitations. Such interactions
|
|
can be quite complex, since the array of substrate/non-substrate and
|
|
inhibitor/non-inhibitor is further clouded by the possibility of multiple
|
|
interaction sites and unwarranted cytotoxicity.</p><p>The initial goal of this high throughput screening campaign was to identify new and
|
|
selective efflux inhibitors for both ABCB1 and ABCG2. Although the project was
|
|
originally proposed to simultaneously screen a transporter triplex including ABCC1,
|
|
a prior MLSCN target project by SRI which identified sulindac sulfide had been
|
|
reported. It was envisioned that the project would identify a scaffold selective for
|
|
individual targets in which medicinal chemistry could optimize individually three
|
|
important elements: selectivity in efflux and chemoreversal, as well as off-target
|
|
toxicity or therapeutic index. Finding selective ABCB1 inhibitors proved to be
|
|
difficult and initial data for probe compound precursors showed potential for ABCG2
|
|
selectivity. ABCG2 relevance as a clinical target has been well
|
|
documented.<sup><a class="bibr" href="#ml230.r55" rid="ml230.r55">55</a></sup> This
|
|
includes a mouse model using a human ovarian xenograft with Igrove1/T8
|
|
tumors,<sup><a class="bibr" href="#ml230.r56" rid="ml230.r56">56</a></sup> a system
|
|
utilizing flavopiridol-resistant human breast cancer cells,<sup><a class="bibr" href="#ml230.r57" rid="ml230.r57">57</a></sup> an FTC/Ko 143 inhibition
|
|
<i>in vitro</i> and mouse intestine model,<sup><a class="bibr" href="#ml230.r48" rid="ml230.r48">48</a></sup> and a phase I/II trial with lapatinib in
|
|
glioblastoma multiforme.<sup><a class="bibr" href="#ml230.r58" rid="ml230.r58">58</a></sup>
|
|
Clinical potential coupled with deficient characterization of the ABCG2 half
|
|
transporter make it a desirable target for a probe candidate exploration.</p><p>Several of the aforementioned small molecule inhibitors were selected to help profile
|
|
the compounds of interest <i>in vitro</i> (<a class="figpopup" href="/books/NBK133425/figure/ml230.f1/?report=objectonly" target="object" rid-figpopup="figml230f1" rid-ob="figobml230f1">Figure 1</a>). Compounds were chosen specifically for their
|
|
reported selectivity profiles. The sub-micromolar modulator of ABCB1 XR9051 (a
|
|
precursor to tariquidar) has been shown to reverse resistance to cytotoxic drugs
|
|
such as doxorubicin and vincristine.<sup><a class="bibr" href="#ml230.r1" rid="ml230.r1">1</a>,<a class="bibr" href="#ml230.r24" rid="ml230.r24">24</a></sup> The
|
|
previously mentioned MK 571 is documented as a specific inhibitor of
|
|
ABCC1.<sup><a class="bibr" href="#ml230.r59" rid="ml230.r59">59</a></sup> For direct
|
|
comparison of selective inhibition of ABCG2 both FTC and Ko 143 were
|
|
chosen.<sup><a class="bibr" href="#ml230.r45" rid="ml230.r45">45</a>–<a class="bibr" href="#ml230.r48" rid="ml230.r48">48</a></sup> Also, the pyrazolopyrimidine
|
|
reversan, with a similar core to our inhibitor class, was identified as an active
|
|
inhibitor of ABCB1 and ABCC1.<sup><a class="bibr" href="#ml230.r50" rid="ml230.r50">50</a></sup> Direct experimental comparison of the prior art inhibitors with
|
|
the probe compound can be found in <a href="#ml230.s30">Section
|
|
4.1</a>, <a class="figpopup" href="/books/NBK133425/figure/ml230.f13/?report=objectonly" target="object" rid-figpopup="figml230f13" rid-ob="figobml230f13">Figure 13</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f13" co-legend-rid="figlgndml230f13"><a href="/books/NBK133425/figure/ml230.f13/?report=objectonly" target="object" title="Figure 13" class="img_link icnblk_img figpopup" rid-figpopup="figml230f13" rid-ob="figobml230f13"><img class="small-thumb" src="/books/NBK133425/bin/ml230f13.gif" src-large="/books/NBK133425/bin/ml230f13.jpg" alt="Figure 13. Quantitative comparison of prior art to SID 88095709." /></a><div class="icnblk_cntnt" id="figlgndml230f13"><h4 id="ml230.f13"><a href="/books/NBK133425/figure/ml230.f13/?report=objectonly" target="object" rid-ob="figobml230f13">Figure 13</a></h4><p class="float-caption no_bottom_margin">Quantitative comparison of prior art to SID 88095709. </p></div></div><div id="ml230.s4"><h3>Intellectual Property Landscape of Probe Structure</h3><p>A specific and general scaffold search was performed in SciFinder on July 6, 2011
|
|
related to the <a href="/pcsubstance/?term=ML230[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML230</a> probe structure. The exact structure
|
|
search of <a href="/pcsubstance/?term=ML230[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML230</a> did not reveal any publications or
|
|
patents. A general scaffold search related to <a href="/pcsubstance/?term=ML230[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML230</a> revealed patents of the following relevancies with respect
|
|
to structure (no patents or literature describe this scaffold intended for
|
|
transporter inhibition). There appears to be space to operate due to limitations
|
|
in claims and/or use.</p><div id="ml230.fu2" class="figure"><div class="graphic"><img src="/books/NBK133425/bin/ml230fu2.jpg" alt="Image ml230fu2" /></div></div><p>Blake, J.F., et al. Bioorganic & Medicinal Chemistry Letters (2010),
|
|
20(19), 5607–5612. “Discovery of pyrrolopyrimidine inhibitors of
|
|
Akt.” The discovery and optimization of a series of pyrrolopyrimidine
|
|
based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure
|
|
based drug design is reported. The compounds demonstrate potent inhibition of
|
|
all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and
|
|
tumor xenografts. Structural modifications are focused on the head group (blue)
|
|
and a modified pyrrolopyrimidine core, optimized to an indolopyrimidine moiety.
|
|
Head group changes of this type were not tolerated for the ABC G2 project.</p><div id="ml230.fu3" class="figure"><div class="graphic"><img src="/books/NBK133425/bin/ml230fu3.jpg" alt="Image ml230fu3" /></div></div><p>Nakai, H., et al. (2005), WO 2005026126 A1 20050324. (Japanese)
|
|
“Preparation of fused pyrimidine and related compounds as CRF
|
|
antagonists.” Compounds of the type indicated are claimed useful for the
|
|
treatment of neuropsychiatric and digestive diseases. Structural modifications
|
|
that could be discerned from a patent written in Japanese appeared to be focused
|
|
on head groups of the type shown in green and with substitution of the
|
|
pyrimidine core (orange) that is not tolerated in the ABC G2 project.</p><p>Paruch, K., et al. (2009) WO 2007/070567 “2-Fluoropyrazolo
|
|
[1,5-A]pyrimidines as protein kinase inhibitors. Invention
|
|
describes exclusively <u>fluorinated</u> pyrimidine cores with
|
|
various functionality attached as useful compounds as CDK-2 or CHK-1
|
|
inhibitors.</p><p>Chang, E., et al. (2009), WO 2009123986 “Preparation of
|
|
pyrazolo[1,5-a]pyrimidine derivatives as apoptosis
|
|
signal-regulating kinase 1 inhibitors” All covered compounds have
|
|
<u>amine-linkages</u> in place of the direct aryl
|
|
substituents that appear in the ABC G2 project.</p><p>Goldfarb, D.S. US 20090163545 (2009), “Method using lifespan-altering
|
|
compounds for altering the lifespan of eukaryotic organisms, and screening for
|
|
such compounds.” Describes the preliminary hits from a HTS screen which
|
|
show activity in a DeaD assay. Screening compounds were taken from the MLPCN and
|
|
are listed by SID. A structure similar to <a href="/pcsubstance/?term=ML230[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML230</a> was not
|
|
identified, but it is assumed that any present would be those predating this
|
|
project and which were also part of our screening deck for this project. Since
|
|
compounds of interest in our project were synthesized recently, they are not
|
|
covered by this document.</p><p>Bearss, D.J., et al. (2008), WO 2008058126 “Preparation of
|
|
imidazo[1,2-b]pyridazine and
|
|
pyrazolo[1,5-a]pyrimidine derivatives as protein kinase
|
|
inhibitors.” Claims require substitutions of the core that are known to
|
|
be orthogonal to those necessary for activity on the ABC G2 target.</p><p>Paruch, K., et al. (2006) US 20060094706 “Preparation of a novel class of
|
|
pyrazolopyrimidines as inhibitors of protein and checkpoint kinases useful in
|
|
treatment and prophylaxis of HCV infection and other diseases such as
|
|
cancer.” Claims require substitutions of the core that are known to be
|
|
orthogonal to those necessary for activity on the ABC G2 target.</p></div></div><div id="ml230.s5"><h2 id="_ml230_s5_">2. Materials and Methods</h2><div id="ml230.s6"><h3>General Information</h3><p>The ABCB1 over-expressing drug-resistant cell line, CCRF-Adr 5000, and its
|
|
parental CCRF-CEM cells were kindly provided by Dr. T. Efferth (Pharmaceutical
|
|
Biology, German Cancer Research Center, Heidelberg, Germany). We have previously
|
|
described the generation of the Jurkat-DNR ABCB1 over-expressing cell
|
|
line.<sup><a class="bibr" href="#ml230.r60" rid="ml230.r60">60</a></sup> We have
|
|
also developed and previously characterized a SupT1-vincristine (Vin)
|
|
drug-resistant cell line that selectively over-expresses ABCC1.<sup><a class="bibr" href="#ml230.r61" rid="ml230.r61">61</a></sup> Ovarian Ig-MXP3 (ABCG2)
|
|
and its parental Igrov1-sensitive cells were kindly provided by Dr. D. Ross
|
|
(Department of Medicine, University of Maryland Greenebaum Cancer Center,
|
|
Baltimore, MD). Cells are grown in RPMI-1640 medium supplemented with
|
|
10% fetal bovine serum (FBS, Hyclone, Logan, UT), 2 mM L-glutamine, 10
|
|
mM HEPES, 10 U/mL penicillin, 10 μg/mL streptomycin, and 4 μg/mL
|
|
ciprofloxacin. Selective pressure for the ABCB1 over-expressing CCRF-ADR 5000
|
|
and Jurkat-DNR cells is maintained by growth in 20 nM daunorubicin (DNR).
|
|
Selective pressure for the ABCG2 over-expressing Ig-MXP3 cells is maintained by
|
|
treatment with 340 nM mitoxantrone (MTX) for 1 hr. prior to harvest. Selective
|
|
pressure for the ABCC1 over-expressing SupT1-Vin cells is maintained by growth
|
|
in 150 nM vincristine (Vin).</p><p>The fluorescent reporter dye JC-1 and cell type differentiation dye
|
|
CellTrace™ Far Red DDAO-SE were obtained from Invitrogen™
|
|
(Eugene, OR). Nicardipine hydrochloride, daunorubicin hydrochloride,
|
|
mitoxantrone dihydrochloride, vincristine sulfate, and Fumitremorgin C were
|
|
purchased from Sigma-Aldrich (St. Louis, MO). XR9051, reversan, MK 571, and Ko
|
|
143 were purchased from Tocris Bioscience (St. Louis, MO). Compounds ordered for
|
|
SAR by commerce were purchased from ChemDiv (San Diego, CA) and Ryan Scientific
|
|
(Mt. Pleasant, SC). Unless otherwise indicated, all compound solutions were
|
|
maintained and diluted in DMSO prior to addition to assay wells. Final DMSO
|
|
concentrations were no more than 1% v/v. A Biomek® NX
|
|
Multichannel (Beckman-Coulter, Fullerton, CA) was used for all cell and compound
|
|
solution transfers for volumes greater than 1 μL. Low volume transfers
|
|
(100 nL) were done via pintool (V&P Scientific, Inc., San Diego, CA).
|
|
Compound dose response plates were generated with the Biomek® NX Span-8
|
|
(Beckman-Coulter, Fullerton, CA).</p><p>The HyperCyt® high throughput flow cytometry platform
|
|
(IntelliCyt™, Albuquerque, NM) was used to sequentially sample cells
|
|
from 384-well microplates (2 μL/sample) for flow cytometer presentation
|
|
at a rate of 40 samples per minute.<sup><a class="bibr" href="#ml230.r62" rid="ml230.r62">62</a>–<a class="bibr" href="#ml230.r63" rid="ml230.r63">63</a></sup>
|
|
Flow cytometric analysis was performed on a CyAn™ flow cytometer
|
|
(Beckman-Coulter, Fullerton, CA). The resulting time-gated data files were
|
|
analyzed with HyperView® software to determine compound activity in each
|
|
well. Inhibition response curves were fitted by Prism® software
|
|
(GraphPad Software, Inc., San Diego, CA) using nonlinear least-squares
|
|
regression in a sigmoidal dose response model with variable slope, also known as
|
|
the four-parameter logistic equation. This type of time-gated flow cytometric
|
|
data analysis was described in detail for a previous ABC transporter screen from
|
|
our group.<sup><a class="bibr" href="#ml230.r52" rid="ml230.r52">52</a></sup></p></div><div id="ml230.s7"><h3>2.1. Assays</h3><div id="ml230.s8"><h4>A. Primary Assay (single point, duplex): High-throughput duplex screen and
|
|
counterscreen for ABC transporter inhibitors. AIDs: <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1325" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1325</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1326" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1326</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1451" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1451</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1453" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1453</a></h4><p>The assay is conducted in 384-well format microplates in a total volume of
|
|
15.1 μL dispensed sequentially as follows: 1) JC-1 substrate (10
|
|
μL/well); 2) test compound (100 nL/well); 3) drug-resistant cells (5
|
|
μL/well). CCRF-Adr cells (ABCB1) are color-coded with 0.5 ng/mL
|
|
CellTrace™ Far Red DDAO-SE for 15 minutes at room temperature,
|
|
washed twice by centrifugation, and then combined with unlabeled Ig-MXP3
|
|
cells (ABCG2) in the assay buffer. Final in-well concentration of test
|
|
compound is 6.6 μM, JC-1 concentration is ~ 1 μM, and the
|
|
cell concentration is 3 × 10<sup>6</sup> cells/mL (1:1 ratio of the
|
|
two cell types). Nicardipine is used as an on plate control for both pumps
|
|
at 50 μM. The plate contents are mixed, rotated end-over-end at 4
|
|
RPM and 25 ºC for 10 minutes, and then cell samples are immediately
|
|
analyzed. Approximately 2 μL volumes from each well are collected at
|
|
a rate of approximately 40 samples per minute. This results in analysis of
|
|
approximately 1,000 cells of each cell type from each well. Flow cytometric
|
|
data of light scatter and fluorescence emission at 530 +/−
|
|
20 nm (488 nm excitation, FL1) and 665 +/− 10 nm (633 nm
|
|
excitation, FL8) are collected.</p></div><div id="ml230.s9"><h4>B. Primary Assay (dose response, single-plex): Dose Response for ABC
|
|
transporter inhibitors. AIDs: <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1689" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1689</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1690" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1690</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/489002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">489002</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/489003" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">489003</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504566" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504566</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504569" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504569</a></h4><p>The assay provider’s ABCB1 over-expressing Jurkat-DNR cell line is
|
|
used for confirmatory follow up instead of the CCRF-Adr cells. Each cell
|
|
line (Jurkat-DNR and Ig-MXP3) is run separately against all compounds (no
|
|
differential cell staining) in dose response. The assay is conducted in
|
|
384-well format in a total volume of 15.1 μL. Cells and reagents are
|
|
added sequentially as follows: 1) PBS buffer (5 μL/well); 2) test
|
|
compound (100 nL/well); 3) drug-resistant cells (10 μL/well)
|
|
pre-stained with the JC-1 substrate at 1 μM. Final in-well
|
|
concentrations of test compound range from 50 μM to 69 nM over an 18
|
|
point dose response and the cell concentration is 1 × 10<sup>6</sup>
|
|
cells/mL. Nicardipine (50 μM) is added to each plate as a
|
|
pan-inhibition positive control. The plate is rotated end-over-end at 4 RPM
|
|
and 25 ºC for 30 minutes and then cell samples are analyzed and flow
|
|
cytometric data of light scatter and fluorescence emission at 530
|
|
+/− 20 nm (488 nm excitation, FL1) are collected.</p></div><div id="ml230.s10"><h4>C. Secondary Assay 1: Chemoreversal assay for compounds that inhibit the
|
|
ABCB1 transporter. AIDs: <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2830" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2830</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488973" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488973</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504476" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504476</a></h4><p>Jurkat-DNR cells are incubated with the test compound (3 order of magnitude
|
|
concentration range) over a 3-day and 7-day period in the presence of the
|
|
inhibitor and DNR, such that a cell concentration of at least 1 ×
|
|
10<sup>5</sup> cells/mL is maintained. Cell viability is determined by
|
|
trypan blue staining and enumeration under light microscopy. At day 3, wells
|
|
with greater than 2 × 10<sup>5</sup> cells are refreshed, to include
|
|
readjustment of DNR and inhibitor concentration. A chemoreversal index
|
|
(Chemoreversal 50, CR<sub>50</sub>) is determined from the viability
|
|
assessment. Using a similar approach, a direct cytotoxicity index (Toxic
|
|
Dose 50, TD<sub>50</sub>) is determined by assessment of cell death of cells
|
|
grown in media alone. Results are compared with the survival of parental
|
|
cells in the presence of the selective agent (DNR; 100% cell death),
|
|
as well as survival of drug-resistant cells in the presence of the
|
|
chemotherapeutic drug (control yields 100% viability). The
|
|
difference between the CR<sub>50</sub> and the TD<sub>50</sub> give an
|
|
approximation of the <i>in vitro</i> therapeutic index for the
|
|
test compound.</p></div><div id="ml230.s11"><h4>D. Secondary Assay 2: Chemoreversal assay for compounds that inhibit the
|
|
ABCG2 transporter. AIDs: <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2833" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2833</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488974" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488974</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504477" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504477</a></h4><p>Ig-MXP3 cells are incubated with the test compound (3 order of magnitude
|
|
concentration range) over a 3-day and 7-day period in the presence of the
|
|
inhibitor and MTX, such that a cell concentration of at least 1 ×
|
|
10<sup>5</sup> cells/mL is maintained. Cell viability is determined by
|
|
trypan blue staining and enumeration under light microscopy. A chemoreversal
|
|
index (Chemoreversal 50, CR<sub>50</sub>) is determined from the viability
|
|
assessment. Using a similar approach, a direct cytotoxicity index (Toxic
|
|
Dose 50, TD<sub>50</sub>) is determined by assessment of cell death of cells
|
|
grown in media alone. Results are compared with the survival of parental
|
|
cells in the presence of the selective agent (MTX; 100% cell death),
|
|
as well as survival of drug-resistant cells in the presence of the
|
|
chemotherapeutic drug (control yields 100% viability). The
|
|
difference between the CR<sub>50</sub> and the TD<sub>50</sub> give an
|
|
approximation of the <i>in vitro</i> therapeutic index for the
|
|
test compound.</p></div></div><div id="ml230.s12"><h3>2.2. Probe Chemical Characterization</h3><div id="ml230.s13"><h4>A. Probe Chemical Structure, Physical Parameters and Probe
|
|
Properties</h4><div id="ml230.f2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK133425/bin/ml230f2.jpg" alt="Figure 2. Property summary of probe compound SID 88095709 (CID 44640177)." /></div><h3><span class="label">Figure 2</span><span class="title">Property summary of probe compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID 44640177)</span></h3></div></div><div id="ml230.s14"><h4>B. Structure Verification and Purity: <sup>1</sup>H NMR, <sup>13</sup>C NMR,
|
|
LCMS and HRMS</h4><p><b>Proton and carbon NMR data for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID
|
|
44640177):</b> Detailed analytical methods and instrumentation are
|
|
described in <a href="#ml230.s19">section 2.3</a>,
|
|
entitled “Probe Preparation” under general experimental and
|
|
analytical details. The numerical experimental proton and carbon data are
|
|
represented below. Associated spectra are also included for reference (<a href="#ml230.app1">Appendix A</a>, see <a class="figpopup" href="/books/NBK133425/figure/ml230.f16/?report=objectonly" target="object" rid-figpopup="figml230f16" rid-ob="figobml230f16">Figure A1</a> and <a class="figpopup" href="/books/NBK133425/figure/ml230.f17/?report=objectonly" target="object" rid-figpopup="figml230f17" rid-ob="figobml230f17">A2</a> for <sup>1</sup>H NMR and
|
|
<sup>13</sup>C NMR respectively).</p><p><b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID 44640177) PROTON NMR
|
|
DATA:</b><sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) d 8.03-8.00
|
|
(m, 2H), 7.83 (m, 1H), 7.62 (m, 1H), 7.52-7.47 (m, 3H), 7.45-7.41 (m, 1H),
|
|
7.23 (dd, <i>J</i> = 3.5, 0.7 Hz, 1H), 6.93 (s, 1H), 6.65
|
|
(m, 1H), 6.62 (dd, <i>J</i> = 3.5, 1.8 Hz, 1H), 6.60 (s,
|
|
1H), 4.08 (b, 4H), 3.92 (b, 4H).</p><p><b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID 44640177) CARBON NMR
|
|
DATA:</b><sup>13</sup>C NMR (125 MHz, CDCl<sub>3</sub>) d 164.1,
|
|
155.4, 152.4, 151.8, 150.1, 148.5, 144.3, 143.8, 143.2, 132.9, 129.0, 128.7,
|
|
126.4, 120.6, 112.6, 110.9, 110.1, 92.9, 88.9, 48.3.</p><p><b>LCMS and HRMS data for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID
|
|
44640177):</b> Detailed analytical methods and instrumentation are
|
|
described in <a href="#ml230.s19">section 2.3</a>,
|
|
entitled “Probe Preparation” under general experimental and
|
|
analytical details. Purity assessment by LCMS at 215 nm for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a> (CID 44640177) revealed a retention time of 3.20 min
|
|
and purity at 215 nm of 100%. The experimental LCMS and HRMS spectra
|
|
are included for reference (<a class="figpopup" href="/books/NBK133425/figure/ml230.f18/?report=objectonly" target="object" rid-figpopup="figml230f18" rid-ob="figobml230f18">Appendix A,
|
|
Figures A3</a> and <a class="figpopup" href="/books/NBK133425/figure/ml230.f19/?report=objectonly" target="object" rid-figpopup="figml230f19" rid-ob="figobml230f19">A4</a>
|
|
respectively).</p></div><div id="ml230.s15"><h4>C. Solubility</h4><p>Aqueous solubility was measured in phosphate buffered saline (PBS) at room
|
|
temperature (23°C). PBS by definition is 137 mM NaCl, 2.7 mM KCl, 10
|
|
mM sodium phosphate dibasic, 2 mM potassium phosphate monobasic and a pH of
|
|
7.4. The solubility of probe <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID
|
|
44640177) was determined to be 0.51 mg/mL.<sup><a class="bibr" href="#ml230.r64" rid="ml230.r64">64</a></sup></p><p>Applying a flow cytometric kinetic solubility protocol,<sup><a class="bibr" href="#ml230.r65" rid="ml230.r65">65</a></sup> we were also able to
|
|
compare solubility across primary, secondary, and profiling buffer
|
|
conditions in house. This method evaluates precipitation as a function of
|
|
side scatter changes (above the buffer baseline); we observed 2 mg/mL
|
|
solubility in PBS alone. This is approximately three fold higher than
|
|
reported above; however, our protocol uses 1% DMSO as compared to
|
|
0.1%. Such changes in the concentration of DMSO can significantly
|
|
increase overall solubility of a compound. The presence of fetal bovine
|
|
serum also affects compound availability and in the primary assay screening
|
|
buffer (6.7% FBS in PBS, 1% DSMO) the precipitation was
|
|
inhibited slightly with no particulate noted at 3 mg/mL. The growth media
|
|
indicated in the methods section (RPMI with 10% FBS, 1%
|
|
DMSO) showed no precipitate forming at 6 mg/mL. It should also be noted that
|
|
compounds with poor solubility at high concentrations (i.e. nicardipine
|
|
above 50 μM) tend to show a response drop-off in the primary dose
|
|
response conditions and this phenomenon was not significantly observed with
|
|
the probe or related compounds. In general, we are confident that compound
|
|
availability is sufficient for the concentration ranges discussed for this
|
|
scaffold set in our described biological systems.</p></div><div id="ml230.s16"><h4>D. Stability</h4><p>Aqueous stability was measured at room temperature (23ºC) in PBS (no
|
|
antioxidants or other protectants and DMSO concentration below
|
|
0.1%). The stability of probe compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a> (CID 44640177), determined as the percent of
|
|
compound remaining after 48 hours, was 10%.<sup><a class="bibr" href="#ml230.r64" rid="ml230.r64">64</a></sup> Stability data are
|
|
depicted as a graph showing the loss of compound with time over a 48 hour
|
|
period with a minimum of 6 time points and provide the percent remaining
|
|
compound at end of the 48 hours (<a class="figpopup" href="/books/NBK133425/figure/ml230.f3/?report=objectonly" target="object" rid-figpopup="figml230f3" rid-ob="figobml230f3">Figure
|
|
3</a>, closed circles).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f3" co-legend-rid="figlgndml230f3"><a href="/books/NBK133425/figure/ml230.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml230f3" rid-ob="figobml230f3"><img class="small-thumb" src="/books/NBK133425/bin/ml230f3.gif" src-large="/books/NBK133425/bin/ml230f3.jpg" alt="Figure 3. Aqueous stability of compound SID 88095709 (CID 44640177) in PBS and no acetonitrile (closed circles), and aqueous stability of compound SID 88095709 (CID 44640177) in PBS with the addition of acetonitrile (50% v/v final, closed triangles)." /></a><div class="icnblk_cntnt" id="figlgndml230f3"><h4 id="ml230.f3"><a href="/books/NBK133425/figure/ml230.f3/?report=objectonly" target="object" rid-ob="figobml230f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Aqueous stability of compound SID 88095709
|
|
(CID 44640177) in PBS and no acetonitrile (closed circles), and
|
|
aqueous stability of compound SID 88095709
|
|
(CID 44640177) in PBS with the addition of acetonitrile (50%
|
|
v/v final, closed triangles). </p></div></div><p>It has been reported by several MLPCN partners and our collaborators at the
|
|
Sanford-Burnham Institute who perform this assay, that the conditions for
|
|
the stability assay as described previously is fundamentally unreliable for
|
|
compounds that exhibit moderate to poor aqueous solubility. Given the low
|
|
solubility of probe <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (0.51 μg/mL, reported in
|
|
<a href="#ml230.s15">Section C</a>), the stability
|
|
experiment was repeated with the addition of acetonitrile (50% v/v
|
|
final) which has been reported to routinely resolve any contributions due to
|
|
insolubility. The stability data under these conditions overlain in the
|
|
<a class="figpopup" href="/books/NBK133425/figure/ml230.f3/?report=objectonly" target="object" rid-figpopup="figml230f3" rid-ob="figobml230f3">Figure 3</a> and is also depicted
|
|
as a graph showing the loss of compound with time over a 48 hour period with
|
|
a minimum of 6 time points and provide the percent remaining compound at end
|
|
of the 48 hours (<a class="figpopup" href="/books/NBK133425/figure/ml230.f3/?report=objectonly" target="object" rid-figpopup="figml230f3" rid-ob="figobml230f3">Figure 3</a>, closed
|
|
triangles). The addition of acetonitrile appears to have solubilized the
|
|
compound and provided a more accurate reading of the stability, which is now
|
|
100% remaining after 48 hours.</p></div><div id="ml230.s17"><h4>E. Synthetic Route</h4><p>The probe compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID 44640177) and many
|
|
analogues were synthesized by the method shown (sequence a–c, <a class="figpopup" href="/books/NBK133425/figure/ml230.f4/?report=objectonly" target="object" rid-figpopup="figml230f4" rid-ob="figobml230f4">Figure 4</a>). Commercial substituted
|
|
aminopyrazoles <b>1</b> were treated with the appropriate
|
|
dialkylmalonate or b-ketoester to give intermediate <b>2</b>, followed
|
|
by chlorination to afford the
|
|
pyrazolo[1,5-<i>a</i>]pyrimidine core intermediate
|
|
<b>3</b>. Installation of the piperazine moiety afforded the probe
|
|
compound directly. In some cases, a Suzuki or Molander type coupling was
|
|
preferred to install aryl functionality at a late stage in the synthesis
|
|
(sequence d–f). Specific experimental details for the probe are
|
|
detailed in <a href="#ml230.s19">section 2.3</a>,
|
|
entitled: “Probe Preparation” and experimentals for the
|
|
analogues are provided in <a href="#ml230.app2">Appendix
|
|
B</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f4" co-legend-rid="figlgndml230f4"><a href="/books/NBK133425/figure/ml230.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml230f4" rid-ob="figobml230f4"><img class="small-thumb" src="/books/NBK133425/bin/ml230f4.gif" src-large="/books/NBK133425/bin/ml230f4.jpg" alt="Figure 4. General synthetic route for probe and associated analogues." /></a><div class="icnblk_cntnt" id="figlgndml230f4"><h4 id="ml230.f4"><a href="/books/NBK133425/figure/ml230.f4/?report=objectonly" target="object" rid-ob="figobml230f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">General synthetic route for probe and associated
|
|
analogues. </p></div></div></div><div id="ml230.s18"><h4>F. Submission of Five Related Analogues to the MLSMR</h4><p>Five analogues have been fully characterized and prepared in sufficient
|
|
quantity for submission to the MLSMR. The five selected analogs are shown in
|
|
<a class="figpopup" href="/books/NBK133425/figure/ml230.f5/?report=objectonly" target="object" rid-figpopup="figml230f5" rid-ob="figobml230f5">Figure 5</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f5" co-legend-rid="figlgndml230f5"><a href="/books/NBK133425/figure/ml230.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml230f5" rid-ob="figobml230f5"><img class="small-thumb" src="/books/NBK133425/bin/ml230f5.gif" src-large="/books/NBK133425/bin/ml230f5.jpg" alt="Figure 5. Five analogues submitted to support probe SID 88095709 (CID 44640177)." /></a><div class="icnblk_cntnt" id="figlgndml230f5"><h4 id="ml230.f5"><a href="/books/NBK133425/figure/ml230.f5/?report=objectonly" target="object" rid-ob="figobml230f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Five analogues submitted to support probe SID 88095709 (CID 44640177). </p></div></div></div></div><div id="ml230.s19"><h3>2.3. Probe Preparation</h3><div id="ml230.s20"><h4>General experimental and analytical details</h4><p><sup>1</sup>H and <sup>13</sup>C NMR spectra were recorded on a Bruker AM 400
|
|
spectrometer (operating at 400 and 101 MHz respectively) or Bruker AM 500
|
|
spectrometer (operating at 500 and 125 MHz respectively) in CDCl<sub>3</sub>
|
|
with 0.03% TMS as an internal standard or DMSO-d<sub>6</sub>. The
|
|
chemical shifts (d) reported are given in parts per million (ppm) and the
|
|
coupling constants (<i>J</i>) are in Hertz (Hz). The spin
|
|
multiplicities are reported as s = singlet, br. s = broad
|
|
singlet, d = doublet, t = triplet, q = quartet, dd
|
|
= doublet of doublet and m = multiplet. The LCMS analysis
|
|
was performed on an Agilent 1200 RRL chromatograph with photodiode array UV
|
|
detection and an Agilent 6224 TOF mass spectrometer. The chromatographic
|
|
method utilized the following parameters: a Waters Acquity BEH C-18 2.1
|
|
× 50 mm, 1.7 μM column; UV detection wavelength =
|
|
214 nm; flow rate = 0.4 mL/min; gradient = 5 –
|
|
100% acetonitrile over 3 minutes with a hold of 0.8 minutes at
|
|
100% acetonitrile; the aqueous mobile phase contained 0.15%
|
|
ammonium hydroxide (v/v). The mass spectrometer utilized the following
|
|
parameters: an Agilent multimode source which simultaneously acquires
|
|
ESI+/APCI+; a reference mass solution consisting of purine
|
|
and hexakis(1H, 1H, 3H-tetrafluoropropoxy) phosphazine; and a make-up
|
|
solvent of 90:10:0.1 MeOH:Water:Formic Acid which was introduced to the LC
|
|
flow prior to the source to assist ionization. The melting point was
|
|
determined on a Stanford Research Systems OptiMelt apparatus.</p><p>The probe was synthesized using the following protocols:</p><div id="ml230.fu4" class="figure"><div class="graphic"><img src="/books/NBK133425/bin/ml230fu4.jpg" alt="Image ml230fu4" /></div></div><p><b>5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one:</b>
|
|
A mixture of 3-phenyl-1H-pyrazol-5-amine (0.318 g, 2.0 mmol, 1.0 eq) and
|
|
methyl 3-(furan-2-yl)-3-oxopropanoate (0.370 g, 2.2 mmol, 1.10 eq) was
|
|
heated in acetic acid (2.0 mL) at 100 °C for 4 hr. After cooling
|
|
down to rt, the precipitate was collected by filtration. The precipitate was
|
|
rinsed with EtOH (15 mL) and dried under air to afford
|
|
5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one
|
|
(0.358 g, 65%) as a white solid. <sup>1</sup>H-NMR (400 MHz,
|
|
DMSO-d<sub>6</sub>) δ 12.70 (s, 1H), 8.06 (m, 1H), 8.00 (m, 1H),
|
|
7.98 (m, 1H), 7.51-7.47 (m, 3H), 7.44-7.42 (m, 1H), 6.81 (dd,
|
|
<i>J</i> = 3.7, 1.8 Hz, 1H), 6.64 (s, 1H), 6.15 (s,
|
|
1H).</p><div id="ml230.fu5" class="figure"><div class="graphic"><img src="/books/NBK133425/bin/ml230fu5.jpg" alt="Image ml230fu5" /></div></div><p><b>7-chloro-5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidine:</b>
|
|
A mixture of
|
|
5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one
|
|
(0.277 g, 1.0 mmol, 1.0 eq), POCl<sub>3</sub> (0.613 g, 4.0 mmol, 4.0 eq),
|
|
<i>N</i>-benzyl-<i>N</i>,<i>N,N</i>-triethylethanaminium
|
|
chloride (0.456 g, 2.0 mmol, 2.0 eq) and
|
|
<i>N</i>,<i>N</i>-dimethylaniline (0.121 g, 1.0
|
|
mmol, 1.0 eq) in acetonitrile (5.0 mL) was heated at 80 °C for 4 hr.
|
|
The completed reaction was diluted with CHCl<sub>3</sub> (20 mL), washed
|
|
with H<sub>2</sub>O (10 mL), and the separated organic layers were dried
|
|
(MgSO<sub>4</sub>) and concentrated. The residue was purified by
|
|
chromatography (Biotage 25 g, EtOAc/Hexane) to afford
|
|
7-chloro-5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidine
|
|
(0.247 g, 84%) as a yellow solid. <sup>1</sup>H-NMR (400 MHz,
|
|
CDCl<sub>3</sub>) δ 7.97-7.94 (m, 2H), 7.56 (m, 1H), 7.43-7.39
|
|
(m, 2H), 7.36-7.34 (m, 1H), 7.19 (s, 1H), 7.17 (dd, <i>J</i>
|
|
= 3.5, 0.5 Hz, 1H), 6.97 (s, 1H), 6.54 (dd, <i>J</i>
|
|
= 3.5, 1.7 Hz, 1H).</p><div id="ml230.fu6" class="figure"><div class="graphic"><img src="/books/NBK133425/bin/ml230fu6.jpg" alt="Image ml230fu6" /></div></div><p><b>(4-(5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)(furan-3-yl)methanone
|
|
(<a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>/ CID 44640177):</b> A
|
|
mixture of
|
|
7-chloro-5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidine
|
|
(0.148 g, 0.5 mmol, 1.0 eq), furan-3-yl(piperazin-1-yl)methanone (0.180 g,
|
|
1.0 mmol, 2.0 eq,) and
|
|
<i>N</i>-ethyl-<i>N</i>-isopropylpropan-2-amine (0.129
|
|
g, 1.0 mmol, 2.0 eq) in acetonitrile (5.0 mL) was heated at 100 °C
|
|
for 3 hr. The completed reaction was purified by chromatography (Biotage 25
|
|
g, EtOAc/Hexane) to afford
|
|
(4-(5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)(furan-3-yl)methanone
|
|
(0.218 g, 99%) as a white solid. <sup>1</sup>H-NMR (400 MHz,
|
|
CDCl<sub>3</sub>) δ 8.03-8.00 (m, 2H), 7.83 (m, 1H), 7.62 (m,
|
|
1H), 7.52-7.47 (m, 3H), 7.45-7.41 (m, 1H), 7.23 (dd, <i>J</i>
|
|
= 3.5, 0.7 Hz, 1H), 6.93 (s, 1H), 6.65 (m, 1H), 6.62 (dd,
|
|
<i>J</i> = 3.5, 1.8 Hz, 1H), 6.60 (s, 1H), 4.08 (b,
|
|
4H), 3.92 (b, 4H). <sup>13</sup>C NMR (125 MHz, CDCl<sub>3</sub>)
|
|
<i>δ</i> 164.1, 155.4, 152.4, 151.8, 150.1, 148.5,
|
|
144.3, 143.8, 143.2, 132.9, 129.0, 128.7, 126.4, 120.6, 112.6, 110.9, 110.1,
|
|
92.9, 88.9, 48.3. LCMS retention time: 3.20 min; purity at 215 nm =
|
|
100%. HRMS <i>m/z</i> calculated for
|
|
C<sub>24</sub>H<sub>27</sub>N<sub>5</sub>O<sub>2</sub>
|
|
([M+H]<sup>+</sup>): 440.1717, found
|
|
440.1715.</p></div></div><div id="ml230.s21"><h3>Submitted Probe Analogs</h3><p>Experimental details and supporting information for the five submitted analogues
|
|
can be found in the <a href="#ml230.app2">Appendix B</a>.</p></div></div><div id="ml230.s22"><h2 id="_ml230_s22_">3. Results</h2><div id="ml230.s23"><h3>3.1. Summary of Screening Results</h3><p>The primary screening results are summarized with a flow chart showing the
|
|
overall workflow for project to include the AIDs uploaded to date (<a class="figpopup" href="/books/NBK133425/figure/ml230.f6/?report=objectonly" target="object" rid-figpopup="figml230f6" rid-ob="figobml230f6">Figure 6</a>). For the primary screening
|
|
protocol, a duplex assay was constructed in which ABCB1 and ABCG2 transporters
|
|
were evaluated in parallel using fluorescent JC-1 as the efflux reporting
|
|
substrate. ABCB1 over-expressing cells (CCRF-Adr) were color-coded to allow
|
|
their distinction from ABCG2-expressing cells (Ig-MXP3). As described in detail
|
|
previously, the assay was a high throughput no-wash procedure conducted in
|
|
384-well format micro plates.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f6" co-legend-rid="figlgndml230f6"><a href="/books/NBK133425/figure/ml230.f6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml230f6" rid-ob="figobml230f6"><img class="small-thumb" src="/books/NBK133425/bin/ml230f6.gif" src-large="/books/NBK133425/bin/ml230f6.jpg" alt="Figure 6. Screening flow chart." /></a><div class="icnblk_cntnt" id="figlgndml230f6"><h4 id="ml230.f6"><a href="/books/NBK133425/figure/ml230.f6/?report=objectonly" target="object" rid-ob="figobml230f6">Figure 6</a></h4><p class="float-caption no_bottom_margin">Screening flow chart. </p></div></div><p>The primary screening results were uploaded as two AIDs; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1326" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1326</a> -
|
|
High-throughput multiplex screening for ABC transporter inhibitors: specifically
|
|
ABCB1 screen, ABCG2 counter-screen, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1325" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1325</a> - High-throughput
|
|
multiplex screening for ABC transporter inhibitors: specifically ABCG2 screen,
|
|
ABCB1 counter-screen. A total of 194,394 compounds were tested with 200 and 130
|
|
actives noted in ABCB1 and ABCG2 respectively. Compounds were deemed active if
|
|
the percent inhibition was greater than 80%. Activity was determined on
|
|
the basis of the median fluorescence intensity (MFI) of JC-1. Percent inhibition
|
|
was calculated as 100 × [1 - (MFI_PC - MFI_Test)/(MFI_PC -
|
|
MFI_NC)] in which MFI_Test, MFI_PC and MFI_NC represent the MFI of cells
|
|
in wells containing test compound, the average MFI of cells in positive control
|
|
wells (maximum fluorescence intensity) and the average MFI of cells in negative
|
|
control wells (minimum fluorescence intensity), respectively. The
|
|
PUBCHEM_ACTIVITY_SCORE is equal to the calculated percent inhibition, except
|
|
when percent inhibition is greater than 100 and less than 0.</p><p>A subsequent SMR cherry pick resulted in single point confirmatory testing of 273
|
|
compounds (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1451" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1451</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1453" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1453</a>) resulting in 18 and 16
|
|
actives in ABCB1 and ABCG2, respectively. A set of related 488/530 nm
|
|
fluorescence compound profiling data was also associated with the SMR cherry
|
|
pick set. These data were uploaded as two AIDs (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1480" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1480</a>
|
|
and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1483" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1483</a>) where the 273 compounds were tested with 83 and 89
|
|
compounds noted as active (i.e. fluorescent) in ABCB1 and ABCG2, respectively.
|
|
Autofluorescence was calculated on the basis of MFI detected in the green
|
|
fluorescence channel (530 +/− 20 nM) and the subtraction of the
|
|
autofluorescence of the cells, as shown in the following equation: Fluorescence
|
|
= MFI_CMPD - MFI_CELL where MFI_CMPD is the MFI of cells in the presence
|
|
of test compound and MFI_CELL is the MFI of cells in the presence of the DMSO
|
|
control. The compound was noted active if the fluorescence was greater than the
|
|
average plus three standard deviations of the control wells on the plate. The
|
|
activity score was calculated based on normalizing the fluorescence to the
|
|
maximum measured.</p><p>The aforementioned single point screen of the 273 compound SMR cherry pick set
|
|
resulted in the dose dependent screening of 40 compounds. This data set was
|
|
uploaded under the AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1689" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1689</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1690" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1690</a> and resulted in 9 actives
|
|
for ABCB1 and 16 active for ABCG2. Inhibitory activity was again determined on
|
|
the basis of the MFI of JC-1. Innate fluorescence of test compound was
|
|
subtracted out based on MFI of unstained cells before calculation of percent
|
|
inhibition of efflux pump activity. The following equations were used to
|
|
calculate percent inhibition: %Inhibition = 100 ×
|
|
(FluorDelta_Sample - FluorDelta_NC)/(FluorDelta_PC - FluorDelta_NC) in which
|
|
FluorDelta_Sample (FluorDelta = MFI_JC-1 - MFI_non-JC-1 in which
|
|
MFI_JC-1 are the MFI of cells in wells in the presence of JC-1 and MFI_non-JC-1
|
|
are the MFI of cells in wells without JC-1) are the differences of JC-1 minus
|
|
non-JC-1 from wells with test compound, FluorDelta_NC are differences from
|
|
negative control wells (cells with DMSO, minimum fluorescence intensity) and
|
|
FluorDelta_PC are differences from nicardipine positive control wells. These
|
|
dose response of %Inhibition data were fitted via GraphPad Prism to a
|
|
sigmoidal dose response curve with variable hillslope: %Inhibition
|
|
= Bottom +
|
|
(Top-Bottom)/(1+10^((LogEC50-LogCmpd)*HillSlope)) where LogCmpd
|
|
is the log of compound concentration in micromolar and Top-Bottom is the
|
|
FIT_PERCENT_SPAN. Prism reports estimated values and fitted statistics for the
|
|
four parameters (Bottom, Top, Hillslope and EC<sub>50</sub>).</p><p>Dose response fits assessed as decent were those with Residual square <
|
|
0.5, Hillslope < 5, Standard deviation of estimated LogEC<sub>50</sub>
|
|
<3, and standard deviation of top/estimate for top < 0.5. Only the
|
|
fits that passed this filter were reported. The activity score was calculated
|
|
based on two weighted criteria; EC<sub>50</sub> < 10 micromolar and
|
|
FIT_PERCENT_SPAN > 20% by the following equation: Activity Score
|
|
= 75 * (EC<sub>50</sub>Cutoff -
|
|
EC<sub>50</sub>)/EC<sub>50</sub>Cutoff + 25*(Span -
|
|
SpanCutoff)/SpanCutoff. Active compounds have activity scores greater than 52,
|
|
inactive compounds have scores less than 52. Values above 100 or below 0 were
|
|
adjusted to 100 or 0 respectively.</p><p>Limited SAR was revealed through the first round of cherry pick analysis, and
|
|
about a third of the compounds were observed to be fluorescent artifacts.
|
|
However, preliminary secondary screening efforts confirmed activity of several
|
|
compounds including MLS000527783 (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/17388272" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 17388272</a>, CID 1434724)
|
|
with which micromolar potentiation and low toxicity was observed, but little
|
|
pump specificity (data not shown). Resupply of this compound (new <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85752814" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
85752814</a>, CID 1434724) confirmed the efflux inhibition, and a
|
|
series of compounds similar in structure was ordered around this SMR hit. These
|
|
31 compounds were tested in dose response in two over-expressing cell lines:
|
|
Jurkat-DNR (ABCB1) and Ig-MXP3 (ABCG2). Expansion of this piperazine substituted
|
|
pyrazolo[1,5-a]pyrimidine substructure resulted in a selectivity
|
|
profile significantly biased toward ABCG2. Of the hits that were identified
|
|
through this commercial SAR endeavor, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85240370</a> (CID 1441553)
|
|
had attractive efflux potency towards ABCG2 and marginal selectivity over ABCB1
|
|
(<a class="figpopup" href="/books/NBK133425/figure/ml230.f7/?report=objectonly" target="object" rid-figpopup="figml230f7" rid-ob="figobml230f7">Fig 7</a>). The KU SCC launched an
|
|
SAR campaign aimed at further understanding the origin of potency and
|
|
selectivity and set out to optimize the compound profile to meet the probe
|
|
criteria for potency and selectivity in the efflux assay. Compounds meeting
|
|
these criteria were then screened in a subsequent chemoreversal assay, a cell
|
|
killing secondary assay that shows potentiation of specific chemotherapeutics
|
|
for each cell line as compared to the compound’s inherent toxicity. The
|
|
chemoreversal assays quantitatively show the potentiation of known killing
|
|
agents for each cell line with efflux inhibitory compounds. The original 15
|
|
compounds tested in these secondary assays are reported in AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2830" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2830</a>
|
|
and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2833" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2833</a>. The subsequent SAR related analogs to <a href="https://pubchem.ncbi.nlm.nih.gov/substance/17388272" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
17388272</a> (CID 1434724) and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85240370</a> (CID 1441553;
|
|
<a class="figpopup" href="/books/NBK133425/figure/ml230.f7/?report=objectonly" target="object" rid-figpopup="figml230f7" rid-ob="figobml230f7">Figure 7</a>) are reported in AIDs
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488973" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488973</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488974" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488974</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504476" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504476</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504477" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504477</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f7" co-legend-rid="figlgndml230f7"><a href="/books/NBK133425/figure/ml230.f7/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figml230f7" rid-ob="figobml230f7"><img class="small-thumb" src="/books/NBK133425/bin/ml230f7.gif" src-large="/books/NBK133425/bin/ml230f7.jpg" alt="Figure 7. Validated hit resulting from the preliminary commercial SAR effort." /></a><div class="icnblk_cntnt" id="figlgndml230f7"><h4 id="ml230.f7"><a href="/books/NBK133425/figure/ml230.f7/?report=objectonly" target="object" rid-ob="figobml230f7">Figure 7</a></h4><p class="float-caption no_bottom_margin">Validated hit resulting from the preliminary commercial SAR
|
|
effort. </p></div></div><p>The probe criteria were set such that micromolar potentiation is desired and the
|
|
TD<sub>50</sub>/CR<sub>50</sub> ratio must be > 10 with overall
|
|
toxicity > 15 μM. One compound was found to meet these secondary
|
|
assay criteria for ABCB1, while 5 compounds matching this profile were
|
|
identified for ABCG2. Structure activity relationships remained unclear at this
|
|
stage. As compared to the efflux inhibition activity for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
85240370</a> (CID 1441553), selectivity in the potentiation assay
|
|
maintained a slight selectivity for ABCG2 with CR<sub>50</sub> = 0.14
|
|
μM vs. 0.70 μM in ABCB1. However, there was significant toxicity
|
|
noted for both cell lines (TD<sub>50</sub> = 6.0 and 3.2 μM for
|
|
ABCG2 and ABCB1 respectively). With these preliminary results in hand, an
|
|
extensive SAR initiative was undertaken.</p></div><div id="ml230.s24"><h3>3.2. Dose Response Curves for Probe</h3><div id="ml230.f8" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%208.%20Efflux%20inhibition%20and%20chemotherapeutic%20potentiation%20of%20SID%2088095709%20(CID%2044640177).&p=BOOKS&id=133425_ml230f8.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133425/bin/ml230f8.jpg" alt="Figure 8. Efflux inhibition and chemotherapeutic potentiation of SID 88095709 (CID 44640177)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 8</span><span class="title">Efflux inhibition and chemotherapeutic potentiation of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a> (CID 44640177)</span></h3><div class="caption"><p><b>A</b>) A representative curve showing efflux inhibition of ABCB1
|
|
in Jurkat-DNR cells (closed circles). The average IC<sub>50</sub> (n
|
|
= 3) is 4.7 ± 0.5 μM. <b>B</b>) A
|
|
representative curve showing efflux inhibition of ABCG2 in Ig-MXP3 cells
|
|
(open circles). The average IC<sub>50</sub> (n = 2) is 0.13
|
|
± 0.30 μM <b>C</b>) Potentiation of DNR mediated
|
|
killing in Jurkat-DNR cells with <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (n
|
|
= 2 per data point). The CR<sub>50</sub> (closed triangles) is
|
|
0.55 μM while the TD<sub>50</sub> (closed squares) is 5.5
|
|
μM. Minimum allowable toxicity is set at 15 μM, thus the
|
|
toxicity here is below the cut-off. <b>D</b>) Potentiation of MTX
|
|
mediated killing in Ig-MXP3 cells (n = 2 per data point). The
|
|
CR<sub>50</sub> (open triangles) is 0.31 μM while the
|
|
TD<sub>50</sub> (open squares) is 18.3 μM. The minimum
|
|
toxicity and the CR<sub>50</sub>/TD<sub>50</sub> ratio (equal to 59)
|
|
meet the cut-off criteria for a desirable compound in the chemoreversal
|
|
secondary ABCG2 assay.</p></div></div></div><div id="ml230.s25"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>The pyrazolo[1,5-<i>a</i>]pyrimidine scaffold and its
|
|
derivatives have been easily handled in terms of stability to reaction
|
|
conditions, exposure to acid or base, heating, and general manipulation. Most
|
|
are isolated as stable solid materials. We have not observed decomposition nor
|
|
have we experienced any chemical liability with these compounds. The structure
|
|
does not contain moieties that are known generally to be reactive. Stability
|
|
assessment was performed in 1x PBS buffer at pH 7.4 and room temperature. After
|
|
48 hours, it was determined that only 10 percent of the parent probe compound
|
|
remained when the experiment was performed in PBS buffer alone, thus possibly
|
|
indicating some structural liability that at this point in time is unknown.
|
|
However, as previously mentioned, the stability assay used with PBS alone is
|
|
likely not suitable for compounds with lower solubility. The experiment was
|
|
repeated with acetonitrile to help solubilize the compound, leading to a
|
|
favorable profile in which 100% of the sample was remaining after 48
|
|
hours and indicating no loss of integrity. Comparative assessment of the
|
|
solubility in multiple assay conditions indicates moderate solubility; however
|
|
this does not appear to be an issue for either primary or secondary screening
|
|
protocols based both on direct observation of activity as well as the flow based
|
|
experimentation briefly described in <a href="#ml230.s12">Section 2.2</a>.</p><p>In a follow up activity for which data will not be available in time for this
|
|
submission, the team is submitting one of the supporting analogs, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
97301789</a> (CID 46245505) for stability assessment, noting that
|
|
this analogue differs structurally in three regions and possesses an improved
|
|
activity profile as compared to the probe. This compound will be proposed for
|
|
further enhancement going forward.</p></div><div id="ml230.s26"><h3>3.4. SAR Tables</h3><p>A total of 165 compounds were assessed in the primary efflux assay (AIDs
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/489002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">489002</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/489003" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">489003</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504566" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504566</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504569" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504569</a>) and of these, 126 were synthesized by the KU SCC. A
|
|
subset of compounds relating to the parent scaffold were purchased and assessed
|
|
as part of the HTS effort at UNMCMD, prior to the KU SCC involvement. Of the ~
|
|
30 commercial compounds assessed by the UNMCMD, a few showed modest ABCG2
|
|
selectivity (<a class="figpopup" href="/books/NBK133425/figure/ml230.f7/?report=objectonly" target="object" rid-figpopup="figml230f7" rid-ob="figobml230f7">Figure 7</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
85240370</a>/CID 1441553), but gaps in the collection did not resolve
|
|
the structural functionality responsible for any significant efflux potency or
|
|
selectivity towards ABCG2 or ABCB1. Due to the diversity of structural changes
|
|
present in the commercial set, additional compounds were needed to construct
|
|
meaningful SAR, and this was done using the primary efflux data as it was more
|
|
readily obtainable. The commercial set contained several members with conserved
|
|
functionality that provided the basis for establishing a methodical SAR
|
|
assessment. The pyrazolo[1,5-<i>a</i>]pyrimidine core
|
|
was preserved, and exchange of the peripheral substituents were surveyed as
|
|
depicted by the shaded regions in <a class="figpopup" href="/books/NBK133425/figure/ml230.f9/?report=objectonly" target="object" rid-figpopup="figml230f9" rid-ob="figobml230f9">Figure
|
|
9</a>. Several compounds of the purchased collection contained a
|
|
3-chlorophenyl substituent at R1, which also reflected the R1 moiety present in
|
|
hit <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
85240370</a> (CID 1441553). As such, initially a series of compounds
|
|
were prepared with these features maintained while adjusting R2-R4 (<a class="figpopup" href="/books/NBK133425/table/ml230.t1/?report=objectonly" target="object" rid-figpopup="figml230t1" rid-ob="figobml230t1">Tables 1</a> and <a class="figpopup" href="/books/NBK133425/table/ml230.t2/?report=objectonly" target="object" rid-figpopup="figml230t2" rid-ob="figobml230t2">2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f9" co-legend-rid="figlgndml230f9"><a href="/books/NBK133425/figure/ml230.f9/?report=objectonly" target="object" title="Figure 9" class="img_link icnblk_img figpopup" rid-figpopup="figml230f9" rid-ob="figobml230f9"><img class="small-thumb" src="/books/NBK133425/bin/ml230f9.gif" src-large="/books/NBK133425/bin/ml230f9.jpg" alt="Figure 9. Focus of SAR expansion efforts based on primary efflux data." /></a><div class="icnblk_cntnt" id="figlgndml230f9"><h4 id="ml230.f9"><a href="/books/NBK133425/figure/ml230.f9/?report=objectonly" target="object" rid-ob="figobml230f9">Figure 9</a></h4><p class="float-caption no_bottom_margin">Focus of SAR expansion efforts based on primary efflux data. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml230t1"><a href="/books/NBK133425/table/ml230.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml230t1" rid-ob="figobml230t1"><img class="small-thumb" src="/books/NBK133425/table/ml230.t1/?report=thumb" src-large="/books/NBK133425/table/ml230.t1/?report=previmg" alt="Table 1. SAR expansion on initial hit SID 85240370." /></a><div class="icnblk_cntnt"><h4 id="ml230.t1"><a href="/books/NBK133425/table/ml230.t1/?report=objectonly" target="object" rid-ob="figobml230t1">Table 1</a></h4><p class="float-caption no_bottom_margin">SAR expansion on initial hit SID
|
|
85240370. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml230t2"><a href="/books/NBK133425/table/ml230.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml230t2" rid-ob="figobml230t2"><img class="small-thumb" src="/books/NBK133425/table/ml230.t2/?report=thumb" src-large="/books/NBK133425/table/ml230.t2/?report=previmg" alt="Table 2. Continuation of SAR expansion on initial hit SID 85240370." /></a><div class="icnblk_cntnt"><h4 id="ml230.t2"><a href="/books/NBK133425/table/ml230.t2/?report=objectonly" target="object" rid-ob="figobml230t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Continuation of SAR expansion on initial hit SID
|
|
85240370. </p></div></div><p>One compound cluster was constructed with R1-R3 groups identical to that of the
|
|
parent hit <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85240370</a> (entries 3–18) while
|
|
modulating R4. Notably, the substitution of the acyl-2 furan for acyl-3-furan
|
|
(entry 4) produced an enhancement in selectivity for ABCG2 (8.6-fold),
|
|
predominately due to erosion of ABCB1 potency, while only modestly attenuating
|
|
ABCG2 potency as compared to the parent hit. Improved ABCG2 potency was achieved
|
|
with installation of an acyl-3-pyridine; however, the selectivity deteriorated
|
|
essentially to pan inhibition (entry 13). Following incorporation of the
|
|
acyl-3-furan as the more optimal R4 substituent, a survey was then done on the
|
|
R2 group while holding constant R1 and R3 (entries 19–25). Substantial
|
|
potency for ABCG2 was gained when R4 was 3-pyridine (entry 23); however, once
|
|
again, selectivity was negatively impacted.</p><p>Alterations in the 3-chlorophenyl R1 substituent were then made while assessing
|
|
several R4 head groups, specifically toggling between acyl-2-furan,
|
|
acyl-3-furan, or benzoyl functionalities (entries 26–36, <a class="figpopup" href="/books/NBK133425/table/ml230.t2/?report=objectonly" target="object" rid-figpopup="figml230t2" rid-ob="figobml230t2">Table 2</a>). No substantial improvements
|
|
were noted with these changes; however, when R1 was changed from 3-chlorophenyl
|
|
to phenyl, and R2 was varied (entries 37–43), it was discovered that a
|
|
2-furan at R2 in concert with the optimized acyl-3-furan afforded a significant
|
|
boost in both ABCG2 potency as well as overall ABCG2 selectivity (entry 37,
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a>, ABCB1 EC<sub>50</sub> = 4.65 μM; ABCG2
|
|
EC<sub>50</sub> = 0.13 μM, selectivity = 36
|
|
fold).</p><p>With this information in hand, the team followed up with an SAR effort aimed at
|
|
demonstrating supportive SAR for compounds bearing an R2 = 2-furyl group
|
|
while also attempting to improve upon the profile of the new lead, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a> (<a class="figpopup" href="/books/NBK133425/figure/ml230.f10/?report=objectonly" target="object" rid-figpopup="figml230f10" rid-ob="figobml230f10">Fig
|
|
10</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f10" co-legend-rid="figlgndml230f10"><a href="/books/NBK133425/figure/ml230.f10/?report=objectonly" target="object" title="Figure 10" class="img_link icnblk_img figpopup" rid-figpopup="figml230f10" rid-ob="figobml230f10"><img class="small-thumb" src="/books/NBK133425/bin/ml230f10.gif" src-large="/books/NBK133425/bin/ml230f10.jpg" alt="Figure 10. Parent hit SID 85240370 modified to a new lead, SID 88095709." /></a><div class="icnblk_cntnt" id="figlgndml230f10"><h4 id="ml230.f10"><a href="/books/NBK133425/figure/ml230.f10/?report=objectonly" target="object" rid-ob="figobml230f10">Figure 10</a></h4><p class="float-caption no_bottom_margin">Parent hit SID 85240370 modified to a new lead,
|
|
SID 88095709. </p></div></div><p>The new lead scaffold, represented by <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>, was further
|
|
studied by adjusting physiochemical and spatial elements in R1 (<a class="figpopup" href="/books/NBK133425/table/ml230.t3/?report=objectonly" target="object" rid-figpopup="figml230t3" rid-ob="figobml230t3">Table 3</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml230t3"><a href="/books/NBK133425/table/ml230.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml230t3" rid-ob="figobml230t3"><img class="small-thumb" src="/books/NBK133425/table/ml230.t3/?report=thumb" src-large="/books/NBK133425/table/ml230.t3/?report=previmg" alt="Table 3. Summary of modifications for R1." /></a><div class="icnblk_cntnt"><h4 id="ml230.t3"><a href="/books/NBK133425/table/ml230.t3/?report=objectonly" target="object" rid-ob="figobml230t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Summary of modifications for R1. </p></div></div><p>Switching out the phenyl ring of the lead with a <i>t</i>-butyl group
|
|
erased much of the gains towards ABCG2 selectivity (entry 2, <a class="figpopup" href="/books/NBK133425/table/ml230.t3/?report=objectonly" target="object" rid-figpopup="figml230t3" rid-ob="figobml230t3">Table 3</a>). Traditional phenyl
|
|
replacements such as thiophene or furan were tolerated, but only led to modest
|
|
selectivity and potencies. The installation of a 4-chlorophenyl substituent led
|
|
to a reduced impact on ABCB1, resulting in selectivity in the efflux assay of
|
|
22-fold (entry 6); however, the change also marginalized the potency on ABCG2.
|
|
Renovating the phenyl substituent with electron donating groups did not appear
|
|
to be beneficial.</p><p>An examination of 2-furan replacements at R2 was also undertaken (<a class="figpopup" href="/books/NBK133425/table/ml230.t4/?report=objectonly" target="object" rid-figpopup="figml230t4" rid-ob="figobml230t4">Table 4</a>). Simple alkyl units such as
|
|
methyl or t-butyl degraded potency and fold-selectivity for both transporters.
|
|
Notably, use of <i>t</i>-butyl actually reversed selectivity for
|
|
ABCB1, albeit at the expense of potency (entry 5).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml230t4"><a href="/books/NBK133425/table/ml230.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml230t4" rid-ob="figobml230t4"><img class="small-thumb" src="/books/NBK133425/table/ml230.t4/?report=thumb" src-large="/books/NBK133425/table/ml230.t4/?report=previmg" alt="Table 4. Summary of modifications for R2." /></a><div class="icnblk_cntnt"><h4 id="ml230.t4"><a href="/books/NBK133425/table/ml230.t4/?report=objectonly" target="object" rid-ob="figobml230t4">Table 4</a></h4><p class="float-caption no_bottom_margin">Summary of modifications for R2. </p></div></div><p>Some R2 revisions resulted in impressive ABCG2 selectivities and potencies. The
|
|
choice of 2-F-phenyl (entry 10, <a class="figpopup" href="/books/NBK133425/table/ml230.t4/?report=objectonly" target="object" rid-figpopup="figml230t4" rid-ob="figobml230t4">Table
|
|
4</a>) slightly degraded potency for ABCB1 as compared to the parent
|
|
(entry 1), leading to a 10-fold selectivity in favor of ABCG2. For the
|
|
fluorinated series (entries 10–12), the potency for both transporters
|
|
decreased as the fluorine atom was migrated from the 2- to 3- to 4-position of
|
|
the aromatic R2 ring. Interestingly, the use of the use of a 3-MeO-phenyl group
|
|
impeded potency for ABCB1 activity while retaining sub micromolar ABCG2 potency
|
|
on par with the parent, leading to an improved 83-fold selectivity between the
|
|
transporters (entry 8). In this series (entries 7–9), however, a trend
|
|
was not observed as the substituent was shifted from each position. Additional
|
|
compounds prepared with the 3-MeO-phenyl group at R2 did not show a consistent
|
|
SAR (data not shown).</p><p>The commercial set of compounds contained a few scaffolds bearing a methyl group
|
|
at R3. SAR generated in the early phases demonstrated some benefit to the
|
|
presence of small alkyl groups at R3; however, this was highly dependent on the
|
|
identity of groups at R1, R2 and R4. For the purposes of expanding the SAR
|
|
around <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>, one analogue was prepared to quickly evaluate the
|
|
effect of this substitution pattern in concert with our chosen functionalities
|
|
at R1, R2 and R4 (<a class="figpopup" href="/books/NBK133425/figure/ml230.f11/?report=objectonly" target="object" rid-figpopup="figml230f11" rid-ob="figobml230f11">Fig 11</a>). ABCB1
|
|
potency was encouragingly impaired, but not without also effecting G2, resulting
|
|
in a marginal selectivity profile.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f11" co-legend-rid="figlgndml230f11"><a href="/books/NBK133425/figure/ml230.f11/?report=objectonly" target="object" title="Figure 11" class="img_link icnblk_img figpopup" rid-figpopup="figml230f11" rid-ob="figobml230f11"><img class="small-thumb" src="/books/NBK133425/bin/ml230f11.gif" src-large="/books/NBK133425/bin/ml230f11.jpg" alt="Figure 11. Effect of R3 alkyl substitution." /></a><div class="icnblk_cntnt" id="figlgndml230f11"><h4 id="ml230.f11"><a href="/books/NBK133425/figure/ml230.f11/?report=objectonly" target="object" rid-ob="figobml230f11">Figure 11</a></h4><p class="float-caption no_bottom_margin">Effect of R3 alkyl substitution. </p></div></div><p>Attention was then turned to investigating the effect of different R4
|
|
functionality appended to the piperazine (<a class="figpopup" href="/books/NBK133425/table/ml230.t5/?report=objectonly" target="object" rid-figpopup="figml230t5" rid-ob="figobml230t5">Table 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml230t5"><a href="/books/NBK133425/table/ml230.t5/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml230t5" rid-ob="figobml230t5"><img class="small-thumb" src="/books/NBK133425/table/ml230.t5/?report=thumb" src-large="/books/NBK133425/table/ml230.t5/?report=previmg" alt="Table 5. Summary of modifications for R4." /></a><div class="icnblk_cntnt"><h4 id="ml230.t5"><a href="/books/NBK133425/table/ml230.t5/?report=objectonly" target="object" rid-ob="figobml230t5">Table 5</a></h4><p class="float-caption no_bottom_margin">Summary of modifications for R4. </p></div></div><p>In earlier SAR sets, activity was found to be sensitive to the identity of R4 and
|
|
the pairing of groups at R2 and R3. In the context of our new lead, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a>, we wanted to better understand the effect of R4 with
|
|
the chosen substituents. It was confirmed that an acyl-3-furan was preferred to
|
|
an acyl-2-furan (entry 2), and simple alkyl substitution of the 3-furan (entries
|
|
5–7) or a larger benzofuran (entry 8), while tolerated, did not reveal
|
|
any benefits. However, the most influential effects on ABCB1 were observed when
|
|
the acyl furan was exchanged for a benzyl ester (entry 11). While ABCG2 potency
|
|
was compromised compared to the lead, ABCB1 potency was completely lost,
|
|
yielding a selectivity of ~ 19 fold.</p><p>In a more aggressive effort, the entire “top piece” of the
|
|
scaffold, consisting of the piperazine and the R4 group, was modified (<a class="figpopup" href="/books/NBK133425/table/ml230.t6/?report=objectonly" target="object" rid-figpopup="figml230t6" rid-ob="figobml230t6">Table 6</a>). Ring-opened piperazine
|
|
equivalents, truncated amino groups, piperidine amides, ring-expanded amines
|
|
(not shown) and various structural variations on a theme did not produce a
|
|
profile superior to that which had already been observed.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml230t6"><a href="/books/NBK133425/table/ml230.t6/?report=objectonly" target="object" title="Table 6" class="img_link icnblk_img figpopup" rid-figpopup="figml230t6" rid-ob="figobml230t6"><img class="small-thumb" src="/books/NBK133425/table/ml230.t6/?report=thumb" src-large="/books/NBK133425/table/ml230.t6/?report=previmg" alt="Table 6. Summary of piperazine and combined R4 modifications (X)." /></a><div class="icnblk_cntnt"><h4 id="ml230.t6"><a href="/books/NBK133425/table/ml230.t6/?report=objectonly" target="object" rid-ob="figobml230t6">Table 6</a></h4><p class="float-caption no_bottom_margin">Summary of piperazine and combined R4 modifications (X). </p></div></div><p>In the process of evaluating these structural modifications, several compounds
|
|
were prepared singly to target possible oversights in SAR, as every possible
|
|
R1-R4 combination cannot be prepared and assessed in a timely way. Others were
|
|
targeted as a means of inserting the best combinations as gleaned from the
|
|
preceding generations of SAR. These compounds were more recently pursued to
|
|
probe-specific structural combinations and are summarized in <a class="figpopup" href="/books/NBK133425/table/ml230.t7/?report=objectonly" target="object" rid-figpopup="figml230t7" rid-ob="figobml230t7">Table 7</a>. Data obtained early on had
|
|
indicated that the acetyl group at R4 was more advantageous than other changes
|
|
that had been surveyed (including the benzyl ester modification), though later
|
|
refinement of these data does not now stand out as particular SAR of interest.
|
|
Based on the information in hand at the time, substituted phenyl derivatives
|
|
possessing a disparate electronic nature at R1 were incorporated with the acetyl
|
|
R4 group in place (entries 2 and 3). No advantages were found.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml230t7"><a href="/books/NBK133425/table/ml230.t7/?report=objectonly" target="object" title="Table 7" class="img_link icnblk_img figpopup" rid-figpopup="figml230t7" rid-ob="figobml230t7"><img class="small-thumb" src="/books/NBK133425/table/ml230.t7/?report=thumb" src-large="/books/NBK133425/table/ml230.t7/?report=previmg" alt="Table 7. Analogues with R1 – R4 substitution patterns in combination." /></a><div class="icnblk_cntnt"><h4 id="ml230.t7"><a href="/books/NBK133425/table/ml230.t7/?report=objectonly" target="object" rid-ob="figobml230t7">Table 7</a></h4><p class="float-caption no_bottom_margin">Analogues with R1 – R4 substitution patterns in
|
|
combination. </p></div></div><p>We were interested in also surveying the effect of reducing the carbonyl of the
|
|
R4 head group to give an amine in place of the amide when some of the preferred
|
|
R1-R3 substituents were incorporated (entry 4) and, as an experimental one-off
|
|
compound, in other pockets of SAR that seemed to be unrelated but were still
|
|
interesting (entry 6). While the effect did not enhance the profile in the case
|
|
of the most closely related analogue to the lead <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a> (entry 4, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/99376134" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 99376134</a>), a profound
|
|
effect was observed for the alternatively substituted compound with <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
97301789</a> (entry 6). As previously mentioned, the combination of
|
|
R1-R4 has been found to radically influence the profile of the compounds towards
|
|
ABCB1 or ABCG2. For example, methylation at R2 and R3 in concert with previously
|
|
surveyed R1 and R4 moieties delivered an analogue which amounts to pan
|
|
inhibition (entry 5). The combination effect cannot be underestimated, as shown
|
|
with entry 6, in which methylation at R2 and R3, in concert with the newly
|
|
discovered R4 head group of CH<sub>2</sub>-3-furan, led to a 233-fold
|
|
selectivity for G2 with comparable potency to the lead compound and abolished
|
|
activity for ABCB1 in the efflux assay! The improved selectivity
|
|
observed with the CH<sub>2</sub>-3-furan in the R4 position could be due to a
|
|
number of effects. Removal of the carbonyl of the parental acyl-3-furan R4 group
|
|
confers basicity to the head group that was previously missing. Removal of the
|
|
carbonyl also changes the conformation of the R4 group in relation of the
|
|
piperidine ring (sp<sup>3</sup> hybridization) versus when the amide of the
|
|
parent is intact (sp<sup>2</sup> hybridization). Although these aspects are
|
|
likely not the only contributors to the observed benefits in selectivity, as a
|
|
previously screened benzyl R4 group did not result in analogous improvements.
|
|
Still, these effects are advantageous only when put in play with a select group
|
|
of R1-R3 substitutions.</p><p>In parallel to the described efforts, compounds were also assessed in
|
|
potentiation secondary assays and associated data are presented in the preceding
|
|
tables; however, the chemoreversal assay is a very low throughput assay and
|
|
compound data from this assay could not be used to drive the SAR program. Key
|
|
data have been collected for some of the most promising compounds (<a class="figpopup" href="/books/NBK133425/figure/ml230.f12/?report=objectonly" target="object" rid-figpopup="figml230f12" rid-ob="figobml230f12">Fig 12</a>). Evaluation of probe compound
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a> shows submicromolar ABCG2 efflux inhibition activity
|
|
with ~ 36-fold selectivity toward ABCG2 over ABCB1. Potent submicromolar
|
|
activity has also been demonstrated in the potentiated killing of both
|
|
over-expressing cell lines with preference for ABCG2 from a toxicity
|
|
perspective, though the degree of selectivity observed in the cell killing assay
|
|
is removed (1.8 fold in chemoreversal vs. 36-fold in efflux assay). The most
|
|
recently advanced analogue, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 97301789</a>, presents as
|
|
an exceedingly potent compound in the potentiation assays with a 4.5-fold window
|
|
between the observed potencies for the two transporters, but in favor of ABCB1.
|
|
Interestingly, the analogue appears to be devoid of toxicity (> 100
|
|
μM) and represents a promising tool for further refinement.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f12" co-legend-rid="figlgndml230f12"><a href="/books/NBK133425/figure/ml230.f12/?report=objectonly" target="object" title="Figure 12" class="img_link icnblk_img figpopup" rid-figpopup="figml230f12" rid-ob="figobml230f12"><img class="small-thumb" src="/books/NBK133425/bin/ml230f12.gif" src-large="/books/NBK133425/bin/ml230f12.jpg" alt="Figure 12. Refinement of structure based on efflux and associated potentiation and toxicity data." /></a><div class="icnblk_cntnt" id="figlgndml230f12"><h4 id="ml230.f12"><a href="/books/NBK133425/figure/ml230.f12/?report=objectonly" target="object" rid-ob="figobml230f12">Figure 12</a></h4><p class="float-caption no_bottom_margin">Refinement of structure based on efflux and associated potentiation
|
|
and toxicity data. </p></div></div></div><div id="ml230.s27"><h3>3.5. Cellular Activity</h3><p>The efflux inhibition assay and the chemoreversal secondaries are both direct
|
|
indication of cellular activity <i>in vitro</i>. To our knowledge, low
|
|
nanomolar chemoreversal activity coupled with direct evidence of efflux
|
|
inhibition for ABCG2 inhibitors is unprecedented.</p></div><div id="ml230.s28"><h3>3.6. Profiling Assays</h3><p>Since ABC transporters are ATP dependant efflux pumps and several kinase targets
|
|
have been implicated in the patent literature with structurally similar
|
|
scaffolds, the probe was profiled against 50 kinases at a single concentration
|
|
of 10 μM to assess promiscuity of the chemotype.<sup><a class="bibr" href="#ml230.r66" rid="ml230.r66">66</a></sup> Probe <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a> was dissolved in DMSO and tested at a final
|
|
concentration of 10 μM. Prior to initiating a profiling campaign, the
|
|
compound was evaluated for false positive against split-luciferase. Profiling
|
|
was done in duplicate for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> against each
|
|
kinase. The Percent Inhibition and Percent Activity Remaining (shown in <a class="figpopup" href="/books/NBK133425/table/ml230.t8/?report=objectonly" target="object" rid-figpopup="figml230t8" rid-ob="figobml230t8">Table 8</a>) are calculated using the
|
|
following equation:</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml230t8"><a href="/books/NBK133425/table/ml230.t8/?report=objectonly" target="object" title="Table 8" class="img_link icnblk_img figpopup" rid-figpopup="figml230t8" rid-ob="figobml230t8"><img class="small-thumb" src="/books/NBK133425/table/ml230.t8/?report=thumb" src-large="/books/NBK133425/table/ml230.t8/?report=previmg" alt="Table 8. Percent of activity remaining for various kinases when inhibited by SID 88095709." /></a><div class="icnblk_cntnt"><h4 id="ml230.t8"><a href="/books/NBK133425/table/ml230.t8/?report=objectonly" target="object" rid-ob="figobml230t8">Table 8</a></h4><p class="float-caption no_bottom_margin">Percent of activity remaining for various kinases when inhibited by
|
|
SID 88095709. </p></div></div><div class="pmc_disp_formula whole_rhythm clearfix" id="ml230.eq1"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow twelve_col">% Inhibition = ALUControl −
|
|
ALUSample × 100<br />ALUControl<br />% Activity Remaining
|
|
= 100 − % Inhibition</div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap"></span></div></div></div><p>The team has also submitted the probe and the analog <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
97301789</a> (CID 46245505) to the NIH National Cancer Institute to
|
|
elucidate the effect of the probe on the cancer cell line panel.</p></div></div><div id="ml230.s29"><h2 id="_ml230_s29_">4. Discussion</h2><div id="ml230.s30"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>ABCB1, ABCC1, and ABCG2 transporters are known to significantly influence the
|
|
ADME-Tox properties of drugs,<sup><a class="bibr" href="#ml230.r2" rid="ml230.r2">2</a></sup> and although a large number of compounds have been
|
|
identified possessing ABC transporter inhibitory properties, only a few of these
|
|
agents are appropriate candidates for clinical use as MDR reversing
|
|
agents.<sup><a class="bibr" href="#ml230.r67" rid="ml230.r67">67</a></sup>
|
|
Clinical trials with late generation modulators (e.g. biricodar, zosuquidar,
|
|
dofequidar, and laniquidar) specifically developed for MDR reversal are
|
|
ongoing.<sup><a class="bibr" href="#ml230.r33" rid="ml230.r33">33</a>,<a class="bibr" href="#ml230.r36" rid="ml230.r36">36</a>,<a class="bibr" href="#ml230.r68" rid="ml230.r68">68</a></sup> Efflux pumps are by design highly
|
|
adaptive and potentially able to adjust to a wide array of chemotypes owing to a
|
|
relatively large cavity (~6000 Å<sup>3</sup>) and at least three
|
|
non-overlapping binding site configurations.<sup><a class="bibr" href="#ml230.r8" rid="ml230.r8">8</a></sup> For example, rhodamine 123 has been used
|
|
in combination with Hoechst 33342 to describe two functional transport sites in
|
|
ABCB1 with complex allosteric interactions.<sup><a class="bibr" href="#ml230.r69" rid="ml230.r69">69</a></sup> Concurrently, rhodamine 123 may bind to
|
|
a different overlapping region, or potentially within the same large flexible
|
|
binding site, as LDS 751.<sup><a class="bibr" href="#ml230.r70" rid="ml230.r70">70</a></sup> It has also been shown that ABCB1 possesses two
|
|
allosterically coupled drug acceptor sites where one binds vinblastine,
|
|
doxorubucin, etoposide and cyclosporin A, and the other binds dexniguldipine and
|
|
other 1,4-dihydropyridines.<sup><a class="bibr" href="#ml230.r71" rid="ml230.r71">71</a></sup> It is thus possible that within a single chemical
|
|
sub-structure class there could be multiple binding patterns leading to both the
|
|
difficulty of direct structure activity relationship comparisons but also to the
|
|
possibility of a tuneable synthetic system allowing selectivity and/or
|
|
cross-transporter inhibition. It should be noted, however, that acquired
|
|
mutations in transporter genes introduce even more complexity, altering the
|
|
pattern of resistance and improving the ability of the mutants to efflux new
|
|
drugs.<sup><a class="bibr" href="#ml230.r72" rid="ml230.r72">72</a></sup> It was
|
|
reported that various drug-selected human tumor cell lines expressed different
|
|
ABCG2 variants, which were suggested to be gain-of-function mutations acquired
|
|
during the course of drug exposure.<sup><a class="bibr" href="#ml230.r73" rid="ml230.r73">73</a></sup> Single amino-acid changes cause an altered drug
|
|
resistance profile and substrate specificity compared to the wild type ABCG2
|
|
transporter.<sup><a class="bibr" href="#ml230.r74" rid="ml230.r74">74</a></sup>
|
|
The lesson to be learned is that high efficacy and good selectivity need to be
|
|
carefully compared in analogous systems and cell lines. This is readily apparent
|
|
in the discrepant activity seen with FTC and Ko 143.</p><p><a class="figpopup" href="/books/NBK133425/figure/ml230.f13/?report=objectonly" target="object" rid-figpopup="figml230f13" rid-ob="figobml230f13">Figure 13</a> summarizes the prior art
|
|
comparison to <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID 44640177). XR9051 and MK 571
|
|
were chosen to verify ABCB1 activity and counterscreen ABCC1 activity,
|
|
respectively in our system. XR9051 does inhibit the efflux of JC-1 in both ABCB1
|
|
and ABCG2 over-expressing cell lines (0.6 and 2.3 μM respectivly).
|
|
Potentiation data indicates submicromolar chemoreversal in both Jurkat-DNR and
|
|
Ig-MXP3 cells with a bias toward ABCB1 at 10 nM as compared to 700 nM for ABCG2.
|
|
Not surprisingly, we didn’t observe any inhibition in ABCB1 or ABCG2
|
|
with MK 571 but we remain interested in the MK 571 response in ABCC1
|
|
over-expressing SupT1-Vin cells. It is likely that the
|
|
“potentiation” seen with MK 571 is simply due to general
|
|
toxicity since in both cell lines the CR<sub>50</sub> is equivalent to the
|
|
TD<sub>50</sub> (curves not shown).</p><p>Direct comparison of reversan in our efflux inhibition system shows low
|
|
micromolar inhibition of both ABCB1 and ABCG2 (4.4 and 0.8 μM
|
|
respectively) with moderate selectivity for ABCG2. In our chemoreversal
|
|
potentiation assay, reversan showed micromolar activity and no apparent
|
|
selectivity (2.2 and 3.6 μM in ABCB1 and ABCG2, respectively). This was
|
|
coupled with significant toxicity in the Jurkat-DNR cell line. FTC showed no
|
|
activity in either cell line in the efflux inhibition assay and was not tested
|
|
in the potentiation assay. Ko 143 has been shown to potentiate mitoxantrone
|
|
(MTX) at nanomolar levels in ABCG2 over-expressing cells.<sup><a class="bibr" href="#ml230.r48" rid="ml230.r48">48</a></sup> In our potentiation
|
|
assay there actually seemed to be a selectivity for ABCB1 over ABCG2
|
|
(CR<sub>50</sub> = 1.0 and 5.9 M respectively) with considerable
|
|
toxicity in both cell lines. The efflux inhibition activity did not mirror this,
|
|
showing no activity in ABCB1 and only 13.6 μM inhibition in ABCG2,
|
|
potentially indicating a binding site difference versus JC-1.</p><p>The entire probe SAR series was also structurally compared via PLS analysis to
|
|
the inhibitors described in <a class="figpopup" href="/books/NBK133425/figure/ml230.f13/?report=objectonly" target="object" rid-figpopup="figml230f13" rid-ob="figobml230f13">Figure
|
|
13</a> as well as the clinically relevant potentiators; Cyclosporin A,
|
|
Biricodar, Tariquidar, Zosuquidar, Elacridar, Laniquidar, Dofequidar, and
|
|
ONT093. The eight biological parameters listed in <a class="figpopup" href="/books/NBK133425/table/ml230.t1/?report=objectonly" target="object" rid-figpopup="figml230t1" rid-ob="figobml230t1">Table 1</a> have been used as dependent variables in the
|
|
Y block of the PLS analysis which was performed. They included the normalized
|
|
percent response and IC<sub>50</sub> values in the primary assay, and the
|
|
CR<sub>50</sub> values in the secondary assay for both ABCB1 and ABCG2
|
|
transporters, and also the associated toxicity TD<sub>50</sub> data for these
|
|
two targets. The goal of this analysis was not only to cluster the compounds in
|
|
the physicochemical molecular descriptors space, but also to map these
|
|
biological parameters and selected physicochemical parameters (computed
|
|
solubility, logD 7.4, MW, hydrogen bond donors and acceptors, etc) in the
|
|
principal components space. <a class="figpopup" href="/books/NBK133425/figure/ml230.f14/?report=objectonly" target="object" rid-figpopup="figml230f14" rid-ob="figobml230f14">Figure
|
|
14</a> illustrates the clustering. This resulted in effectively three
|
|
groupings based on the similarity comparisons. The probe (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a>, CID 44640177) and analogs with aryl and heteroaryl R1
|
|
and R2 groups (excluding those with modifications to the piperizine) obviously
|
|
clustered together and those like <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 97301789</a> (CID 46245505)
|
|
with alkyl R2 substituents were grouped together. The third set is included in
|
|
the remainder of compared structures that did not show significant similarity to
|
|
one another or the probe class scaffolds. In conjunction with the unique
|
|
chemical space covered, the calculated solubility for the SAR structures appear
|
|
to be potentially better than those previously described in clinical trials.
|
|
Interestingly, the calculated solubility of compounds with greater selectivity
|
|
toward ABCG2 efflux inhibition of JC-1 seem to generally be poorer (more
|
|
lipophilic) than those for ABCB1 inhibition where greater
|
|
solubility/hydrophilicity appears to be required. Although the experimental
|
|
solubility of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> is less than ultimately desirable,
|
|
we are confident that the availability is sufficient for all biological
|
|
conditions outlined in this report. The probe compound also shows good solution
|
|
stability and appears to not be a kinase inhibitor based on the profile outlined
|
|
<a href="#ml230.s28">Section 3.6</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f14" co-legend-rid="figlgndml230f14"><a href="/books/NBK133425/figure/ml230.f14/?report=objectonly" target="object" title="Figure 14" class="img_link icnblk_img figpopup" rid-figpopup="figml230f14" rid-ob="figobml230f14"><img class="small-thumb" src="/books/NBK133425/bin/ml230f14.gif" src-large="/books/NBK133425/bin/ml230f14.jpg" alt="Figure 14. Map of the computed solubility of selected compounds in the PLS principal component space." /></a><div class="icnblk_cntnt" id="figlgndml230f14"><h4 id="ml230.f14"><a href="/books/NBK133425/figure/ml230.f14/?report=objectonly" target="object" rid-ob="figobml230f14">Figure 14</a></h4><p class="float-caption no_bottom_margin">Map of the computed solubility of selected compounds in the PLS
|
|
principal component space. Only prior art compounds and compounds tested in the secondary assays
|
|
have been included. Most of the newly synthesized compounds show higher
|
|
computed solubility <a href="/books/NBK133425/figure/ml230.f14/?report=objectonly" target="object" rid-ob="figobml230f14">(more...)</a></p></div></div><p>The primary screening conditions outlined here are a model system where JC-1 is
|
|
an efflux inhibition surrogate for chemotherapeutics and it must be noted that
|
|
there is not necessarily a one to one comparison of substrate recognition by
|
|
either efflux pump. Previous experimentation from our group has validated the
|
|
utility of such a model.<sup><a class="bibr" href="#ml230.r52" rid="ml230.r52">52</a>,<a class="bibr" href="#ml230.r75" rid="ml230.r75">75</a></sup>
|
|
However, this does not exclude the possibility that JC-1 efflux inhibition will
|
|
not match more phenotypic cell killing assay conditions such as the potentiation
|
|
assays outlined in this report. Our group has extensively looked at profiling
|
|
dozens of fluorescent substrates against a panel of known efflux inhibitors in
|
|
several ABC transporters and observed distinctly different activities dependent
|
|
on the substrate inhibitor pairing in each over-expression system (unpublished
|
|
results, manuscript in preparation). This, however, does not diminish the
|
|
utility of small molecules with specific efflux inhibition profiles. Such
|
|
inhibitors can be useful tools to look more closely at the nature of such pump
|
|
poly-specific substrate recognition, ultimately allowing for generation of
|
|
better model systems.</p><p>Probe <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a> demonstrates a 36-fold better efflux inhibition of JC-1
|
|
efflux in ABCG2 over ABCB1, thus establishing its usefulness in exploration of
|
|
the system from a biochemical perspective. This result, coupled with the noted
|
|
cellular activity in the potentiation assay justifies the overall utility of
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
88095709</a> as a probe for ABCG2. <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> showed greater
|
|
potency and ABCG2 selectivity than any of the aforementioned literature
|
|
precedent compounds in the efflux inhibition screening conditions. Only XR9051
|
|
seems to have better activity in the potentiation assay although with reversed
|
|
selectivity toward ABCB1. More work needs to be done in this subclass to
|
|
understand the difference in efflux inhibitions, as compared to
|
|
potentiation.</p><p>Interestingly, the structurally-related, but SAR-distinct analogue of the probe
|
|
that has an improved selectivity toward ABCG2 in the efflux assessment, compound
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
97301789</a>, was shown to have significantly more potent cell
|
|
killing activity in the chemoreversal assay (with no observed toxicity) than the
|
|
probe compound, however, the efflux inhibition selectivity appears to be lost.
|
|
The emergence of this compound occurred after extensive supporting SAR had been
|
|
established for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>, thus limiting the expansion of
|
|
another arm of SAR in support of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 97301789</a> as a probe in
|
|
this report; however, this development provides an exciting opportunity for
|
|
refinement as an extended project, particularly in the context of the observed
|
|
ABCG2 tumor reduction preliminary results that were mentioned in the
|
|
“<a href="#ml230.s2">Recommendations for scientific
|
|
use of the probe</a>” section.</p></div><div id="ml230.s31"><h3>4.2. Mechanism of Action Studies</h3><p>In relation to the phenotypic readout of the potentiation assay, the primary
|
|
efflux inhibition assay is a direct indication of the mode of action for the
|
|
compounds discussed. Further studies with other fluorescent substrates could be
|
|
used to further indicate site of action with each given transporter depending on
|
|
the substrate selectivity profiles.</p></div><div id="ml230.s32"><h3>4.3. Planned Future Studies</h3><div id="ml230.s33"><h4>Probe Enhancement</h4><p>This project will be submitted for approval as a candidate for probe
|
|
enhancement via the “Further Development of a Probe with Extended
|
|
Characterization” outlined by the NIH and MLP. We have defined a
|
|
scaffold with efflux activity for both targets as well as reversal of drug
|
|
resistance conferred on both targets with the identification of an ABCG2
|
|
selective probe <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>. There are > 30 compounds
|
|
in this subclass to support the SAR discussion. Furthermore, we have
|
|
identified a late stage, structurally-related, but SAR-distinct analogue of
|
|
the probe that has an improved selectivity toward ABCG2 in the efflux
|
|
assessment, demonstrates sub-nanomolar potentiation activity in the
|
|
chemoreversal assays, and is devoid of toxicity (> 100 μM).
|
|
The emergence of this compound occurred after extensive supporting SAR had
|
|
been established for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>, thus limiting the expansion of
|
|
another arm of SAR in support of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 97301789</a> as the
|
|
probe in this report; however, this development provides an exciting
|
|
opportunity for refinement in an extended project and the candidate for
|
|
preliminary animal studies. The probe extension proposal consists of: 1)
|
|
<i>in vitro</i> testing characterization of the compound
|
|
selectivity against other transporters in the portfolio of the UNMCMD Center
|
|
Driven Project on Transporters: 2) evaluation of the <i>in
|
|
vivo</i> characteristics and lead-like properties of the probe
|
|
<i>in vitro</i>; and 3) medicinal chemistry to establish SAR
|
|
around analogue <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 97301789</a> and overcome liabilities that
|
|
are identified through the current studies.</p><div id="ml230.s34"><h5>Chemistry (KUSCC)</h5><p>As previously discussed, the combination of R1-R4 has been found to
|
|
radically influence the profile of the compounds towards ABCB1 or ABCG2,
|
|
and distinct lines of SAR seemed to result depending on the nature of
|
|
this substitution. As analogue <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 97301789</a>
|
|
represents a line of SAR which was sidelined before the impact of the
|
|
benzyl R4 head group was discovered, the team proposes to investigate
|
|
the nature of this R4 substituent and others like it in concert with the
|
|
disubstituted core (R2 = aryl, R3 = Me, <a class="figpopup" href="/books/NBK133425/figure/ml230.f15/?report=objectonly" target="object" rid-figpopup="figml230f15" rid-ob="figobml230f15">Figure 15</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml230f15" co-legend-rid="figlgndml230f15"><a href="/books/NBK133425/figure/ml230.f15/?report=objectonly" target="object" title="Figure 15" class="img_link icnblk_img figpopup" rid-figpopup="figml230f15" rid-ob="figobml230f15"><img class="small-thumb" src="/books/NBK133425/bin/ml230f15.gif" src-large="/books/NBK133425/bin/ml230f15.jpg" alt="Figure 15. SAR enhancement of SID 97301789." /></a><div class="icnblk_cntnt" id="figlgndml230f15"><h4 id="ml230.f15"><a href="/books/NBK133425/figure/ml230.f15/?report=objectonly" target="object" rid-ob="figobml230f15">Figure 15</a></h4><p class="float-caption no_bottom_margin">SAR enhancement of SID
|
|
97301789. </p></div></div><p>Enhancement of the probe or one of the analogues such as <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
97301789</a> will also require resynthesis of compound(s) as
|
|
well as potential medicinal chemistry optimization for liabilities in
|
|
solubility, permeability, and toxicity. Along with this synthetic
|
|
effort, lead-like properties will be assessed via chemical
|
|
characterization, compound profiling, and <i>in vivo</i>
|
|
analysis.</p><p>Specifically, during the probe enhancement phase the optimized probe will
|
|
be provided in sufficient quantities and purity for the proposed studies
|
|
and be further refined structurally to tune physiochemical and
|
|
pharmacokinetic parameters necessary for adequate analysis in rodent
|
|
models. The probe would be optimized to: possess suitable aqueous
|
|
solubility, stability, and cellular permeability; possess reasonable
|
|
microsomal stability, plasma protein binding and plasma stability; be
|
|
assessed for <i>in vivo</i> pharmacokinetics; show minimal off
|
|
target effects as determined by a broad spectrum profiling panel such as
|
|
Ricerca panel and PDSP GPCR panel. The probe will also be compared to
|
|
the state of the art for ABCG2 relevant efflux
|
|
inhibitors/potentiators.</p></div><div id="ml230.s35"><h5>Biology (UNMCMD, Target Provider at UNM)</h5><p>Further selectivity profiling across related, cancer relevant transporter
|
|
families will be performed both in the efflux inhibition screen as well
|
|
as in the drug potentiation assays available for each of the transporter
|
|
expressing cell lines. Preliminary <i>in vivo</i> mouse
|
|
studies will be done on the most promising <i>in vitro</i>
|
|
compound(s).</p><p>Specifically, in the probe enhancement phase the optimized probe will
|
|
profile the existing SAR series against a SupT1-Vin ABCC1
|
|
over-expressing cell line in: 1) the original HTS flow cytometric efflux
|
|
inhibition screen as compared to ABCB1 and ABCG2; 2) a modified
|
|
cell-based potentiation assay using the CellTiter-Glo® (Promega)
|
|
luminescent cell viability assay as a pre-screen for compounds going
|
|
into the traditional direct viability count potentiation assay; and 3)
|
|
the traditional trypan blue viability count potentiation assay to
|
|
determine inhibition mediated cell killing as well as compound
|
|
toxicity.</p><p>The enhancement will also initiate pilot studies of compound efficacy in
|
|
mouse cancer models, specifically: 1) determine the optimal dose of the
|
|
inhibitor via small scale dose response; 2) apply optimized inhibitor
|
|
dose in larger scale survival study; 3) assess acute toxicity; and 4)
|
|
test expression effects by measuring RNA expression of ABCG2 by RT-PCR
|
|
in the tumors. Probe compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> is
|
|
currently in process for preliminary studies and the data will likely be
|
|
included in resubmission of the enhancement proposal.</p><p><i>Details for the proposed biological experimentation in the
|
|
enhancement are located in</i>
|
|
<a href="#ml230.app3">Appendix C</a>.</p></div></div></div></div><div id="ml230.s36"><h2 id="_ml230_s36_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml230.r1">Mistry P, Plumb J, Eccles S, Watson S, Dale I, Ryder H, Box G, Charlton P, Templeton D, Bevan PB. In vivo efficacy of XR9051, a potent modulator
|
|
of P-glycoprotein mediated multidrug
|
|
resistance. <span><span class="ref-journal">British Journal of
|
|
Cancer. </span>1999;<span class="ref-vol">79</span>:1672–1678.</span> [<a href="/pmc/articles/PMC2362811/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2362811</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10206276" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10206276</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml230.r2">Szakacs G, Varadi A, Ozvegy-Laczka C, Sarkadi B. The role of ABC transporters in drug
|
|
absorption, distribution, metabolism, excretion and toxicity
|
|
(ADME-Tox). <span><span class="ref-journal">Drug Discovery
|
|
Today. </span>2008;<span class="ref-vol">13</span>:379–393.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18468555" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18468555</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml230.r3">O’Connor R. The pharmacology of cancer
|
|
resistance. <span><span class="ref-journal">Anticancer
|
|
Research. </span>2007;<span class="ref-vol">27</span>:1267–1272.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17593618" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17593618</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml230.r4">Gillet J-P, Efferth T, Remacle J. Chemotherapy-induced resistance by ATP-binding
|
|
cassette transporter genes. <span><span class="ref-journal">Biochimica et
|
|
Biophysica
|
|
Acta. </span>2007;<span class="ref-vol">1775</span>:237–262.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17572300" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17572300</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml230.r5">Goldman B. Multidrug resistance: can new drugs help
|
|
chemotherapy score against cancer? <span><span class="ref-journal">Journal of the
|
|
National Cancer
|
|
Institute. </span>2003;<span class="ref-vol">95</span>:255–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12591977" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12591977</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml230.r6">Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer.
|
|
Mechanisms, reversal using modulators of MDR and the role of MDR
|
|
modulators in influencing the pharmacokinetics of anticancer
|
|
drugs. <span><span class="ref-journal">European Journal of Pharmaceutical
|
|
Sciences. </span>2000;<span class="ref-vol">11</span>:265–283.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11033070" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11033070</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml230.r7">Sarkadi B, Homolya L, Szakacs G, Varadi A. Human multidrug resistance ABCB and ABCG
|
|
transporters: participation in a chemoimmunity defense
|
|
system. <span><span class="ref-journal">Physiological
|
|
Reviews. </span>2006;<span class="ref-vol">86</span>:1179–1236.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17015488" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17015488</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml230.r8">Eckford PDW, Sharom FJ. ABC Efflux Pump-Based Resistance to
|
|
Chemotherapy Drugs. <span><span class="ref-journal">Chemical
|
|
Reviews. </span>2009;<span class="ref-vol">109</span>:2989–3011.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19583429" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19583429</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml230.r9">Kawase M, Motohashi N. New multidrug resistance reversal
|
|
agents. <span><span class="ref-journal">Current Drug
|
|
Targets. </span>2003;<span class="ref-vol">4</span>:31–43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12528988" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12528988</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml230.r10">Avendano C, Menendez JC. Recent advances in multidrug resistance
|
|
modulators. <span><span class="ref-journal">Medicinal Chemistry
|
|
Reviews. </span>2004;<span class="ref-vol">1</span>:419–444.</span></div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml230.r11">Broccatelli F, Carosati E, Neri A, Frosini M, Goracci L, Oprea TI, Cruciani G. A Novel Approach for Predicting P-Glycoprotein
|
|
(ABCB1) Inhibition Using Molecular Interaction
|
|
Fields. <span><span class="ref-journal">J. Med.
|
|
Chem. </span>2011;<span class="ref-vol">54</span>:1740–1751.</span> [<a href="/pmc/articles/PMC3069647/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3069647</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21341745" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21341745</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml230.r12">Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y. Overcoming of vincristine resistance in P388
|
|
leukemia in vivo and in vitro through enhanced cytotoxicity of
|
|
vincristine and vinblastine by verapamil. <span><span class="ref-journal">Cancer
|
|
Research. </span>1981;<span class="ref-vol">41</span>:1967–72.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7214365" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7214365</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml230.r13">Yung BYM, Chang FJ, Bor AMS. Modulation of the reversibility of actinomycin
|
|
D cytotoxicity in HeLa cells by verapamil. <span><span class="ref-journal">Cancer
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C. <span><span class="ref-journal">Molecular Cancer
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Therapeutics. </span>2002;<span class="ref-vol">1</span>:417–425.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12477054" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12477054</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>49.</dt><dd><div class="bk_ref" id="ml230.r49">Liu J, Cui G, Zhao M, Cui C, Ju J, Peng S. Dual-acting agents that possess reversing
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Pharmacol. </span>2010;<span class="ref-vol">65</span>:353–361.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19499221" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19499221</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>59.</dt><dd><div class="bk_ref" id="ml230.r59">Vellenga E, Tuyt L, Wierenga B-J, Muller M, Dokter W. Interleukin-6 production by activated human
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Haematology. </span>2007;<span class="ref-vol">139</span>:20–30.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17854304" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17854304</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>61.</dt><dd><div class="bk_ref" id="ml230.r61">Winter SS, Jiang Z, Khawaja HM, Griffin T, Devidas M, Asselin BL, Larson RS. Identification of genomic classifiers that
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Group. <span><span class="ref-journal">Blood. </span>2007;<span class="ref-vol">110</span>:1429–1438.</span> [<a href="/pmc/articles/PMC1975833/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1975833</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17495134" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17495134</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>62.</dt><dd><div class="bk_ref" id="ml230.r62">Kuckuck FW, Edwards BS, Sklar LA. High throughput flow
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cytometry. <span><span class="ref-journal">Cytometry. </span>2001;<span class="ref-vol">44</span>:83–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11309812" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11309812</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>63.</dt><dd><div class="bk_ref" id="ml230.r63">Ramirez S, Aiken Charity T, Andrzejewski B, Sklar Larry A, Edwards Bruce S. High-throughput flow cytometry: validation in
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bioassays. <span><span class="ref-journal">Cytometry. </span>2003;<span class="ref-vol">53</span>:55–65.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12701132" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12701132</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>64.</dt><dd><div class="bk_ref" id="ml230.r64">Solubility and stability data assessment was
|
|
outsourced to and data was collected by the Sanford-Burnham Center, under
|
|
the direction of Dr. Layton Smith.</div></dd></dl><dl class="bkr_refwrap"><dt>65.</dt><dd><div class="bk_ref" id="ml230.r65"><span class="ref-journal">Protocol Based on BD Gentest solubility
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measurements - i.e. Goodwin, J. Poor Aqueous Solubility and Compound
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Aggregation: Detection, Differences, and Impact on In-Vitro Screens;
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Crespi, et al Aqueous Solubility by Flow Cytometry II: New Prototypes
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Optimized for Drug Solubility Testing. Poster
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Presentation.</span> BD Gentest, A BD Biosciences
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Company; Woburn, MA
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01801: </div></dd></dl><dl class="bkr_refwrap"><dt>66.</dt><dd><div class="bk_ref" id="ml230.r66">Data obtained from Luceome Biotechnologies using the
|
|
KinaseSeeker™ assay. For information on the assay principle and
|
|
method prt, <span class="element-citation" id="ml230.d1e15318">Jester BW, Cox KJ, Gaj A, Shomin CD, Porter JR, Ghosh I A Coiled-Coil Enabled Split-Luciferase
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Three-Hybrid System: Applied Toward Profiling Inhibitors of
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Protein Kinases. <span><span class="ref-journal">J. Am. Chem.
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Soc. </span>2010;<span class="ref-vol">132</span>:11727–11735.</span> <span class="nowrap">[<a class="int-reflink" href="articlerender.fcgi?accid=PMC2966823">PMC free article</a>]</span> <span class="nowrap">[<a href="https://scholar.google.com/scholar_lookup?journal=J.+Am.+Chem. Soc&title=A+Coiled-Coil+Enabled+Split-Luciferase Three-Hybrid+System:+Applied+Toward+Profiling+Inhibitors+of Protein+Kinases&author=BW+Jester&author=KJ+Cox&author=A+Gaj&author=CD+Shomin&author=JR+Porter&volume=132&publication_year=2010&pages=11727-11735&pmid=20669947&" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</span></span></div></dd></dl><dl class="bkr_refwrap"><dt>67.</dt><dd><div class="bk_ref" id="ml230.r67">Mayur YC, Peters GJ, Prasad VVSR, Lemos C, Sathish NK. Design of new drug molecules to be used in
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reversing multidrug resistance in cancer
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cells. <span><span class="ref-journal">Current Cancer Drug
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Targets. </span>2009;<span class="ref-vol">9</span>:298–306.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19442050" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19442050</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>68.</dt><dd><div class="bk_ref" id="ml230.r68">Seelig A, Gatlik-Landwojtowicz E. Inhibitors of multidrug efflux transporters:
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their membrane and protein
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interactions. <span><span class="ref-journal">Mini-Reviews in Medicinal
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Chemistry. </span>2005;<span class="ref-vol">5</span>:135–151.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15720284" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15720284</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>69.</dt><dd><div class="bk_ref" id="ml230.r69">Shapiro AB, Ling V. Positively cooperative sites for drug
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transport by P-glycoprotein with distinct drug
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specificities. <span><span class="ref-journal">European Journal of
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Biochemistry. </span>1997;<span class="ref-vol">250</span>:130–137.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9432000" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9432000</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>70.</dt><dd><div class="bk_ref" id="ml230.r70">Lugo MR, Sharom FJ. Interaction of LDS-751 and Rhodamine 123 with
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P-Glycoprotein: Evidence for Simultaneous Binding of Both
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Drugs. <span><span class="ref-journal">Biochemistry. </span>2005;<span class="ref-vol">44</span>:14020–14029.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16229491" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16229491</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>71.</dt><dd><div class="bk_ref" id="ml230.r71">Malkhandi J, Ferry DR, Boer R, Gekeler V, Ise W, Kerr DJ. Dexniguldipine-HCl is a potent allosteric
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inhibitor of [3H]vinblastine binding to P-glycoprotein
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of CCRF ADR 5000 cells. <span><span class="ref-journal">European Journal of
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Pharmacology, Molecular Pharmacology
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Section. </span>1994;<span class="ref-vol">288</span>:105–14.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7705462" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7705462</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>72.</dt><dd><div class="bk_ref" id="ml230.r72">Allen JD, Jackson SC, Schinkel AH. A mutation hot spot in the Bcrp1 (Abcg2)
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multidrug transporter in mouse cell lines selected for doxorubicin
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resistance. <span><span class="ref-journal">Cancer
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Research. </span>2002;<span class="ref-vol">62</span>:2294–2299.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11956086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11956086</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>73.</dt><dd><div class="bk_ref" id="ml230.r73">Mitomo H, Kato R, Ito A, Kasamatsu S, Ikegami Y, Kii I, Kudo A, Kobatake E, Sumino Y, Ishikawa T. A functional study on polymorphism of the
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ATP-binding cassette transporter ABCG2: critical role of arginine-482 in
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methotrexate transport. <span><span class="ref-journal">Biochemical
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Journal. </span>2003;<span class="ref-vol">373</span>:767–774.</span> [<a href="/pmc/articles/PMC1223553/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1223553</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12741957" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12741957</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>74.</dt><dd><div class="bk_ref" id="ml230.r74">Ozvegy-Laczka C, Koblos G, Sarkadi B, Varadi A. Single amino acid (482) variants of the ABCG2
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multidrug transporter: major differences in transport capacity and
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substrate recognition. <span><span class="ref-journal">Biochimica et Biophysica
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acta. </span>2005;<span class="ref-vol">1668</span>:53–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15670731" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15670731</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>75.</dt><dd><div class="bk_ref" id="ml230.r75">Winter SS, Lovato DM, Khawaja HM, Edwards BS, Steele ID, Young SM, Oprea TI, Sklar LA, Larson RS. High-throughput screening for
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daunorubicin-mediated drug resistance identifies mometasone furoate as a
|
|
novel ABCB1-reversal agent. <span><span class="ref-journal">J. Biomol.
|
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Screening. </span>2008;<span class="ref-vol">13</span>:185–193.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18310528" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18310528</span></a>]</div></dd></dl></dl></div><div id="ml230.app1"><h2 id="_ml230_app1_">APPENDIX A. NMR Data and LCMS Data for Probe <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID
|
|
44640177)</h2><p id="ml230.f16"><a href="/books/NBK133425/figure/ml230.f16/?report=objectonly" target="object" rid-ob="figobml230f16" class="figpopup">Figure A1. Proton data for SID 88095709 (CID
|
|
44640177)</a></p><p id="ml230.f17"><a href="/books/NBK133425/figure/ml230.f17/?report=objectonly" target="object" rid-ob="figobml230f17" class="figpopup">Figure A2. Carbon data for SID 88095709 (CID
|
|
44640177)</a></p><p id="ml230.f18"><a href="/books/NBK133425/figure/ml230.f18/?report=objectonly" target="object" rid-ob="figobml230f18" class="figpopup">Figure A3. LCMS purity data at 215 nm for SID 88095709 (CID
|
|
44640177)</a></p><p id="ml230.f19"><a href="/books/NBK133425/figure/ml230.f19/?report=objectonly" target="object" rid-ob="figobml230f19" class="figpopup">Figure A4. HRMS data for SID 88095709 (CID 44640177)</a></p></div><div id="ml230.app2"><h2 id="_ml230_app2_">APPENDIX B. Continuation of Section 2.3:
|
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Probe Preparation</h2><p><i>Supporting information for the five analogues submitted with the probe is
|
|
detailed here.</i></p><div id="ml230.fu7" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml230fu25&p=BOOKS&id=133425_ml230fu25.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133425/bin/ml230fu25.jpg" alt="Image ml230fu25" class="tileshop" title="Click on image to zoom" /></a></div></div><p><b>1-(4-(5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)ethanone
|
|
(<a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022055" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 96022055</a>/CID 46173053):</b> Isolated as a tan solid
|
|
(40 mg, 93% yield). <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>)
|
|
<i>δ</i> 7.99 (m, 2H), 7.59 (dd, <i>J</i>
|
|
= 0.7, 1.7 Hz, 1H), 7.47, (m, 2H), 7.40 (m, 1H), 7.19 (dd,
|
|
<i>J</i> = 0.7, 3.5 Hz, 1H), 6.89 (s, 1H), 6.59 (dd,
|
|
<i>J</i> = 1.8, 3.4 Hz, 1H), 6.56 (s, 1H), 3.99 –
|
|
3.91 (m, 4H), 3.84 – 3.79 (m, 2H), 3.78 – 3.72 (m, 2H), 2.20 (s,
|
|
3H). <sup>13</sup>C NMR (125 MHz, CDCl<sub>3</sub>) δ169.2, 155.3,
|
|
152.4, 151.8, 150.1, 148.5, 144.3, 132.9, 129.0, 128.7, 126.4, 112.6, 110.8,
|
|
92.9, 88.8, 48.2, 48.1, 45.8, 40.8, 21.4. LCMS retention time 2.95 min; LCMS
|
|
purity at 215 nm = 100%. HRMS <i>m/z</i> calculated
|
|
for C<sub>22</sub>H<sub>22</sub>N<sub>5</sub>O<sub>2</sub>
|
|
([M+H]<sup>+</sup>): 388.1768, found
|
|
388.1774.</p><div id="ml230.fu8" class="figure"><div class="graphic"><img src="/books/NBK133425/bin/ml230fu26.jpg" alt="Image ml230fu26" /></div></div><p><b>5-(furan-2-yl)-7-(4-(furan-3-ylmethyl)piperazin-1-yl)-2-(p-tolyl)pyrazolo[1,5-a]pyrimidine
|
|
(<a href="https://pubchem.ncbi.nlm.nih.gov/substance/99376134" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 99376134</a>/CID 46912091):</b> A solution of
|
|
(4-(5-(furan-2-yl)-2-(p-tolyl)pyrazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)(furan-3-yl)methanone
|
|
(15 mg, 1.0 eq, 0.033 mmol) in THF (0.75 mL) was added dropwise to a suspension
|
|
of LiAlH<sub>4</sub> (5.0 eq, 0.165 mmol, 6.61 mg) in THF (0.25 mL). The mixture
|
|
was stirred under inert atmosphere at 64 °C for 16 hr. The cooled
|
|
reaction mixture was treated with 10% NaOH and H<sub>2</sub>O, and
|
|
extracted with EtOAc (2 x 15 mL). The combined organic layers were dried
|
|
(MgSO<sub>4</sub>) and concentrated. The residue was purified by
|
|
chromatography to afford
|
|
5-(furan-2-yl)-7-(4-(furan-3-ylmethyl)piperazin-1-yl)-2-(p-tolyl)pyrazolo[1,5-a]pyrimidine
|
|
(3.6 mg, 25%) as light yellow oil. <sup>1</sup>H-NMR (400 MHz,
|
|
CDCl<sub>3</sub>) δ 7.81 (s, 1H), 7.79 (s, 1H), 7.50 (m, 1H),
|
|
7.36-7.34 (m, 2H), 7.10 (dd, <i>J</i> = 3.4, 0.56 Hz, 1H),
|
|
6.76 (s, 1H), 6.50 (dd, <i>J</i> = 3.5, 1.8 Hz, 1H), 6.46 (s,
|
|
1H), 6.39 (m, 1H), 3.83 (m, 4H), 3.46 (s, 2H), 2.72 (m, 4H), 2.34 (s, 3H). LCMS
|
|
retention time 3.72 min; LCMS purity at 215 nm = 85.7%. HRMS
|
|
<i>m/z</i> calculated for
|
|
C<sub>26</sub>H<sub>25</sub>N<sub>5</sub>O<sub>2</sub>
|
|
([M+H]<sup>+</sup>): 440.2081, found
|
|
440.2077.</p><div id="ml230.fu9" class="figure"><div class="graphic"><img src="/books/NBK133425/bin/ml230fu27.jpg" alt="Image ml230fu27" /></div></div><p><b>7-(4-(furan-2-ylmethyl)piperazin-1-yl)-2-(3-methoxyphenyl)-5,6-dimethylpyrazolo[1,5-a]pyrimidine
|
|
(<a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 97301789</a>/CID 46245505):</b> Isolated as a light
|
|
yellow solid (12 mg, 29%). <sup>1</sup>H-NMR (400 MHz, CDCl<sub>3</sub>)
|
|
δ 7.61-7.59 (m, 2H), 7.46 (m, 1H), 7.39 (t, <i>J</i> =
|
|
8.1 Hz, 1H), 6.94 (m, 1H), 6.76 (s, 1H), 6.38 (m, 1H), 6.30 (m, 1H), 3.93 (s,
|
|
3H), 3.70-3.68 (m, 6H), 2.78 (t, <i>J</i> = 4.7 Hz, 4H), 2.54
|
|
(s, 3H), 2.28 (s, 3H). <sup>13</sup>C NMR (125 MHz, CDCl<sub>3</sub>) δ
|
|
160.3, 159.8, 153.6, 151.4, 150.0, 147.5, 142.4, 135.0, 129.6, 119.0, 114.0,
|
|
111.7, 110.1, 109.1, 107.2, 91.5, 55.34, 55.28, 53.5, 49.4, 29.7, 24.2, 14.1
|
|
LCMS retention time: 3.43 min; LCMS purity at 215 nm = 100%.
|
|
HRMS <i>m/z</i> calculated for
|
|
C<sub>24</sub>H<sub>27</sub>N<sub>5</sub>O<sub>2</sub>
|
|
([M+H]<sup>+</sup>): 418.2165, found
|
|
418.2238. Mp 148.4-149.6 °C.</p><div id="ml230.fu10" class="figure"><div class="graphic"><img src="/books/NBK133425/bin/ml230fu28.jpg" alt="Image ml230fu28" /></div></div><p><b>(4-(2,5-di(furan-2-yl)pyrazolo[1,5-</b><b><i>a</i></b><b>]pyrimidin-7-yl)piperazin-1-yl)(furan-3-yl)methanone
|
|
(<a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361155" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 99361155</a>/CID 46905000):</b> Isolated as an off-white
|
|
solid (83 mg, 22% yield). <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>)
|
|
δ 7.79 (dd, 1H); 7.59 (dd, 1H); 7.55 (dd, 1H); 7.48 (dd, 1H); 7.20 (d,
|
|
1H); 6.91 (d, 1H); 6.80 (s, 1H); 6.61 (dd, 1H); 6.59 (dd, 1H); 6.58 (s, 1H);
|
|
6.53 (dd, 1H); 4.03 (bs, 4H); 3.84 (bs, 4H). <sup>13</sup>C NMR (125 MHz,
|
|
CDCl<sub>3</sub>) δ 164.0; 152.3; 151.5; 150.1; 148.7; 148.5; 147.7;
|
|
144.4; 143.8; 143.2; 143.1; 120.6; 112.6; 111.6; 111.0; 110.1; 108.1; 92.7;
|
|
89.1; 48.3; 48.2; 31.5; 30.2. LCMS retention time: 3.016 min; LCMS purity at 215
|
|
nm = 100%. HRMS <i>m/z</i> calculated for
|
|
C<sub>23</sub>H<sub>19</sub>N<sub>5</sub>O<sub>4</sub>
|
|
([M+H]<sup>+</sup>): 430.1437, found:
|
|
430.1514.</p><div id="ml230.fu11" class="figure"><div class="graphic"><img src="/books/NBK133425/bin/ml230fu29.jpg" alt="Image ml230fu29" /></div></div><p><b>1-(4-(5-(furan-2-yl)-2-(3-methoxyphenyl)pyrazolo[1,5-</b><b><i>a</i></b><b>]pyrimidin-7-yl)piperazin-1-yl)ethanone
|
|
(<a href="https://pubchem.ncbi.nlm.nih.gov/substance/99376137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 99376137</a>/CID 46912090):</b> Isolated as a yellow
|
|
solid (22 mg, 6% yield). <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>)
|
|
δ 7.56 (m, 3H); 7.39 (dd, 1H); 7.20 (d, 1H); 6.96 (dd, 1H); 6.88 (s,
|
|
1H); 6.59 (dd, 1H); 6.56 (s, 1H); 3.96 (m, 2H); 3.93 (m, 2H); 3.90 (s, 3H); 3.81
|
|
(m, 2H); 3.74 (m, 2H); 2.20 (s, 3H). <sup>13</sup>C NMR (125 MHz,
|
|
CDCl<sub>3</sub>) δ 169.3; 159.9; 155.2; 152.4; 151.8; 150.0; 148.5;
|
|
144.3; 134.3; 129.8; 119.1; 114.2; 112.6; 112.1; 110.9; 93.1; 88.8; 55.3; 48.2;
|
|
45.8; 31.4; 30.2; 21.4. LCMS retention time: 3.042 min; LCMS purity at 215 nm
|
|
= 100%. HRMS m/z calculated for
|
|
C<sub>23</sub>H<sub>23</sub>N<sub>5</sub>O<sub>3</sub>
|
|
([M+H]<sup>+</sup>): 418.1801, found:
|
|
418.1873.</p></div><div id="ml230.app3"><h2 id="_ml230_app3_">APPENDIX C. Proposed Biological Experimentation for Probe Enhancement</h2><div id="ml230.s38"><h3><i>In vitro</i> methods</h3><p><i>Efflux inhibition primary screen protocol:</i> The assay is
|
|
conducted in 384-well format in a total volume of 15.1 μL. Cells and
|
|
reagents are added sequentially as follows: 1) PBS buffer (5
|
|
μL/well); 2) test compound (0.1 μL/well); 3) drug-resistant
|
|
cells (10 μL/well) pre-stained with the JC-1 substrate at 1
|
|
μM. Final in-well concentration of test compound ranges from 50
|
|
μM to 69 nM over an 18 point dose response and the cell
|
|
concentration is 1 million cells/mL. Nicardipine (50 μM) is added to
|
|
each plate as a pan-inhibition positive control. The plate is rotated
|
|
end-over-end at 4 RPM and 25 °C for 30 minutes and then cell samples
|
|
are analyzed via the HyperCyt® high throughput flow cytometry
|
|
platform. Flow cytometric data for light scatter and fluorescence emission
|
|
at 530 +/− 20 nm (FL1) are collected via CyAn flow cytometer
|
|
(Beckman Coulter). The resulting time-resolved single data file per plate is
|
|
analyzed by HyperView software to determine the compound activity in each
|
|
well. Methods previously published.<sup><a class="bibr" href="#ml230.r52" rid="ml230.r52">52</a></sup></p><p><i>Chemoreversal assay in efflux pump over-expressing cells (trypan
|
|
blue):</i> Cells are incubated with test compound (concentration
|
|
range of 3 logs) over 3 and 7-day periods in the presence of selective agent
|
|
such that a cell concentration of at least 1 X 10<sup>5</sup> cells/mL was
|
|
maintained. Cell viability was determined by trypan blue staining and
|
|
enumeration under light microscopy. A chemoreversal index (Chemoreversal 50,
|
|
CR<sub>50</sub>) is determined from the viability assessment. Using a
|
|
similar approach, direct cytotoxicity index (Toxic Dose 50, TD<sub>50</sub>)
|
|
was determined by assessment of cell death of cells grown in media alone.
|
|
Results were compared with the survival of parental cells in the presence of
|
|
the selective agent (DNR/MTX/Vin/etc.; 100% cell death), as well as
|
|
survival of drug-resistant cells in the presence of the chemotherapeutic
|
|
drug (control yields 100% viability). The difference between the
|
|
CR<sub>50</sub> and the TD<sub>50</sub> give an estimation of the
|
|
<i>in vitro</i> therapeutic index for the test compound.
|
|
Sub-micromolar potency is desired along with a
|
|
TD<sub>50</sub>/CR<sub>50</sub> ratio of at least 10.</p><p><i>Chemoreversal assay in efflux pump over-expressing cells
|
|
(luminescence):</i> Compound dilution plates are made containing
|
|
DMSO control wells and duplicate rows of 100x concentrations of compounds
|
|
half-fold diluted from 1 mM to 3.91 μM. All 96-well assay plates
|
|
contain media only, 1% DMSO, and 1% DMSO +
|
|
potentiating agent control wells along with dose response compound wells
|
|
(assay well concentration range 100 μM to 39.1 nM). Cells are plated
|
|
in opaque white 96-well plates at 2500–5000 cells (depending on cell
|
|
line) in 50 μL RPMI media/well with sub-inhibitor concentrations of
|
|
the corresponding chemotherapeutic drug. Then, 1 μL of compounds
|
|
from dilution plates was added to applicable wells. Plates are allowed to
|
|
incubate ~72 hr, 37°C, 5% CO<sub>2</sub>.
|
|
CellTiter-Glo® is then added to plates following
|
|
manufacturer’s instructions, and plates are read on a plate reader
|
|
to collect fluorescence data. Curve fits were normalized based on viability
|
|
of the control wells containing chemotherapeutic killing agent and a
|
|
comparison was then made similar to what is described for the trypan blue
|
|
methods. This secondary assay has been applied as a means of quickly
|
|
profiling compounds and determining those that will be taken into the more
|
|
labor intensive trypan blue potentiation assay.</p></div><div id="ml230.s39"><h3><i>In vivo</i> animal study methods</h3><p>Due to the defined nature of this study, we will focus on the <i>in
|
|
vivo</i> efficacy of our ABCG2 inhibitor. Our studies will
|
|
demonstrate that we can effectively administer an ABCG2 inhibitor in a
|
|
manner that will lead to <i>in vivo</i> killing of a
|
|
drug-resistant tumor and increased survival. We will also perform limited
|
|
acute toxicity studies and verify that <i>in vivo</i> growth does
|
|
not alter ABCG2 expression.</p><p><i>Model and study design</i>: For the <i>in vivo</i>
|
|
studies, we employ the same cell lines that were used in our <i>in
|
|
vitro</i> screening assays and secondary confirmatory assay.
|
|
Specific-pathogen-free adult CB-17 female SCID mice (5–6 weeks of
|
|
age) weighing 20–25 g, are purchased. Briefly, ABCG2 over-expressing
|
|
Igrov1/T8 cells are injected (5 x 10<sup>6</sup> cells/mouse). Prior to
|
|
injection, Igrov1/T8 cells are maintained in topotecan in order to assure
|
|
continuous expression of ABCG2. Tumors are allowed to grow for 3–4
|
|
weeks or until tumor volumes are greater than ~100 cubic millimeters, at
|
|
which time they are stratified into treatment groups. Treatment is
|
|
administered and we observe the size of the tumor and weight of the mouse
|
|
over a 7 day period. At the end of 7 days, we: 1) sacrifice the animal; 2)
|
|
measure and weigh the tumor (if present); 3) analyze the histology of the
|
|
tumor as well as other organs for evidence of toxicity; and 4) measure the
|
|
expression of ABCG2 receptors on the tumor to determine if <i>in
|
|
vivo</i> growth has altered ABCG2 expression. In our initial
|
|
studies, we have generally observed high survival at 4 weeks
|
|
(>90%) which escalates rapidly with near 100%
|
|
mortality by 6 weeks. This approach is well described elsewhere.<sup><a class="bibr" href="#ml230.r56" rid="ml230.r56">56</a></sup></p><p>In the proposed experimentation, three groups of mice will be studied: 1)
|
|
mice with Igrov11T8 tumors and injected with ABCG2 inhibitor; 2) mice with
|
|
Igrov11T8 tumors that are sham injected; and 3) mice with parental cells
|
|
that are not resistant to topotecan. In the first set of studies, we will
|
|
determine the optimal dose of the ABCG2 inhibitor using primarily Group 1
|
|
mice. Using the <i>in vitro</i> cell killing data as a guide, we
|
|
will test 6 doses of the ABCG2 inhibitor (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/103911215" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 103911215</a>) over 2
|
|
logs of final blood concentration (10 nM to 1 μM). In order to
|
|
assure statistical significance, we will study 5 mice in each group. Results
|
|
will be compared against one group of mice from Groups 2 and 3. The
|
|
reduction of the size of the tumor will be used as the principal factor in
|
|
determining the optimal dose, although toxicity will also be considered.</p><p>In the second set of studies, we will employ all three groups of mice using
|
|
the optimal dose of ABCG2 inhibitor for Group 1. We will examine mice for
|
|
overall survival at 6 weeks (including tumor size and body weight), acute
|
|
toxicity due to the administration of the ABCG2 inhibitor, and tumors to
|
|
make sure that the level of ABCG2 expression is not altered by <i>in
|
|
vivo</i> growth.</p><p><i>Acute toxicity</i>: Since prior information regarding the acute
|
|
toxicity of the ABCG2 inhibitor is not available, body weight and histology
|
|
of liver, kidneys, spleen, lungs, and heart will be obtained and analyzed.
|
|
In addition to standard histologic stains, immunohistochemical stains to
|
|
detect apoptosis will be obtained in order to compare organs and toxicity
|
|
from sham and ABCG2 injected animals.</p><p><i>ABCG2 expression by RT-PCR</i>: We will also measure the RNA
|
|
expression of ABCG2 by RT-PCR in 10 tumors from treated and sham-injected
|
|
mice in order to measure the effects of <i>in vivo</i> growth and
|
|
treatment on the expression of ABCG2 in these tumors. Finally, we will
|
|
perform limited toxicity studies and any acute toxicity leading to cell
|
|
necrosis or other histologic change will be observed. Pharmacokinetic
|
|
sampling and analysis will be performed in subsequent studies outside of
|
|
this proposal.</p><p><i>Regulatory</i>: Mice will be studied and maintained in
|
|
accordance with guidelines of our Institutional Animal Research Committee at
|
|
UNM HSC. We have already obtained IACUC approval.</p></div></div><div style="display:none"><div style="display:none" id="figml230f16"><img alt="Image ml230f16" src-large="/books/NBK133425/bin/ml230f16.jpg" /></div><div style="display:none" id="figml230f17"><img alt="Image ml230f17" src-large="/books/NBK133425/bin/ml230f17.jpg" /></div><div style="display:none" id="figml230f18"><img alt="Image ml230f18" src-large="/books/NBK133425/bin/ml230f18.jpg" /></div><div style="display:none" id="figml230f19"><img alt="Image ml230f19" src-large="/books/NBK133425/bin/ml230f19.jpg" /></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK133425_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">J. Jacob Strouse</span>,<sup>1,4</sup> <span itemprop="author">Irena Ivnitski-Steele</span>,<sup>1,4</sup> <span itemprop="author">Hadya M. Njus</span>,<sup>3</sup> <span itemprop="author">Terry D. Foutz</span>,<sup>1,4</sup> <span itemprop="author">Tuanli Yao</span>,<sup>6</sup> <span itemprop="author">Warren S. Weiner</span>,<sup>6</sup> <span itemprop="author">Chad E. Schroeder</span>,<sup>6</sup> <span itemprop="author">Denise S. Simpson</span>,<sup>6</sup> <span itemprop="author">Brooks E. Maki</span>,<sup>6</sup> <span itemprop="author">Kelin Li</span>,<sup>6</sup> <span itemprop="author">Jennifer E. Golden</span>,<sup>6</sup> <span itemprop="author">Anna Waller</span>,<sup>1,4</sup> <span itemprop="author">Annette M. Evangelisti</span>,<sup>1,4</sup> <span itemprop="author">Susan M. Young</span>,<sup>1,4</sup> <span itemprop="author">Dominique Perez</span>,<sup>1,4</sup> <span itemprop="author">Stephanie E. Chavez</span>,<sup>1,4</sup> <span itemprop="author">Mathew J. Garcia</span>,<sup>1,4</sup> <span itemprop="author">Oleg Ursu</span>,<sup>4,5</sup> <span itemprop="author">Dan C. Fara</span>,<sup>4,5</sup> <span itemprop="author">Cristian G. Bologa</span>,<sup>4,5</sup> <span itemprop="author">Mark B. Carter</span>,<sup>1,4</sup> <span itemprop="author">Virginia M. Salas</span>,<sup>1,4</sup> <span itemprop="author">George P. Tegos</span>,<sup>3,4</sup> <span itemprop="author">Tudor I. Oprea</span>,<sup>4,5</sup> <span itemprop="author">Bruce S. Edwards</span>,<sup>1,3,4</sup> <span itemprop="author">Richard S. Larson</span>,<sup>2,3</sup> <span itemprop="author">Jeffrey Aubé</span>,<sup>6,7</sup> and <span itemprop="author">Larry A. Sklar</span><sup>1,3,4</sup><sup>,*</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
|
|
Cytometry, Cancer Research and Treatment Center, Albuquerque, NM.</div><div class="affiliation"><sup>2</sup>
|
|
Office of Research, Cancer Research and Treatment Center, Albuquerque,
|
|
NM.</div><div class="affiliation"><sup>3</sup>
|
|
Department of Pathology, Cancer Research and Treatment Center,
|
|
Albuquerque, NM.</div><div class="affiliation"><sup>4</sup>
|
|
University of New Mexico Center for Molecular Discovery, Albuquerque,
|
|
NM.</div><div class="affiliation"><sup>5</sup>
|
|
Division of Biocomputing, University of New Mexico Health Sciences
|
|
Center, Albuquerque, NM.</div><div class="affiliation"><sup>6</sup>
|
|
University of Kansas Specialized Chemistry Center, Lawrence, KS.</div><div class="affiliation"><sup>7</sup>
|
|
Department of Medicinal Chemistry, University of Kansas, Lawrence,
|
|
KS.</div><div class="affiliation">
|
|
<sup>*</sup> Corresponding author: Larry A. Sklar, Ph.D. – E-mail
|
|
<a href="mailto:dev@null" data-email="ude.mnu.dulas@ralksl" class="oemail">ude.mnu.dulas@ralksl</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">November 30, 2010</span>; Last Update: <span itemprop="dateModified">February 25, 2013</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Strouse JJ, Ivnitski-Steele I, Njus HM, et al. Selective Efflux Inhibition of ATP-binding Cassette Sub-family G Member 2. 2010 Nov 30 [Updated 2013 Feb 25]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml231/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml229/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml230fu1"><div id="ml230.fu1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230fu1.jpg" alt="ML230." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML230[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML230</a></span></h3></div></article><article data-type="table-wrap" id="figobml230tu1"><div id="ml230.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133425/table/ml230.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml230.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml230.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID/ML#</th><th id="hd_h_ml230.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target Name</th><th id="hd_h_ml230.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">EC<sub>50</sub> (nM) [SID,
|
|
AID]</th><th id="hd_h_ml230.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-target Name(s)</th><th id="hd_h_ml230.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">EC<sub>50</sub> (μM)
|
|
[SID, AID]</th><th id="hd_h_ml230.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fold Selective</th><th id="hd_h_ml230.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay(s) Name
|
|
ER<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml230.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 44640177/<a href="/pcsubstance/?term=ML230[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML230</a></td><td headers="hd_h_ml230.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ABCG2</td><td headers="hd_h_ml230.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">EC<sub>50</sub> = 130 nM
|
|
[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504566" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID
|
|
504566</a>]</td><td headers="hd_h_ml230.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ABCB1</td><td headers="hd_h_ml230.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">EC<sub>50</sub> = 4.65
|
|
μM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>,
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504569" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504569</a>]</td><td headers="hd_h_ml230.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">36</td><td headers="hd_h_ml230.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Chemoreversal<br />CR<sub>50</sub>
|
|
= 310 nM<br />TD<sub>50</sub> = 18300 nM
|
|
[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/8895709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 8895709</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504477" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID
|
|
504477</a>]</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml230f1"><div id="ml230.f1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%201.%20Structures%20of%20small%20molecules%20chosen%20for%20direct%20experimental%20comparison.&p=BOOKS&id=133425_ml230f1.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f1.jpg" alt="Figure 1. Structures of small molecules chosen for direct experimental comparison." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 1</span><span class="title">Structures of small molecules chosen for direct experimental
|
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comparison</span></h3></div></article><article data-type="fig" id="figobml230f13"><div id="ml230.f13" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%2013.%20Quantitative%20comparison%20of%20prior%20art%20to%20SID%2088095709.&p=BOOKS&id=133425_ml230f13.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f13.jpg" alt="Figure 13. Quantitative comparison of prior art to SID 88095709." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 13</span><span class="title">Quantitative comparison of prior art to <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a></span></h3></div></article><article data-type="fig" id="figobml230fu2"><div id="ml230.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230fu2.jpg" alt="Image ml230fu2" /></div></div></article><article data-type="fig" id="figobml230fu3"><div id="ml230.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230fu3.jpg" alt="Image ml230fu3" /></div></div></article><article data-type="fig" id="figobml230f2"><div id="ml230.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230f2.jpg" alt="Figure 2. Property summary of probe compound SID 88095709 (CID 44640177)." /></div><h3><span class="label">Figure 2</span><span class="title">Property summary of probe compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID 44640177)</span></h3></div></article><article data-type="fig" id="figobml230f3"><div id="ml230.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%20Aqueous%20stability%20of%20compound%20SID%2088095709%20(CID%2044640177)%20in%20PBS%20and%20no%20acetonitrile%20(closed%20circles)%2C%20and%20aqueous%20stability%20of%20compound%20SID%2088095709%20(CID%2044640177)%20in%20PBS%20with%20the%20addition%20of%20acetonitrile%20(50%25%20v%2Fv%20final%2C%20closed%20triangles).&p=BOOKS&id=133425_ml230f3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f3.jpg" alt="Figure 3. Aqueous stability of compound SID 88095709 (CID 44640177) in PBS and no acetonitrile (closed circles), and aqueous stability of compound SID 88095709 (CID 44640177) in PBS with the addition of acetonitrile (50% v/v final, closed triangles)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title">Aqueous stability of compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>
|
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(CID 44640177) in PBS and no acetonitrile (closed circles), and
|
|
aqueous stability of compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a>
|
|
(CID 44640177) in PBS with the addition of acetonitrile (50%
|
|
v/v final, closed triangles)</span></h3></div></article><article data-type="fig" id="figobml230f4"><div id="ml230.f4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20General%20synthetic%20route%20for%20probe%20and%20associated%20analogues.&p=BOOKS&id=133425_ml230f4.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f4.jpg" alt="Figure 4. General synthetic route for probe and associated analogues." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">General synthetic route for probe and associated
|
|
analogues</span></h3></div></article><article data-type="fig" id="figobml230f5"><div id="ml230.f5" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%205.%20Five%20analogues%20submitted%20to%20support%20probe%20SID%2088095709%20(CID%2044640177).&p=BOOKS&id=133425_ml230f5.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f5.jpg" alt="Figure 5. Five analogues submitted to support probe SID 88095709 (CID 44640177)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 5</span><span class="title">Five analogues submitted to support probe <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID 44640177)</span></h3></div></article><article data-type="fig" id="figobml230fu4"><div id="ml230.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230fu4.jpg" alt="Image ml230fu4" /></div></div></article><article data-type="fig" id="figobml230fu5"><div id="ml230.fu5" class="figure"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230fu5.jpg" alt="Image ml230fu5" /></div></div></article><article data-type="fig" id="figobml230fu6"><div id="ml230.fu6" class="figure"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230fu6.jpg" alt="Image ml230fu6" /></div></div></article><article data-type="fig" id="figobml230f6"><div id="ml230.f6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%206.%20Screening%20flow%20chart.&p=BOOKS&id=133425_ml230f6.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f6.jpg" alt="Figure 6. Screening flow chart." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 6</span><span class="title">Screening flow chart</span></h3></div></article><article data-type="fig" id="figobml230f7"><div id="ml230.f7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230f7.jpg" alt="Figure 7. Validated hit resulting from the preliminary commercial SAR effort." /></div><h3><span class="label">Figure 7</span><span class="title">Validated hit resulting from the preliminary commercial SAR
|
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effort</span></h3></div></article><article data-type="fig" id="figobml230f8"><div id="ml230.f8" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%208.%20Efflux%20inhibition%20and%20chemotherapeutic%20potentiation%20of%20SID%2088095709%20(CID%2044640177).&p=BOOKS&id=133425_ml230f8.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f8.jpg" alt="Figure 8. Efflux inhibition and chemotherapeutic potentiation of SID 88095709 (CID 44640177)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 8</span><span class="title">Efflux inhibition and chemotherapeutic potentiation of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
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88095709</a> (CID 44640177)</span></h3><div class="caption"><p><b>A</b>) A representative curve showing efflux inhibition of ABCB1
|
|
in Jurkat-DNR cells (closed circles). The average IC<sub>50</sub> (n
|
|
= 3) is 4.7 ± 0.5 μM. <b>B</b>) A
|
|
representative curve showing efflux inhibition of ABCG2 in Ig-MXP3 cells
|
|
(open circles). The average IC<sub>50</sub> (n = 2) is 0.13
|
|
± 0.30 μM <b>C</b>) Potentiation of DNR mediated
|
|
killing in Jurkat-DNR cells with <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (n
|
|
= 2 per data point). The CR<sub>50</sub> (closed triangles) is
|
|
0.55 μM while the TD<sub>50</sub> (closed squares) is 5.5
|
|
μM. Minimum allowable toxicity is set at 15 μM, thus the
|
|
toxicity here is below the cut-off. <b>D</b>) Potentiation of MTX
|
|
mediated killing in Ig-MXP3 cells (n = 2 per data point). The
|
|
CR<sub>50</sub> (open triangles) is 0.31 μM while the
|
|
TD<sub>50</sub> (open squares) is 18.3 μM. The minimum
|
|
toxicity and the CR<sub>50</sub>/TD<sub>50</sub> ratio (equal to 59)
|
|
meet the cut-off criteria for a desirable compound in the chemoreversal
|
|
secondary ABCG2 assay.</p></div></div></article><article data-type="fig" id="figobml230f9"><div id="ml230.f9" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230f9.jpg" alt="Figure 9. Focus of SAR expansion efforts based on primary efflux data." /></div><h3><span class="label">Figure 9</span><span class="title">Focus of SAR expansion efforts based on primary efflux data</span></h3></div></article><article data-type="table-wrap" id="figobml230t1"><div id="ml230.t1" class="table"><h3><span class="label">Table 1</span><span class="title">SAR expansion on initial hit <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
|
|
85240370</a></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133425/table/ml230.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml230.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml230.t1_1_1_1_1" rowspan="3" colspan="1" headers="hd_h_ml230.t1_1_1_1_1" style="text-align:center;vertical-align:middle;">Entry</th><th id="hd_h_ml230.t1_1_1_1_2" rowspan="3" colspan="1" headers="hd_h_ml230.t1_1_1_1_2" style="text-align:center;vertical-align:middle;">SID/CID</th><th id="hd_h_ml230.t1_1_1_1_3" rowspan="3" colspan="1" headers="hd_h_ml230.t1_1_1_1_3" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th id="hd_h_ml230.t1_1_1_1_4" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">
|
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu7.jpg" alt="Image ml230fu7.jpg" /></div></th><th id="hd_h_ml230.t1_1_1_1_5" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Potency (μM)
|
|
mean (n = # replicates)</th><th id="hd_h_ml230.t1_1_1_1_6" rowspan="3" colspan="1" headers="hd_h_ml230.t1_1_1_1_6" style="text-align:center;vertical-align:middle;">Selectivity
|
|
B1:G2</th><th id="hd_h_ml230.t1_1_1_1_7" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Potentiation
|
|
Assays</th></tr><tr><th headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" id="hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R1</th><th headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" id="hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R2</th><th headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" id="hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R3</th><th headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" id="hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R4</th><th headers="hd_h_ml230.t1_1_1_1_5" id="hd_h_ml230.t1_1_1_2_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t1_1_1_1_5" id="hd_h_ml230.t1_1_1_2_6" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th><th headers="hd_h_ml230.t1_1_1_1_7" id="hd_h_ml230.t1_1_1_2_7" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t1_1_1_1_7" id="hd_h_ml230.t1_1_1_2_8" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th></tr><tr><th headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5" id="hd_h_ml230.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5" id="hd_h_ml230.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
|
|
(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6" id="hd_h_ml230.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6" id="hd_h_ml230.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
|
|
(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7" id="hd_h_ml230.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7" id="hd_h_ml230.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7" id="hd_h_ml230.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
|
|
CR<sub>50</sub></th><th headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8" id="hd_h_ml230.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8" id="hd_h_ml230.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8" id="hd_h_ml230.t1_1_1_3_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
|
|
CR<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID644556</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">methyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">methyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-2 furan</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8.40 (123)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.64 (105)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.2</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.58</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">63</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.17</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">47.40</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">282</td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240363" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID85240363</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID652994</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">methyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-2 furan</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.88 (60)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.78 (82)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.1</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240365" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID85240365</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID1441553</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-2 furan</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.18 (69)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.96 (66)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.4</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.25</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.77</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.14</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.00</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID85240370</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640182</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3 furan</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8.58 (144)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.19 (115)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7.2</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095708" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095708</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44607976</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-thiophene</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.97 (128)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.40 (87)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.9</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87457381" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87457381</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44602407</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO- phenyl</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.42 (115)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.45 (107)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87550711" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87550711</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45105078</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-2-MeO-Ph</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.73 (45)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.92 (44)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.9</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92123926" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92123926</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45105074</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-MeO-Ph</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.64 (70)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.45 (44)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.6</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.35</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">289</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.21</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">100.80</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">492</td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92123925" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92123925</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">9</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45105073</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-4-MeO-Ph</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.89 (65)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.73 (45)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.7</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92123919" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92123919</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45105075</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-2-Cl-Ph</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.85 (20)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.31 (33)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.5</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92123923" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92123923</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45105080</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-Cl-Ph</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.19 (20)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.95 (19)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.4</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92123920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92123920</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">12</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45105081</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-4-Cl-Ph</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.36 (15)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.67 (19)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.9</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92123921" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92123921</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">13</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44623842</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-pyridine</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.57 (165)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.234 (137)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.17</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.72</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.13</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10.30</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87550712" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87550712</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">14</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44630540</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-4-pyridine</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.16 (158)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.03 (142)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.2</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.25</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10.90</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.15</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">28.30</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">190</td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87577986" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87577986</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">15</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45281172</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO- cyclohexyl</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.31 (10)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.67 (21)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.2</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92764888" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92764888</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">16</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44602405</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">COCH<sub>3</sub></td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.67 (222)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.07 (169)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.9</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87350360" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87350360</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">17</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45105082</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-Bn</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.68 (27)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.76 (37)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.8</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.51</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">17.80</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">35</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.60</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">167</td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92123924" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92123924</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">18</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44607585</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">SO<sub>2-</sub>phenyl</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">50.00</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">50.00</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NA</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87357357" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87357357</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">19</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44631077</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-F phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3- furan</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.69 (87)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.93 (95)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87677875" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87677875</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44629741</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-F phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3- furan</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.65 (128)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.41 (101)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.3</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87557812" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87557812</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">21</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44630538</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-MeO phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3- furan</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.17 (123)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.14 (101)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.9</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87577985" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87577985</a></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">22</td><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44629740</td><td headers="hd_h_ml230.t1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-MeO phenyl</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t1_1_1_1_4 hd_h_ml230.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3- furan</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_5 hd_h_ml230.t1_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.12 (131)</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t1_1_1_1_5 hd_h_ml230.t1_1_1_2_6 hd_h_ml230.t1_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.71 (98)</td><td headers="hd_h_ml230.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_7 hd_h_ml230.t1_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t1_1_1_1_7 hd_h_ml230.t1_1_1_2_8 hd_h_ml230.t1_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87557813" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87557813</a></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml230.tfn1"><p class="no_margin">Percent Response;</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml230.tfn2"><p class="no_margin">S = synthesized; P = purchased; NT = not
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tested</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml230t2"><div id="ml230.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Continuation of SAR expansion on initial hit <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
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85240370</a></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133425/table/ml230.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml230.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml230.t2_1_1_1_1" rowspan="3" colspan="1" headers="hd_h_ml230.t2_1_1_1_1" style="text-align:center;vertical-align:middle;">Entry</th><th id="hd_h_ml230.t2_1_1_1_2" rowspan="3" colspan="1" headers="hd_h_ml230.t2_1_1_1_2" style="text-align:center;vertical-align:middle;">SID/CID</th><th id="hd_h_ml230.t2_1_1_1_3" rowspan="3" colspan="1" headers="hd_h_ml230.t2_1_1_1_3" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th id="hd_h_ml230.t2_1_1_1_4" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu8.jpg" alt="Image ml230fu8.jpg" /></div></th><th id="hd_h_ml230.t2_1_1_1_5" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Potency (μM)
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mean (n = # replicates)</th><th id="hd_h_ml230.t2_1_1_1_6" rowspan="3" colspan="1" headers="hd_h_ml230.t2_1_1_1_6" style="text-align:center;vertical-align:middle;">Selectivity
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B1:G2</th><th id="hd_h_ml230.t2_1_1_1_7" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Potentiation
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Assays</th></tr><tr><th headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" id="hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R1</th><th headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" id="hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R2</th><th headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" id="hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R3</th><th headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" id="hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R4</th><th headers="hd_h_ml230.t2_1_1_1_5" id="hd_h_ml230.t2_1_1_2_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t2_1_1_1_5" id="hd_h_ml230.t2_1_1_2_6" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th><th headers="hd_h_ml230.t2_1_1_1_7" id="hd_h_ml230.t2_1_1_2_7" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t2_1_1_1_7" id="hd_h_ml230.t2_1_1_2_8" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th></tr><tr><th headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5" id="hd_h_ml230.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5" id="hd_h_ml230.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6" id="hd_h_ml230.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6" id="hd_h_ml230.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7" id="hd_h_ml230.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7" id="hd_h_ml230.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7" id="hd_h_ml230.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th><th headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8" id="hd_h_ml230.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8" id="hd_h_ml230.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8" id="hd_h_ml230.t2_1_1_3_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">23</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44629742</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3- pyridine</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.77 (132)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.27 (99)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.7</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.20</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.33</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.02</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.77</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87557811" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87557811</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">24</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44630541</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4- pyridine</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.68 (63)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.46 (88)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.5</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.60</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">13.50</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.89</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">57.80</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">65</td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87577984" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87577984</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">25</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44631078</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">ethyne</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10.16 (157)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.36 (115)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.3</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87677876" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87677876</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">26</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44623844</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-Br- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.31 (1.7)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.76 (98)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.7</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87550709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87550709</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">27</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640183</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-MeO- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.17 (130)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.45 (107)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.8</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.45</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.37</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.49</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.50</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095704" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095704</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">28</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44623840</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-MeO- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.26 (136)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.14 (118)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.0</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87550708" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87550708</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">29</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44607592</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-MeO- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.44 (170)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.16 (94)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.2</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.23</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.54</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.38</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">263</td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87357359" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87357359</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">30</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640176</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-MeO- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-2-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.00 (121)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.03 (101)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.9</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095711" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095711</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">31</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44968166</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-MeO- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-2-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.77 (135)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.40 (113)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.4</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944695" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID90944695</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">32</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID492424</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-Cl- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-2-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.63 (80)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.37 (67)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.6</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240373" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID85240373</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">33</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45105079</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Me- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-2-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.88 (102)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.46 (46)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.0</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92123922" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92123922</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">34</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640179</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-MeO- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-phenyl</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.31 (158)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.76 (11)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.9</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095712" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095712</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">35</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44968164</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-F- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-phenyl</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.34 (130)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.27 (123)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.9</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944697" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID90944697</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">36</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44968158</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-F- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-phenyl</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.99 (124)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.03 (111)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.0</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944698" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID90944698</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">37</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640177</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-furan</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.65 (112)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.13 (98)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">35.8</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.55</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.52</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.31</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">18.30</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">59</td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095709</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">38</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905002</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-MeO- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.52 (116)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.66 (99)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.2</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.17</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.73</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.68</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7.62</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361146" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361146</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">39</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905009</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-MeO- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.55 (127)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.37 (84)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.9</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361144" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361144</a></td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">40</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46904993</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-F- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.61 (133)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.56 (95)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10.0</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361147" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361147</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">41</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905008</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-F- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7.07 (145)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.68 (112)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.2</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361145" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361145</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">42</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46904994</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-F- phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11.82 (102)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.45 (106)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.8</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361149" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361149</a></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">43</td><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905006</td><td headers="hd_h_ml230.t2_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">t-Butyl</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t2_1_1_1_4 hd_h_ml230.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_5 hd_h_ml230.t2_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.62 (94)</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t2_1_1_1_5 hd_h_ml230.t2_1_1_2_6 hd_h_ml230.t2_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">25.90 (104)</td><td headers="hd_h_ml230.t2_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.2</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_7 hd_h_ml230.t2_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t2_1_1_1_7 hd_h_ml230.t2_1_1_2_8 hd_h_ml230.t2_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361157" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361157</a></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml230.tfn3"><p class="no_margin">Percent Response;</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml230.tfn4"><p class="no_margin">S = synthesized; P = purchased; NT = not
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tested</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml230f10"><div id="ml230.f10" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%2010.%20Parent%20hit%20SID%2085240370%20modified%20to%20a%20new%20lead%2C%20SID%2088095709.&p=BOOKS&id=133425_ml230f10.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f10.jpg" alt="Figure 10. Parent hit SID 85240370 modified to a new lead, SID 88095709." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 10</span><span class="title">Parent hit <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85240370</a> modified to a new lead,
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a></span></h3></div></article><article data-type="table-wrap" id="figobml230t3"><div id="ml230.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Summary of modifications for R1</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133425/table/ml230.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml230.t3_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml230.t3_1_1_1_1" rowspan="3" colspan="1" headers="hd_h_ml230.t3_1_1_1_1" style="text-align:center;vertical-align:middle;">Entry</th><th id="hd_h_ml230.t3_1_1_1_2" rowspan="3" colspan="1" headers="hd_h_ml230.t3_1_1_1_2" style="text-align:center;vertical-align:middle;">SID/CID</th><th id="hd_h_ml230.t3_1_1_1_3" rowspan="3" colspan="1" headers="hd_h_ml230.t3_1_1_1_3" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th id="hd_h_ml230.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu9.jpg" alt="Image ml230fu9.jpg" /></div></th><th id="hd_h_ml230.t3_1_1_1_5" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Efflux Assay Potency
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(μM) mean (n = # replicates)</th><th id="hd_h_ml230.t3_1_1_1_6" rowspan="3" colspan="1" headers="hd_h_ml230.t3_1_1_1_6" style="text-align:center;vertical-align:middle;">Selectivity
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B1:G2</th><th id="hd_h_ml230.t3_1_1_1_7" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Potentiation
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Assays</th></tr><tr><th headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" id="hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R1</th><th headers="hd_h_ml230.t3_1_1_1_5" id="hd_h_ml230.t3_1_1_2_2" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t3_1_1_1_5" id="hd_h_ml230.t3_1_1_2_3" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th><th headers="hd_h_ml230.t3_1_1_1_7" id="hd_h_ml230.t3_1_1_2_4" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t3_1_1_1_7" id="hd_h_ml230.t3_1_1_2_5" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th></tr><tr><th headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2" id="hd_h_ml230.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2" id="hd_h_ml230.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
|
|
(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3" id="hd_h_ml230.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3" id="hd_h_ml230.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
|
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4" id="hd_h_ml230.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4" id="hd_h_ml230.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4" id="hd_h_ml230.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
|
|
CR<sub>50</sub></th><th headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5" id="hd_h_ml230.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5" id="hd_h_ml230.t3_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5" id="hd_h_ml230.t3_1_1_3_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095709</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.65 (112)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.13 (98)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">35.8</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.55</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.52</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.31</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">18.30</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">59</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640177</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99376135" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99376135</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">t-butyl</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.31 (89)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.97 (102)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.7</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46912088</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361154" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361154</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2- thiophene</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8.42 (107)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.56 (100)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.4</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905003</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361155" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361155</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-furan</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.70 (84)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.35 (99)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.7</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.19</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.93</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.21</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">83</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905000</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92123918" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92123918</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl- phenyl</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.42 (112)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.55 (84)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.5</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.53</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8.53</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.38</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10.80</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45105077</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361153" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361153</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-Cl- phenyl</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">41.54 (79)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.89 (101)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">22.0</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46904995</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361150" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361150</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-MeO- phenyl</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.57 (124)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.76 (104)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.0</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905004</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92764890" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID92764890</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-MeO- phenyl</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7.40 (89)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.26 (78)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.3</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.47</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.52</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.00</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">100</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45281176</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">9</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/93619266" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID93619266</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-MeO- phenyl</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.45 (51)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.89 (68)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.9</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.77</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">17</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.76</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">131</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45489721</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361151" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361151</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Me- phenyl</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.45 (123)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.58 (103)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.0</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905007</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361152" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361152</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-Me- phenyl</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11.27 (109)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.19 (102)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.2</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46904998</td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">12</td><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095710" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095710</a></td><td headers="hd_h_ml230.t3_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t3_1_1_1_4 hd_h_ml230.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-(2-furyl)-
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phenyl</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_2 hd_h_ml230.t3_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.98 (100)</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t3_1_1_1_5 hd_h_ml230.t3_1_1_2_3 hd_h_ml230.t3_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.93 (82)</td><td headers="hd_h_ml230.t3_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.3</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_4 hd_h_ml230.t3_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t3_1_1_1_7 hd_h_ml230.t3_1_1_2_5 hd_h_ml230.t3_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640180</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml230.tfn5"><p class="no_margin">Percent Response;</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml230.tfn6"><p class="no_margin">S = synthesized; P = purchased; NT = not
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tested</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml230t4"><div id="ml230.t4" class="table"><h3><span class="label">Table 4</span><span class="title">Summary of modifications for R2</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133425/table/ml230.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml230.t4_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml230.t4_1_1_1_1" rowspan="3" colspan="1" headers="hd_h_ml230.t4_1_1_1_1" style="text-align:center;vertical-align:middle;">Entry</th><th id="hd_h_ml230.t4_1_1_1_2" rowspan="3" colspan="1" headers="hd_h_ml230.t4_1_1_1_2" style="text-align:center;vertical-align:middle;">SID/CID</th><th id="hd_h_ml230.t4_1_1_1_3" rowspan="3" colspan="1" headers="hd_h_ml230.t4_1_1_1_3" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th id="hd_h_ml230.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu10.jpg" alt="Image ml230fu10.jpg" /></div></th><th id="hd_h_ml230.t4_1_1_1_5" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Efflux Assay Potency
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(μM) mean (n = # replicates)</th><th id="hd_h_ml230.t4_1_1_1_6" rowspan="3" colspan="1" headers="hd_h_ml230.t4_1_1_1_6" style="text-align:center;vertical-align:middle;">Selectivity
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B1:G2</th><th id="hd_h_ml230.t4_1_1_1_7" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Potentiation
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Assays</th></tr><tr><th headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" id="hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>2</sub></th><th headers="hd_h_ml230.t4_1_1_1_5" id="hd_h_ml230.t4_1_1_2_2" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t4_1_1_1_5" id="hd_h_ml230.t4_1_1_2_3" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th><th headers="hd_h_ml230.t4_1_1_1_7" id="hd_h_ml230.t4_1_1_2_4" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t4_1_1_1_7" id="hd_h_ml230.t4_1_1_2_5" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th></tr><tr><th headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2" id="hd_h_ml230.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2" id="hd_h_ml230.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3" id="hd_h_ml230.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3" id="hd_h_ml230.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4" id="hd_h_ml230.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4" id="hd_h_ml230.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4" id="hd_h_ml230.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th><th headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5" id="hd_h_ml230.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5" id="hd_h_ml230.t4_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5" id="hd_h_ml230.t4_1_1_3_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095709</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-furyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.65 (112)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.13 (98)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">35.8</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.55</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.52</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.31</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">18.30</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">59</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640177</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361159" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361159</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-furyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.60 (107)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.4 (106)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.1</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.42</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7.33</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.76</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">18.30</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">24</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905005</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87350359" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87350359</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.79 (172)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.58 (96)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.0</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44602406</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87357354" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87357354</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">methyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">15.81 (98)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7.27 (88)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.2</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44607586</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361157" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361157</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">tert-butyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.62 (94)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">25.9 (104)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.2</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905006</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361156" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361156</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-thiophene</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.46 (120)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.64 (95)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.1</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905001</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361146" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361146</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-MeO-phenyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.52 (116)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.66 (99)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.2</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.17</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.73</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.68</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7.62</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905002</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361148" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361148</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-MeO-phenyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">16.42 (127)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.20 (104)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">82.7</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.18</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.77</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.68</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">67.80</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">100</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46904996</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">9</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361144" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361144</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-MeO-phenyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.55 (127)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.37 (84)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.9</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905009</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361147" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361147</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-F-phenyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.61 (133)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.56 (95)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10.0</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46904993</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361145" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361145</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-F-phenyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7.07 (145)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.68 (112)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.2</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46905008</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">12</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361149" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361149</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-F-phenyl</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11.82 (102)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.45 (106)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.8</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46904994</td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">13</td><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99361158" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99361158</a></td><td headers="hd_h_ml230.t4_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t4_1_1_1_4 hd_h_ml230.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-(5-methyl-furan)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_2 hd_h_ml230.t4_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.68 (57)</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t4_1_1_1_5 hd_h_ml230.t4_1_1_2_3 hd_h_ml230.t4_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.84 (85)</td><td headers="hd_h_ml230.t4_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.8</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_4 hd_h_ml230.t4_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t4_1_1_1_7 hd_h_ml230.t4_1_1_2_5 hd_h_ml230.t4_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46904999</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml230.tfn7"><p class="no_margin">Percent Response;</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml230.tfn8"><p class="no_margin">S = synthesized; P = purchased; NT = not
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tested</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml230f11"><div id="ml230.f11" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230f11.jpg" alt="Figure 11. Effect of R3 alkyl substitution." /></div><h3><span class="label">Figure 11</span><span class="title">Effect of R3 alkyl substitution</span></h3></div></article><article data-type="table-wrap" id="figobml230t5"><div id="ml230.t5" class="table"><h3><span class="label">Table 5</span><span class="title">Summary of modifications for R4</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133425/table/ml230.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml230.t5_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml230.t5_1_1_1_1" rowspan="3" colspan="1" headers="hd_h_ml230.t5_1_1_1_1" style="text-align:center;vertical-align:middle;">Entry</th><th id="hd_h_ml230.t5_1_1_1_2" rowspan="3" colspan="1" headers="hd_h_ml230.t5_1_1_1_2" style="text-align:center;vertical-align:middle;">SID/CID</th><th id="hd_h_ml230.t5_1_1_1_3" rowspan="3" colspan="1" headers="hd_h_ml230.t5_1_1_1_3" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th id="hd_h_ml230.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu11.jpg" alt="Image ml230fu11.jpg" /></div></th><th id="hd_h_ml230.t5_1_1_1_5" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Efflux Assay Potency
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(μM) mean (n = # replicates)</th><th id="hd_h_ml230.t5_1_1_1_6" rowspan="3" colspan="1" headers="hd_h_ml230.t5_1_1_1_6" style="text-align:center;vertical-align:middle;">Selectivity
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B1:G2</th><th id="hd_h_ml230.t5_1_1_1_7" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Potentiation
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Assays</th></tr><tr><th headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" id="hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R4</th><th headers="hd_h_ml230.t5_1_1_1_5" id="hd_h_ml230.t5_1_1_2_2" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t5_1_1_1_5" id="hd_h_ml230.t5_1_1_2_3" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th><th headers="hd_h_ml230.t5_1_1_1_7" id="hd_h_ml230.t5_1_1_2_4" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t5_1_1_1_7" id="hd_h_ml230.t5_1_1_2_5" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th></tr><tr><th headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2" id="hd_h_ml230.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2" id="hd_h_ml230.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3" id="hd_h_ml230.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3" id="hd_h_ml230.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4" id="hd_h_ml230.t5_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4" id="hd_h_ml230.t5_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4" id="hd_h_ml230.t5_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th><th headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5" id="hd_h_ml230.t5_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5" id="hd_h_ml230.t5_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5" id="hd_h_ml230.t5_1_1_3_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095709</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-furan</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.65 (112)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.13 (98)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">35.8</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.55</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.52</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.31</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">18.30</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">59</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640177</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022056" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022056</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-2-furan</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.57 (68)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.77 (71)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173049</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022058" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022058</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3- thiophene</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.93 (58)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.38 (48)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.6</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173055</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022057" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022057</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-phenyl</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.56 (61)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.62 (62)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.4</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173043</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022050" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022050</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-
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(2-Me-furan)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11.9 (58)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.33 (65)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.1</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173050</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022052" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022052</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-
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(2,4-diMe-furan)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7.32 (54)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.68 (63)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.0</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173047</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022053" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022053</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3-
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(2,5-diMe-furan)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">12 (74)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.37 (65)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.6</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173046</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022054" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022054</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3- benzofuran</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8.83 (78)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.84 (42)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.1</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173052</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">9</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022055" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022055</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">COCH<sub>3</sub></td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.63 (71)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.52 (52)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.9</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.19</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10.10</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.93</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">108</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173053</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/93619269" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID93619269</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CH<sub>2</sub>-phenyl</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8.99 (84)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.07 (66)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.9</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45489722</td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11</td><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/93619263" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID93619263</a></td><td headers="hd_h_ml230.t5_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t5_1_1_1_4 hd_h_ml230.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO<sub>2</sub>-benzyl</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_2 hd_h_ml230.t5_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">50 (NA)</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t5_1_1_1_5 hd_h_ml230.t5_1_1_2_3 hd_h_ml230.t5_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.71 (59)</td><td headers="hd_h_ml230.t5_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">18.5</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_4 hd_h_ml230.t5_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t5_1_1_1_7 hd_h_ml230.t5_1_1_2_5 hd_h_ml230.t5_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45489719</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml230.tfn9"><p class="no_margin">Percent Response;</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml230.tfn10"><p class="no_margin">S = synthesized; P = purchased; NT = not
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tested</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml230t6"><div id="ml230.t6" class="table"><h3><span class="label">Table 6</span><span class="title">Summary of piperazine and combined R4 modifications (X)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133425/table/ml230.t6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml230.t6_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml230.t6_1_1_1_1" rowspan="3" colspan="1" headers="hd_h_ml230.t6_1_1_1_1" style="text-align:center;vertical-align:middle;">Entry</th><th id="hd_h_ml230.t6_1_1_1_2" rowspan="3" colspan="1" headers="hd_h_ml230.t6_1_1_1_2" style="text-align:center;vertical-align:middle;">SID/CID</th><th id="hd_h_ml230.t6_1_1_1_3" rowspan="3" colspan="1" headers="hd_h_ml230.t6_1_1_1_3" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th id="hd_h_ml230.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu12.jpg" alt="Image ml230fu12.jpg" /></div></th><th id="hd_h_ml230.t6_1_1_1_5" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Efflux Assay Potency
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(μM) mean (n = # replicates)</th><th id="hd_h_ml230.t6_1_1_1_6" rowspan="3" colspan="1" headers="hd_h_ml230.t6_1_1_1_6" style="text-align:center;vertical-align:middle;">Selectivity
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B1:G2</th><th id="hd_h_ml230.t6_1_1_1_7" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Potentiation
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Assays</th></tr><tr><th headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" id="hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">X</th><th headers="hd_h_ml230.t6_1_1_1_5" id="hd_h_ml230.t6_1_1_2_2" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t6_1_1_1_5" id="hd_h_ml230.t6_1_1_2_3" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th><th headers="hd_h_ml230.t6_1_1_1_7" id="hd_h_ml230.t6_1_1_2_4" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t6_1_1_1_7" id="hd_h_ml230.t6_1_1_2_5" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th></tr><tr><th headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2" id="hd_h_ml230.t6_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2" id="hd_h_ml230.t6_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3" id="hd_h_ml230.t6_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3" id="hd_h_ml230.t6_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4" id="hd_h_ml230.t6_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4" id="hd_h_ml230.t6_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4" id="hd_h_ml230.t6_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th><th headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5" id="hd_h_ml230.t6_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5" id="hd_h_ml230.t6_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5" id="hd_h_ml230.t6_1_1_3_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095709</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu13.jpg" alt="Image ml230fu13.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.65 (112)</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.13 (98)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">35.8</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.55</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.52</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.31</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">18.30</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">59</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640177</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/93619270" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID93619270</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu14.jpg" alt="Image ml230fu14.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">23.56 (66)</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.71 (58)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.1</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45489714</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/93619259" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID93619259</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu15.jpg" alt="Image ml230fu15.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">50.00</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8.88 (52)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.6</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45489720</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/93619262" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID93619262</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu16.jpg" alt="Image ml230fu16.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11.92 (80)</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">25.47 (81)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.5</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45489718</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/93619261" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID93619261</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu17.jpg" alt="Image ml230fu17.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">17.54 (65)</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">13.05 (82)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.3</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45489715</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022048" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022048</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu18.jpg" alt="Image ml230fu18.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">13.06 (69)</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.43 (63)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173045</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/93619264" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID93619264</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu19.jpg" alt="Image ml230fu19.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">27.67 (84)</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7.68 (83)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.6</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45489712</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/93619268" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID93619268</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu20.jpg" alt="Image ml230fu20.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.06 (68)</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.64 (66)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.5</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID45489716</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">9</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022049" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022049</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu21.jpg" alt="Image ml230fu21.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">50.00</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8.03 (24)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6.2</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173044</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/96022051" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID96022051</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu22.jpg" alt="Image ml230fu22.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">19.14 (76)</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.25 (66)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8.5</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46173054</td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11</td><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301786" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID97301786</a></td><td headers="hd_h_ml230.t6_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t6_1_1_1_4 hd_h_ml230.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu23.jpg" alt="Image ml230fu23.jpg" /></div></td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_2 hd_h_ml230.t6_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.27 (87)</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t6_1_1_1_5 hd_h_ml230.t6_1_1_2_3 hd_h_ml230.t6_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.65 (48)</td><td headers="hd_h_ml230.t6_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.7</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_4 hd_h_ml230.t6_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t6_1_1_1_7 hd_h_ml230.t6_1_1_2_5 hd_h_ml230.t6_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46245506</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml230.tfn11"><p class="no_margin">Percent Response;</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml230.tfn12"><p class="no_margin">S = synthesized; P = purchased; NT = not
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tested</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml230t7"><div id="ml230.t7" class="table"><h3><span class="label">Table 7</span><span class="title">Analogues with R1 – R4 substitution patterns in
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combination</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133425/table/ml230.t7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml230.t7_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml230.t7_1_1_1_1" rowspan="3" colspan="1" headers="hd_h_ml230.t7_1_1_1_1" style="text-align:center;vertical-align:middle;">Entry</th><th id="hd_h_ml230.t7_1_1_1_2" rowspan="3" colspan="1" headers="hd_h_ml230.t7_1_1_1_2" style="text-align:center;vertical-align:middle;">SID/CID</th><th id="hd_h_ml230.t7_1_1_1_3" rowspan="3" colspan="1" headers="hd_h_ml230.t7_1_1_1_3" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th id="hd_h_ml230.t7_1_1_1_4" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK133425/bin/ml230fu24.jpg" alt="Image ml230fu24.jpg" /></div></th><th id="hd_h_ml230.t7_1_1_1_5" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Efflux Assay Potency
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(μM) mean (n = # replicates)</th><th id="hd_h_ml230.t7_1_1_1_6" rowspan="3" colspan="1" headers="hd_h_ml230.t7_1_1_1_6" style="text-align:center;vertical-align:middle;">Selectivity
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B1:G2</th><th id="hd_h_ml230.t7_1_1_1_7" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Potentiation
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Assays</th></tr><tr><th headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_1" id="hd_h_ml230.t7_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R1</th><th headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_2" id="hd_h_ml230.t7_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R2</th><th headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_3" id="hd_h_ml230.t7_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R3</th><th headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_4" id="hd_h_ml230.t7_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R4</th><th headers="hd_h_ml230.t7_1_1_1_5" id="hd_h_ml230.t7_1_1_2_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t7_1_1_1_5" id="hd_h_ml230.t7_1_1_2_6" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th><th headers="hd_h_ml230.t7_1_1_1_7" id="hd_h_ml230.t7_1_1_2_7" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC B1</th><th headers="hd_h_ml230.t7_1_1_1_7" id="hd_h_ml230.t7_1_1_2_8" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">ABC G2</th></tr><tr><th headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5" id="hd_h_ml230.t7_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5" id="hd_h_ml230.t7_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6" id="hd_h_ml230.t7_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n</th><th headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6" id="hd_h_ml230.t7_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> μM
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(% Res)<sup>a</sup></th><th headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7" id="hd_h_ml230.t7_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7" id="hd_h_ml230.t7_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7" id="hd_h_ml230.t7_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th><th headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8" id="hd_h_ml230.t7_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CR<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8" id="hd_h_ml230.t7_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub> (μM)</th><th headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8" id="hd_h_ml230.t7_1_1_3_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">TD<sub>50</sub>/
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CR<sub>50</sub></th></tr></thead><tbody><tr><td headers="hd_h_ml230.t7_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID88095709</a></td><td headers="hd_h_ml230.t7_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-furyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3- furan</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4.65 (112)</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.13 (98)</td><td headers="hd_h_ml230.t7_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">35.8</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.55</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5.52</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.31</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">18.30</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">59</td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44640177</td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99376136" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99376136</a></td><td headers="hd_h_ml230.t7_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-Cl-phenyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-furyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">COCH<sub>3</sub></td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.80 (113)</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.56 (127)</td><td headers="hd_h_ml230.t7_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.4</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.08</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">17.60</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">232</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.58</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">174</td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46912089</td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99376137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99376137</a></td><td headers="hd_h_ml230.t7_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-MeO-phenyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-furyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">COCH<sub>3</sub></td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.64 (66)</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.9 (121)</td><td headers="hd_h_ml230.t7_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.9</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.32</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">49.30</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">155</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.18</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">85</td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46912090</td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99376134" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID99376134</a></td><td headers="hd_h_ml230.t7_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4-Me-phenyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2-furyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CH<sub>2</sub>-3-
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furan</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8.7 (114)</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.67 (64)</td><td headers="hd_h_ml230.t7_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3.3</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.35</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">12.50</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">toxic</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.68</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">57.80</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">34</td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46912091</td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87557810" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID87557810</a></td><td headers="hd_h_ml230.t7_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">phenyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">methyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">methyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CO-3- furan</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1.63 (33)</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2.18 (94)</td><td headers="hd_h_ml230.t7_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.7</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">NT</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID44629743</td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID97301789</a></td><td headers="hd_h_ml230.t7_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3-MeO-phenyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">methyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">methyl</td><td headers="hd_h_ml230.t7_1_1_1_4 hd_h_ml230.t7_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CH<sub>2</sub>-3-
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furan</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_5 hd_h_ml230.t7_1_1_3_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">50.00</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml230.t7_1_1_1_5 hd_h_ml230.t7_1_1_2_6 hd_h_ml230.t7_1_1_3_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.21 (82)</td><td headers="hd_h_ml230.t7_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">233.2</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.02</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_7 hd_h_ml230.t7_1_1_3_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5495</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">0.09</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml230.t7_1_1_1_7 hd_h_ml230.t7_1_1_2_8 hd_h_ml230.t7_1_1_3_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1176</td></tr><tr><td headers="hd_h_ml230.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID46245505</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml230.tfn13"><p class="no_margin">Percent Response;</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml230.tfn14"><p class="no_margin">S = synthesized; P = purchased; NT = not
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tested</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml230f12"><div id="ml230.f12" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%2012.%20Refinement%20of%20structure%20based%20on%20efflux%20and%20associated%20potentiation%20and%20toxicity%20data.&p=BOOKS&id=133425_ml230f12.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f12.jpg" alt="Figure 12. Refinement of structure based on efflux and associated potentiation and toxicity data." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 12</span><span class="title">Refinement of structure based on efflux and associated potentiation
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and toxicity data</span></h3></div></article><article data-type="table-wrap" id="figobml230t8"><div id="ml230.t8" class="table"><h3><span class="label">Table 8</span><span class="title">Percent of activity remaining for various kinases when inhibited by
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133425/table/ml230.t8/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml230.t8_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Kinase</th><th id="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Family</th><th id="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">% Activity Remaining</th><th id="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Entry</th><th id="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Kinase</th><th id="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Family</th><th id="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">% Activity Remaining</th></tr></thead><tbody><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AKT1(Full Length)</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AGC</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">84.4</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">26</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLK3</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TKL</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AMPK-a1</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">27</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MST2</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">STE</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AURKA</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Other</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">91.7</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">28</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">p38-g</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CMGC</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AURKB</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Other</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">29</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PAK1</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">STE</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BLK</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">30</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PDGFRB</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK1</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">85.7</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">31</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PDK1</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AGC</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK1G</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">97.4</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">32</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PIM1</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK2B</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">33</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PIM2</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">75.5</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMKK1</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Other</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">34</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PKA</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AGC</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CHEK1</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">35</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PKC-e</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AGC</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CLK1</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CMGC</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">36</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PKG1</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AGC</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CLK2</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CMGC</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">96.3</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">37</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PLK4</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Other</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">99.2</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">DDR2</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">38</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PRKD3</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">FLT1</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">87.9</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">39</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PTK2</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">FLT2</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">40</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PTK2B</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">FLT3</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">99.6</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">41</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">RPS6KA1</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AGC</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">FYN</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">42</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">RPS6KA4</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AGC</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">GSK3-a</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CMGC</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">43</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SIK1</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">94.9</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IGFR1</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SIK2</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">99.5</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IKK-e</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Other</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SLK</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">STE</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ITK</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">46</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SNARK</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">LYN</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">93.9</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">47</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SYK</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MARK1</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CAMK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">48</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TNK2</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MET</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">49</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VEGFR2</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TK</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr><tr><td headers="hd_h_ml230.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLK1</td><td headers="hd_h_ml230.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">TKL</td><td headers="hd_h_ml230.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">84.2</td><td headers="hd_h_ml230.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">50</td><td headers="hd_h_ml230.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">YSK1</td><td headers="hd_h_ml230.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">STE</td><td headers="hd_h_ml230.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.0</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml230f14"><div id="ml230.f14" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%2014.%20Map%20of%20the%20computed%20solubility%20of%20selected%20compounds%20in%20the%20PLS%20principal%20component%20space.&p=BOOKS&id=133425_ml230f14.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f14.jpg" alt="Figure 14. Map of the computed solubility of selected compounds in the PLS principal component space." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 14</span><span class="title">Map of the computed solubility of selected compounds in the PLS
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principal component space</span></h3><div class="caption"><p>Only prior art compounds and compounds tested in the secondary assays
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have been included. Most of the newly synthesized compounds show higher
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computed solubility (green) than prior art compounds which show a low
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one (red). The proposed chemical probe is marked with a red circle.</p></div></div></article><article data-type="fig" id="figobml230f15"><div id="ml230.f15" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230f15.jpg" alt="Figure 15. SAR enhancement of SID 97301789." /></div><h3><span class="label">Figure 15</span><span class="title">SAR enhancement of <a href="https://pubchem.ncbi.nlm.nih.gov/substance/97301789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID
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97301789</a></span></h3></div></article><article data-type="fig" id="figobml230f16"><div id="ml230.f16" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A1.%20Proton%20data%20for%20SID%2088095709%20(CID%2044640177).&p=BOOKS&id=133425_ml230f16.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f16.jpg" alt="Figure A1. Proton data for SID 88095709 (CID 44640177)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A1</span><span class="title">Proton data for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID
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44640177)</span></h3></div></article><article data-type="fig" id="figobml230f17"><div id="ml230.f17" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A2.%20Carbon%20data%20for%20SID%2088095709%20(CID%2044640177).&p=BOOKS&id=133425_ml230f17.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230f17.jpg" alt="Figure A2. Carbon data for SID 88095709 (CID 44640177)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A2</span><span class="title">Carbon data for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID
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44640177)</span></h3></div></article><article data-type="fig" id="figobml230f18"><div id="ml230.f18" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230f18.jpg" alt="Figure A3. LCMS purity data at 215 nm for SID 88095709 (CID 44640177)." /></div><h3><span class="label">Figure A3</span><span class="title">LCMS purity data at 215 nm for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID
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44640177)</span></h3><div class="caption"><p>LCMS retention time: 3.20 min; purity at 215 nm =
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100%.</p></div></div></article><article data-type="fig" id="figobml230f19"><div id="ml230.f19" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230f19.jpg" alt="Figure A4. HRMS data for SID 88095709 (CID 44640177)." /></div><h3><span class="label">Figure A4</span><span class="title">HRMS data for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/88095709" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 88095709</a> (CID 44640177)</span></h3><div class="caption"><p>HRMS <i>m</i>/<i>z</i> calculated for
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C<sub>25</sub>H<sub>22</sub>N<sub>5</sub>O<sub>3</sub>
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[M<sup>+</sup> + H]: 440.1717, found
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440.1715.</p></div></div></article><article data-type="fig" id="figobml230fu7"><div id="ml230.fu7" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml230fu25&p=BOOKS&id=133425_ml230fu25.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133425/bin/ml230fu25.jpg" alt="Image ml230fu25" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobml230fu8"><div id="ml230.fu8" class="figure"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230fu26.jpg" alt="Image ml230fu26" /></div></div></article><article data-type="fig" id="figobml230fu9"><div id="ml230.fu9" class="figure"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230fu27.jpg" alt="Image ml230fu27" /></div></div></article><article data-type="fig" id="figobml230fu10"><div id="ml230.fu10" class="figure"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230fu28.jpg" alt="Image ml230fu28" /></div></div></article><article data-type="fig" id="figobml230fu11"><div id="ml230.fu11" class="figure"><div class="graphic"><img data-src="/books/NBK133425/bin/ml230fu29.jpg" alt="Image ml230fu29" /></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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