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<meta name="ncbi_pagename" content="Identification of Small Molecules that Selectively Inhibit Fluconazole-Resistant Candida Albicans in the Presence of Fluconazole but not in its Absence - Probe 3 - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf">
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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Identification of Small Molecules that Selectively Inhibit Fluconazole-Resistant Candida Albicans in the Presence of Fluconazole but not in its Absence - Probe 3 - 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="Identification of Small Molecules that Selectively Inhibit Fluconazole-Resistant Candida Albicans in the Presence of Fluconazole but not in its Absence - Probe 3">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2011/11/21">
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<meta name="citation_author" content="Cathy L Hartland">
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<meta name="citation_author" content="Willmen Youngsaye">
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<meta name="citation_author" content="Chris Dockendorff">
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<meta name="citation_author" content="Stephen Johnston">
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<meta name="citation_author" content="Joshua Bittker">
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<meta name="citation_author" content="Benjamin Vincent">
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<meta name="citation_author" content="Luke Whitesell">
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<meta name="citation_author" content="Sivaraman Dandapani">
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<meta name="citation_author" content="Lawrence MacPherson">
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<meta name="citation_author" content="Benito Munoz">
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<meta name="citation_author" content="Michelle Palmer">
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<meta name="citation_author" content="Susan Lindquist">
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<meta name="citation_author" content="Stuart L Schreiber">
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<meta name="citation_pmid" content="22834035">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK98918/">
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<meta name="DC.Title" content="Identification of Small Molecules that Selectively Inhibit Fluconazole-Resistant Candida Albicans in the Presence of Fluconazole but not in its Absence - Probe 3">
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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="Cathy L Hartland">
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<meta name="DC.Contributor" content="Willmen Youngsaye">
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<meta name="DC.Contributor" content="Chris Dockendorff">
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<meta name="DC.Contributor" content="Stephen Johnston">
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<meta name="DC.Contributor" content="Joshua Bittker">
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<meta name="DC.Contributor" content="Benjamin Vincent">
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<meta name="DC.Contributor" content="Luke Whitesell">
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<meta name="DC.Contributor" content="Sivaraman Dandapani">
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<meta name="DC.Contributor" content="Lawrence MacPherson">
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<meta name="DC.Contributor" content="Benito Munoz">
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<meta name="DC.Contributor" content="Michelle Palmer">
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<meta name="DC.Contributor" content="Susan Lindquist">
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<meta name="DC.Contributor" content="Stuart L Schreiber">
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<meta name="DC.Date" content="2011/11/21">
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<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK98918/">
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<meta name="description" content="The effectiveness of the potent antifungal drug fluconazole has been compromised by the rise of drug-resistant fungal pathogens. It has been observed that inhibition of Hsp90 can reverse drug resistance in Candida; however, it is challenging to find fungal-specific inhibitors of Hsp90 that do not also impair the human host protein. The Molecular Libraries Probe Production Centers Network (MLPCN) library was screened in duplicate dosings to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A tetracyclic heterocycle (CID7693498) was identified as the initial hit, and subsequent SAR identified a more potent analog as a new probe compound (CID7694069/ML229).">
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<meta name="og:title" content="Identification of Small Molecules that Selectively Inhibit Fluconazole-Resistant Candida Albicans in the Presence of Fluconazole but not in its Absence - Probe 3">
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<meta name="og:description" content="The effectiveness of the potent antifungal drug fluconazole has been compromised by the rise of drug-resistant fungal pathogens. It has been observed that inhibition of Hsp90 can reverse drug resistance in Candida; however, it is challenging to find fungal-specific inhibitors of Hsp90 that do not also impair the human host protein. The Molecular Libraries Probe Production Centers Network (MLPCN) library was screened in duplicate dosings to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A tetracyclic heterocycle (CID7693498) was identified as the initial hit, and subsequent SAR identified a more potent analog as a new probe compound (CID7694069/ML229).">
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cnt"><div class="jr-objectbox-drawer"></div></div></aside><nav id="jr-pm-left" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Previous Page</text></svg></nav><nav id="jr-pm-right" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Next Page</text></svg></nav><nav id="jr-fip" class="hidden"><nav id="jr-fip-term-p"><input type="search" placeholder="search this page" id="jr-fip-term" autocorrect="off" autocomplete="off" /><a id="jr-fip-mg" class="wsprkl btn" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav 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="_NBK98918_"><span class="title" itemprop="name">Identification of Small Molecules that Selectively Inhibit Fluconazole-Resistant
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<i>Candida Albicans</i> in the Presence of Fluconazole but not in its
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Absence - Probe 3</span></h1><p class="contribs">Hartland CL, Youngsaye W, Dockendorff C, et al.</p><p class="fm-aai"><a href="#_NBK98918_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>The effectiveness of the potent antifungal drug fluconazole has been compromised by
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the rise of drug-resistant fungal pathogens. It has been observed that inhibition of
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Hsp90 can reverse drug resistance in <i>Candida</i>; however, it is
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challenging to find fungal-specific inhibitors of Hsp90 that do not also impair the
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human host protein. The Molecular Libraries Probe Production Centers Network (MLPCN) library was screened in duplicate dosings to identify
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compounds that selectively reverse fluconazole resistance in a <i>Candida
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albicans</i> clinical isolate, while having no antifungal activity when
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administered as a single agent. A tetracyclic heterocycle (CID7693498) was
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identified as the initial hit, and subsequent SAR identified a more potent analog as
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a new probe compound (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>).</p></div><div class="h2"></div><p><b>Assigned Assay Grant No:</b> 1 R03 MH086456-01</p><p><b>Screening Center Name & PI:</b> Broad institute Probe Development Center, Stuart Schreiber, PhD</p><p><b>Chemistry Center Name & PI:</b> Broad institute Probe Development Center, Stuart Schreiber, PhD</p><p><b>Assay Submitter & Institution:</b> Susan Lindquist, PhD. Whitehead Institute, Cambridge, MA</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2007" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2007</a></p><div id="ml229.s1"><h2 id="_ml229_s1_">Probe Structure & Characteristics</h2><div id="ml229.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK98918/bin/ml229fu1.jpg" alt="ML229." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a></span></h3></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml229tu1"><a href="/books/NBK98918/table/ml229.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml229tu1" rid-ob="figobml229tu1"><img class="small-thumb" src="/books/NBK98918/table/ml229.tu1/?report=thumb" src-large="/books/NBK98918/table/ml229.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml229.tu1"><a href="/books/NBK98918/table/ml229.tu1/?report=objectonly" target="object" rid-ob="figobml229tu1">Table</a></h4></div></div></div><div id="ml229.s2"><h2 id="_ml229_s2_">Recommendations for the scientific use of this probe</h2><p>Acquired drug resistance by medically relevant microorganisms poses a grave threat to human health and has enormous economic consequences. Fungal pathogens present a particular challenge because they are eukaryotes and share many of the same mechanisms that support the growth and survival of the human host cells they infect. The number of drug classes that have unique targets in fungi is very limited, and the usefulness of current antifungal drugs is compromised by either dose-limiting host toxicity or the frequent emergence of high-grade resistance.</p><p>The objective of this project is to discover compounds capable of reversing fungal drug resistance, thereby making currently available antifungal drugs more effective and reducing dosage-related side effects. Inhibition of the molecular chaperone Hsp90 is one approach that can abrogate drug resistance in diverse fungi including species of both <i>Candida</i> and <i>Aspergillus</i> (<a class="bibr" href="#ml229.r1" rid="ml229.r1">1</a>). At concentrations that demonstrate no antifungal activity on their own, classical Hsp90 inhibitors dramatically reduce azole antibiotic resistance of clinical isolates and transform conventional fungistatic azole compounds into fungicidal drug combinations. This probe could greatly improve the ability to control otherwise lethal fungal infections in severely immunocompromised hosts, especially cancer patients undergoing high-dose chemotherapy and/or bone marrow transplantation. This high-throughput screen (HTS) project seeks to identify novel small molecules that can prevent fungal growth in combination with a sublethal dose of fluconazole.</p></div><div id="ml229.s3"><h2 id="_ml229_s3_">1. Introduction</h2><div id="ml229.s4"><h3>Scientific Rationale</h3><p>Modulators of the fungal stress response could greatly improve the ability to control otherwise lethal fungal infections in immunocompromised hosts, especially cancer patients undergoing high-dose chemotherapy and/or bone marrow transplant procedures. Although Hsp90 and calcineurin inhibitors under current development appear to be well-tolerated in early phase cancer clinical trials, compromise of host chaperone protein function could have very deleterious effects in the context of active infection and the associated stresses of fever and cardiovascular instability. For example, host immune response is compromised by treatment with nonselective calcineurin inhibitors such as cyclosporin A and FK506. An obvious way to avoid this problem would be the identification of fungal-specific inhibitors that do not impair the host chaperone protein. To address these concerns, this project seeks to identify new fungal-selective chemosensitizers. In particular, the design of the screening cascade will also allow capture of compounds targeting still other, as yet unknown, components of fungal stress response pathways that enable the emergence and maintenance of resistance to current antifungal drugs.</p><p>Several compounds have been previously identified as chemosensitizers, increasing the susceptibility of various <i>C.albicans</i> strains to fluconazole treatment (<a class="bibr" href="#ml229.r2" rid="ml229.r2">2</a>,<a class="bibr" href="#ml229.r3" rid="ml229.r3">3</a>,<a class="bibr" href="#ml229.r4" rid="ml229.r4">4</a>,<a class="bibr" href="#ml229.r5" rid="ml229.r5">5</a>). Cernicka et al. previously reported that the compound 7-chlorotetrazolo[5,1-<i>c</i>]benzo[1,2,4]triazine (CTBT, <a class="figpopup" href="/books/NBK98918/figure/ml229.f1/?report=objectonly" target="object" rid-figpopup="figml229f1" rid-ob="figobml229f1">Figure 1</a>) was capable of chemosensitizing <i>C.albicans</i> strains to fluconazole (<a class="bibr" href="#ml229.r3" rid="ml229.r3">3</a>). Against fluconazole-susceptible <i>C.albicans</i> strain 90028 and fluconazole-resistant <i>C.albicans</i> strain Gu5, CTBT was effective with an MIC value of 2.4 μM when combined with fluconazole. In the absence of fluconazole, CTBT demonstrated no activity against <i>C.albicans</i> strain 90028, but did inhibit growth of <i>C.albicans</i> strain Gu5 at concentrations greater than 2.4 μM. The anti-arrhythmic drug amiodarone was recently demonstrated to act synergistically with fluconazole in <i>C.albicans</i> with MIC values ranging between 1.6 μM to 18.8 μM (<a class="bibr" href="#ml229.r4" rid="ml229.r4">4</a>). Plagiochin E, a natural product isolated from liverwort, increased yeast susceptibility to fluconazole at 2.4 μM (<a class="bibr" href="#ml229.r5" rid="ml229.r5">5</a>). These agents were not considered for the current project because of their documented single-agent antifungal activity (amiodarone, an MIC<sub>50</sub> value of 3.1 μM [6]; plagiochin E, an IC<sub>50</sub> value of 3.8 μM [5]).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml229f1" co-legend-rid="figlgndml229f1"><a href="/books/NBK98918/figure/ml229.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml229f1" rid-ob="figobml229f1"><img class="small-thumb" src="/books/NBK98918/bin/ml229f1.gif" src-large="/books/NBK98918/bin/ml229f1.jpg" alt="Figure 1. Chemosensitizing Agents for Reversing Fluconazole Resistance." /></a><div class="icnblk_cntnt" id="figlgndml229f1"><h4 id="ml229.f1"><a href="/books/NBK98918/figure/ml229.f1/?report=objectonly" target="object" rid-ob="figobml229f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Chemosensitizing Agents for Reversing Fluconazole Resistance. </p></div></div><p>The most potent compounds currently known are several HDAC inhibitors previously reported by Mai et al. (<a class="bibr" href="#ml229.r7" rid="ml229.r7">7</a>). As depicted in <a class="figpopup" href="/books/NBK98918/figure/ml229.f2/?report=objectonly" target="object" rid-figpopup="figml229f2" rid-ob="figobml229f2">Figure 2</a>, compounds <b>4</b> and <b>5</b> are uracil-derived hydroxamic acids that exhibited MIC values ranging from 1.2 μM to 1.4 μM when combined with fluconazole. When tested independently, neither compound demonstrated activity against <i>C. albicans</i> at concentrations up to 368 μM. When compounds <b>4</b> and <b>5</b> were evaluated in a biochemical binding assay with murine HDAC1, their IC<sub>50</sub> values were measured at 37 and 51 nM, respectively (<a class="bibr" href="#ml229.r7" rid="ml229.r7">7</a>). In addition, closely related analogs inhibit human HDAC1 and HDAC4 and were further shown to possess antiproliferative and cytotoxic effects against several human cell lines (<a class="bibr" href="#ml229.r8" rid="ml229.r8">8</a>,<a class="bibr" href="#ml229.r9" rid="ml229.r9">9</a>). These findings strongly suggest that compounds <b>4</b> and <b>5</b> would not be particularly selective for fungal protein targets, diminishing their potential as fungal-selective chemosensitizers. At the present time, compounds <b>4</b> and <b>5</b> have not been registered with MLSMR, are not sold commercially, and as such, are not available for evaluation in the current investigation. Ideally, screening the MLPCN compound collection would yield novel chemical hits that work by new modes of action that could be investigated by the Assay Provider, but one backup option that is available is to identify fungal selective HDAC inhibitors.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml229f2" co-legend-rid="figlgndml229f2"><a href="/books/NBK98918/figure/ml229.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml229f2" rid-ob="figobml229f2"><img class="small-thumb" src="/books/NBK98918/bin/ml229f2.gif" src-large="/books/NBK98918/bin/ml229f2.jpg" alt="Figure 2. Uracil-derived HDAC Inhibitors Capable of Reversing Antifungal Drug Resistance." /></a><div class="icnblk_cntnt" id="figlgndml229f2"><h4 id="ml229.f2"><a href="/books/NBK98918/figure/ml229.f2/?report=objectonly" target="object" rid-ob="figobml229f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Uracil-derived HDAC Inhibitors Capable of Reversing Antifungal Drug Resistance. </p></div></div></div></div><div id="ml229.s5"><h2 id="_ml229_s5_">2. Materials and Methods</h2><p>Compounds that can successfully inhibit <i>Candida</i> CaCi-2 cell growth in the presence of sublethal doses of fluconazole as measured in a fluorescence reporter assay were further tested against a highly-resistant <i>Candida</i> CaCi-8 strain in the presence of fluconazole. Those that inhibited growth in the resistant strain were also tested for toxicity against <i>Candida</i> in the absence of fluconazole and for toxicity against mammalian cells using a fluorescence reporter assay. The positive control for screening in the <i>Candida</i> and mammalian cell assays was the Hsp90 inhibitor geldanamycin (acting in concert with fluconazole; see <a class="figpopup" href="/books/NBK98918/figure/ml229.f3/?report=objectonly" target="object" rid-figpopup="figml229f3" rid-ob="figobml229f3">Figure 3</a>). Compounds that passed these four hurdles were binned through use of a <i>Saccharomyces</i> assay to determine whether the mechanism of action might be through the Hsp90 pathway, the calcineurin pathway, or an uncategorized mechanism.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml229f3" co-legend-rid="figlgndml229f3"><a href="/books/NBK98918/figure/ml229.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml229f3" rid-ob="figobml229f3"><img class="small-thumb" src="/books/NBK98918/bin/ml229f3.gif" src-large="/books/NBK98918/bin/ml229f3.jpg" alt="Figure 3. Positive Controls for Biological Assays." /></a><div class="icnblk_cntnt" id="figlgndml229f3"><h4 id="ml229.f3"><a href="/books/NBK98918/figure/ml229.f3/?report=objectonly" target="object" rid-ob="figobml229f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Positive Controls for Biological Assays. </p></div></div><div id="ml229.s6"><h3>2.1. Assays</h3><p>A summary listing of completed assays and corresponding PubChem AID numbers is provided in <a href="#ml229.app1">Appendix A</a> (<a class="figpopup" href="/books/NBK98918/table/ml229.t6/?report=objectonly" target="object" rid-figpopup="figml229t6" rid-ob="figobml229t6">Table A1</a>). Refer to <a href="#ml229.app2">Appendix B</a> for the detailed assay protocols.</p><div id="ml229.s7"><h4>2.1.1. Primary CaCi-2 (AID No. <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1979" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1979</a>), CaCi-2 Dose-Response Retest (AID Nos. <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1979" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1979</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2467" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2467</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488836</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493150" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493150</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504502" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504502</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493081" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493081</a>)</h4><div id="ml229.s8"><h5>Materials and Reagents</h5><p>Clear, flat-bottom, black, 384-well plates were obtained from Corning (Catalog no. 3712BC; Lot no. 35808016). Geldanamycin (Catalog no. G-1047) was obtained from AG Scientific and prepared in 15 mM stock solution in DMSO (control). Fluconazole was obtained from Sequoia Research Products, Ltd. and prepared in a 2 mg/mL stock solution in phosphate buffered saline (PBS). Alamar Blue was obtained from BioSource International Inc. (Catalog no. DAL1100; Lot no.151016SA). PBS (Catalog no. 21-040-CV) without calcium and magnesium was obtained from Cellgro. Penicillin/Streptomycin (Pen/Strep) was obtained from Gibco and prepared 100X in PBS.</p><div id="ml229.s9"><h5>Synthetic Defined Growth Medium</h5><p>RPMI 1640 medium, (powder without sodium bicarbonate; Catalog no. 31800-089, Lot no. 648072) was obtained from Invitrogen. Uridine 8 mg/mL in water (Catalog no. U3750; Lot no. 028KO760), glucose 40% (w/v) in water (Catalog no. G-5400), and MOPS Buffer (Catalog no. M-1254, Lot no. 098K0033) were obtained from Sigma.</p><p>RPMI medium (1X) was prepared by dissolving 10.4 g powdered medium in 800 ml water. A buffer of 34.52 g MOPS was added. While stirring, pH was adjusted to 7.0 with 10N NaOH. Next, 10 ml uridine solution and 50 ml glucose solution were added. The final volume was adjusted to 1000 ml, and filter sterilized.</p></div><div id="ml229.s10"><h5>Fungal Inoculum</h5><p>The following yeast strains were used in this study: <i>C. albicans</i> CaCi-2. Fungal inoculum was prepared as follows: 500 μl of strain was inoculated from cryopreserved stock into a 250-ml shaker flask containing 30 ml growth medium and shaken overnight at 30 °C.</p><p>The optical density (OD 600) of 1 ml fungal culture in a cuvette was read using a standard optical density reader (Eppendorf BioPhotometer Plus), with growth medium as a background blank. The desired volume of fungal inoculums was diluted according to the formula specified in the protocol (see <a href="#ml229.app2">Appendix B</a>).</p></div></div><div id="ml229.s11"><h5>Procedures</h5><p>Fluconazole stock solution was added to the fungal inoculum to achieve 8 μg/ml. Pen/Strep was added to media to a 1% concentration (v/v). A Thermo Combi nL was used to dispense 20 μl/well of assay media into all wells. Geldanamycin was dispensed in positive control wells using Thermo Combi nL for a final concentration of 3 μM. Then, 100 nl of test compound was pinned from compound plates into assay plates using a CyBi-Well pin tool. A further 20 μl/well of culture was dispensed into the assay media in all wells. The plates were incubated in a humidified (90% humidity) Liconic incubator at 37 °C without agitation for 48 hours. Alamar Blue was diluted 1:40 in Ca/Mg-free PBS. To all plates, 5 μl/well of the diluted Alamar Blue was added to plates to a final dilution factor of 1:200. The plates were incubated an additional 2 hours. Then, Relative Fluorescence Intensity (RFU) of each well was read on standard plate reader as a measure of relative fungal growth. EnVision (Perkin Elmer) plate reader setup: Ex 544 nm, Em 590 nm, Bandwidth 12 nm, Top read.</p></div></div><div id="ml229.s12"><h4>2.1.2. Counterscreen Mammalian Cell Toxicity Assay (AID Nos. <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2327" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2327</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488809" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488809</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504525" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504525</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493147" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493147</a>)</h4><div id="ml229.s13"><h5>Materials and Reagents</h5><p>Clear, flat-bottom, black, 384-well plates were obtained from Corning (Catalog no. 3712BC; Lot no. 35808016). Geldanamycin (Catalog no. G-1047) was obtained from AG Scientific and prepared in 15 mM stock solution in DMSO (control). Fluconazole was obtained from Sequoia Research Products, Ltd. and prepared in a 2 mg/ml stock solution in PBS. Alamar Blue was obtained from BioSource International (Catalog no. DAL1100; Lot no. 151016SA). Phosphate buffered saline (PBS; Catalog no. 21-040-CV) without calcium and magnesium was obtained from Cellgro.</p><div id="ml229.s14"><h5>Assay Medium</h5><p>Optimem medium (Catalog no.31985-070; Lot no. 548536) and Pen/Strep 1% (v/v) solution (Catalog no.15140-122;Lot no. 529891) were obtained from Invitrogen. Fetal bovine serum 2.5% (v/v) (Catalog no. 30071.03; Lot no. <a href="/protein/1178747184/?report=GenPept" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=genpept">ARF26748</a>) was obtained from Hyclone.</p></div><div id="ml229.s15"><h5>Cell Inoculum</h5><p>The following test strain was used in this study: NIH-3T3 mammalian fibroblasts (ATCC; CRL no. 1658). Cell inoculum was prepared as follows: Cells were plated at 6,000 cells/well in 20 μl assay medium and cultured overnight at 37 °C under 5% CO<sub>2</sub> in 384-well, clear-bottom, black, tissue culture-treated, bar-coded assay plates.</p></div></div><div id="ml229.s16"><h5>Procedures</h5><p>After overnight culture, compounds were pinned into wells at 100 nl/well using the CyBio CyBi-Well pinning instrument. After compounds were pinned, an additional 20 μl of assay medium supplemented with fluconazole (16 μg/ml) was added to each well. The final nominal concentration in the well was 50 μM of test compound and 8 μg/ml fluconazole. The plates were returned to the tissue culture incubator, and the culture continued for an additional 48 hours at 37 °C under 5% CO<sub>2</sub>. At the completion of this incubation, Alamar Blue Reagent diluted 1:40 in Ca/Mg-free PBS was added to each well (10 μl/well) to achieve a final dilution of 1:200. The plates were incubated for an additional 2 to 3 hours at 37 °C under 5% CO<sub>2,</sub> and then RFU as a measure of relative viable cell number was determined on an EnVision plate reading fluorometer. EnVision (Perkin Elmer) plate reader set-up: Excitation 544 nm, Emission 590 nm, Bandwidth 12 nm, Top read.</p></div></div><div id="ml229.s17"><h4>2.1.3. Secondary Single-Agent (No-Fluconazole) Activity Assay (AID Nos. <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2387" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2387</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488802" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488802</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493157" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493157</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504499" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504499</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493134" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493134</a>)</h4><div id="ml229.s18"><h5>Materials and Reagents</h5><p>Clear, flat-bottom, black, 384-well plates were obtained from Corning. Geldanamycin was obtained from AG Scientific G-1047 and prepared in 15 mM stock solution in DMSO. Pen/Strep was obtained from Gibco and prepared 100X in PBS. Fluconazole was obtained from Sigma and prepared in 2 mg/ml stock solution in PBS. Alamar Blue was obtained from BioSource International Inc. (Catalog no. DAL1100). Phosphate buffered solution (PBS) without calcium and magnesium was obtained from Cellgro.</p><div id="ml229.s19"><h5>Synthetic Defined Growth Medium</h5><p>For the synthetic defined growth medium, RPMI 1640 medium (powder without sodium bicarbonate; was obtained from Invitrogen. Uridine (8 mg/ml in water), glucose 40% (w/v) in water, and MOPS buffer was obtained from Sigma.</p><p>RPMI medium (1X) was prepared by dissolving 10.4 g powdered medium in 800 ml water. A buffer of 34.52 g MOPS was added. While stirring, pH was adjusted to 7.0 with 10N NaOH. Next, 10 ml uridine solution and 50 ml glucose solution were added. The final volume was adjusted to 1000 ml, and the solution was filter sterilized.</p></div><div id="ml229.s20"><h5>Fungal Inoculum</h5><p>The following yeast strain was used in this study: <i>C. albicans</i> CaCi-2 (<a class="bibr" href="#ml229.r10" rid="ml229.r10">10</a>). Fungal inoculum was prepared as follows: 500 μl of yeast was inoculated from cryopreserved stock into a 250 ml shaker flask containing 30 ml growth medium and shaken overnight (16 hours) at 30 °C. The culture was spun down, and the broth was poured off and washed with RPMI medium. The culture was spun down again, the broth poured off and resuspended in RPMI medium. The OD 600 of 1 ml of fungal culture in a cuvette was read using a standard optical density reader with growth medium as a background blank. The desired volume of fungal inoculum was diluted to starting OD of the fungal inoculum of 0.00015 A600.</p></div></div><div id="ml229.s21"><h5>Procedures</h5><p>Pen/Strep was added to the media to a final 1% concentration. A Combi NL (Thermo) was used to dispense 20 μl/well of assay media into all wells. Geldanamycin (1.5 mM) and fluconazole (0.2 mg/ml) were mixed for the positive control. Then, 80 nl of positive control solution was dispensed into the positive control wells using Thermo Combi nL for a final concentration of 3 μM geldanamycin, and 8 μg/ml fluconazole. Then, 100 nl of test compound were pinned from compound plates into assay plates using a CyBi-Well pin tool. A further 20 μl/well of RPMI synthetic defined medium culture was dispensed into 384-well, black plates. Fungal suspension (20 μl/well) was dispensed into all wells. The plates were incubated in a humidified (90% humidity) Liconic incubator at 37 °C without agitation for 48 hours. Alamar Blue Reagent was diluted 1:40 in Ca/Mg-free PBS. To all plates, 6.4 μl/well of the diluted Alamar Blue was added to the plates to a final dilution factor 1:200. The plates were incubated for 2 hours at room temperature. Next, RFU of wells was read on a standard plate reader as measure of relative fungal growth. EnVision (Perkin Elmer) plate reader set-up: Ex 544 nm, Em 590 nm, Bandwidth 12 nm, Top read.</p></div></div><div id="ml229.s22"><h4>2.1.4. Hsp90 Binning (AID Nos.<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2400" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2400</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504390" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504390</a>)</h4><div id="ml229.s23"><h5>Materials and Reagents</h5><p>White, 384-well plates were obtained from Corning (Catalog no. 8867BC; Lot no. 22609019). Tropix Gal-Screen was obtained from Applied Biosystems (Catalog no. T2359; Lot no. 0903044).</p><div id="ml229.s24"><h5>Assay Media</h5><div id="ml229.s25"><h5>SD-ADE yeast nitrogen base w/o ammonium sulfate, minus adenine</h5><p>SD Growth Media was obtained from MP Biomedical (Catalog no. 4027-012; Lot no. 119458). Complete Supplement Media minus adenine was obtained from Sunrise Science (Catalog no.1029-100; Lot no. 070409). Deoxycorticosterone (DOC) steroid was obtained from Sigma.</p><p>To prepare the assay media, 100 ml (20% [w/v] dextrose and 780 mg Complete Supplement) was added to 100 ml SD Growth Media. Water was added to a final volume of 1 liter, and the solution was filter sterilized.</p></div><div id="ml229.s26"><h5>DOC Media</h5><p>For DOC media, 1 ml DOC was added to 100 ml SD-ADE media.</p></div></div><div id="ml229.s27"><h5>Cell Inoculum</h5><p>The following test strain was used in this study: <i>Saccharomyces cerevisiae</i> W303 reporter strain (ATCC 201238). Cell Inoculum was prepared as follows: Reporter <i>Saccharomyces</i> strain was inoculated from cryopreserved stock into a 250 ml shaker flask containing 20 ml SD-ADE media. The reporter strain W303 was incubated overnight (16 hours) at 37 °C and 150 rpm.</p></div></div><div id="ml229.s28"><h5>Procedures</h5><p>The OD 600 of 1 ml of culture in a cuvette was read using a standard optical density reader with growth medium as a background blank. Cells were diluted to OD = 0.04 in SD-ADE media. To each 384-well, white plate, 20 μl of diluted culture was dispensed using a Combi NL (Thermo). Then, 100 nl of test compound were pinned into plates with a CyBi-Well pin tool. Next, 5 μM radicicol was added as positive control in the control wells, dispensing with a Combi NL (Thermo). With Combi, 20 μl of 20 μM DOC (steroid) in SD-ADE media was dispensed in pinned plates. The plates were incubated at 30 °C for 75 minutes with agitation. Using Combi, 40 μl Gal-Screen reagent was dispensed. The plates were incubated at 30°C for 25 minutes. Luminescence of the wells was read on a standard plate reader as a measure of relative fungal growth. EnVision (Perkin Elmer) plate reader set-up: Top read; Luminescence filter (560 nm) at 0.1 second.</p></div></div></div><div id="ml229.s29"><h3>2.2. Probe Chemical Characterization</h3><p>After preparation as described in <a href="#ml229.s30">Section 2.3</a>, the probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 103023254</a>) was analyzed by UPLC, <sup>1</sup>H and <sup>13</sup>C NMR spectroscopy, and high-resolution mass spectrometry. The data obtained from NMR and mass spectroscopy were consistent with the structure of the probe, and UPLC indicated an isolated purity of greater than 98%. The architecture of the tetracyclic core was confirmed by X-ray analysis of a closely related analog. The associated spectroscopic data is provided in <a href="#ml229.app3">Appendix C</a>, and the crystal structure is provided in <a href="#ml229.app5">Appendix E</a>.</p><p>The observed solubility of the probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) was calculated to be 95.4 μM in PBS solution. The probe appears to be exceptionally stable in PBS solution (>99% remaining after a 48 hour incubation). The data from the PBS stability assay is provided in <a class="figpopup" href="/books/NBK98918/figure/ml229.f4/?report=objectonly" target="object" rid-figpopup="figml229f4" rid-ob="figobml229f4">Figure 4</a>. Plasma protein binding (PPB) was determined to be 87% bound in human plasma. The probe is stable in human plasma with greater than 99% remaining after a 5-hour incubation period. The solubility, PPB, and plasma stability results are summarized in <a href="#ml229.s37">Section 3.4</a> (entry 9, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). The <i>in vivo</i> metabolic and pharmacokinetic (DMPK) properties of <a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a> have not been investigated.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml229f4" co-legend-rid="figlgndml229f4"><a href="/books/NBK98918/figure/ml229.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml229f4" rid-ob="figobml229f4"><img class="small-thumb" src="/books/NBK98918/bin/ml229f4.gif" src-large="/books/NBK98918/bin/ml229f4.jpg" alt="Figure 4. Stability of the Probe (CID7694069/ML229) in PBS at 23 °C." /></a><div class="icnblk_cntnt" id="figlgndml229f4"><h4 id="ml229.f4"><a href="/books/NBK98918/figure/ml229.f4/?report=objectonly" target="object" rid-ob="figobml229f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Stability of the Probe (CID7694069/ML229) in PBS at 23 °C. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml229t1"><a href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml229t1" rid-ob="figobml229t1"><img class="small-thumb" src="/books/NBK98918/table/ml229.t1/?report=thumb" src-large="/books/NBK98918/table/ml229.t1/?report=previmg" alt="Table 1. Evaluation of 16 Synthetic Ester and Amide Analogs." /></a><div class="icnblk_cntnt"><h4 id="ml229.t1"><a href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-ob="figobml229t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Evaluation of 16 Synthetic Ester and Amide Analogs. </p></div></div><p>The probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) and five additional analogs were submitted to the SMR collection MLS003390980 (probe), MLS003390979 (CID7693333), MLS003390981 (CID17581618), MLS003390982 (CID1507946), MLS003390983 (CID7708820), and MLS003390984 (CID17581348).</p></div><div id="ml229.s30"><h3>2.3. Probe Preparation</h3><p>The probe compound <b>8</b> (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) was prepared in one step by <i>N</i>-alkylation of the commercially available heterocyclic core <b>6</b> with α-chloroamide <b>7</b> (<a class="figpopup" href="/books/NBK98918/figure/ml229.f11/?report=objectonly" target="object" rid-figpopup="figml229f11" rid-ob="figobml229f11">Scheme 1</a>). Alternatively, this compound may be obtained from a commercial vendor (e.g., Vitas-M Laboratory, Ltd.; Catalog No. STK582969) Full experimental details are provided in this section.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml229f11" co-legend-rid="figlgndml229f11"><a href="/books/NBK98918/figure/ml229.f11/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml229f11" rid-ob="figobml229f11"><img class="small-thumb" src="/books/NBK98918/bin/ml229f11.gif" src-large="/books/NBK98918/bin/ml229f11.jpg" alt="Scheme 1. Synthesis of Probe (CID7694069/ML229)." /></a><div class="icnblk_cntnt" id="figlgndml229f11"><h4 id="ml229.f11"><a href="/books/NBK98918/figure/ml229.f11/?report=objectonly" target="object" rid-ob="figobml229f11">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Synthesis of Probe (CID7694069/ML229). </p></div></div><p><b>General details.</b> All reagents and solvents were purchased from commercial vendors and used as received. NMR spectra were recorded on a Bruker 300 MHz or Varian 500 MHz spectrometer using CDCl<sub>3</sub>, acetone-d<sub>6</sub>, CD<sub>3</sub>OD, or DMSO-d<sub>6</sub> solvents, as indicated. Proton and carbon chemical shifts are reported in ppm (δ) relative to tetramethylsilane (<sup>1</sup>H δ 0.00) or residual chloroform in CDCl<sub>3</sub> solvent (<sup>1</sup>H δ 7.24, <sup>13</sup>C δ 77.0). NMR data are reported as follows: chemical shifts, multiplicity (obs. = obscured, br = broad, s = singlet, d = doublet, t = triplet, m = multiplet); coupling constant(s) in Hz; integration.</p><p>Unless otherwise indicated, NMR data were collected at 25 °C. Flash chromatography was performed using 40–60 μm Silica Gel (60 Å mesh) on a Teledyne Isco Combiflash R<i><sub>f</sub></i> system. Tandem Liquid Chromatography/Mass Spectrometry (LC/MS) was performed on a Waters 2795 separations module and 3100 mass detector. Analytical thin layer chromatography (TLC) was performed on EM Reagent 0.25 mm silica gel 60-F plates. Visualization was accomplished with UV light and aqueous potassium permanganate (KMnO<sub>4</sub>) stain followed by heating. High-resolution mass spectra were obtained at the MIT Mass Spectrometry Facility with a Bruker Daltonics APEXIV 4.7 Tesla Fourier Transform Ion Cyclotron Resonance mass spectrometer. X-ray crystallography was performed at the MIT Department of Chemistry X-Diffraction Facility with a Siemens three-circle Platform diffractometer, coupled to a Bruker-APEX CCD detector.</p><p>Compound purity and identity were determined by UPLC-MS (Waters, Milford, MA). Purity was measured by UV absorbance at 210 nm. Identity was determined on an SQ mass spectrometer by positive electrospray ionization. Mobile Phase A consisted of either 0.1% ammonium hydroxide or 0.1% trifluoroacetic acid in water, while mobile Phase B consisted of the same additives in acetonitrile. The gradient ran from 5% to 95% mobile Phase B over 0.8 minutes at 0.45 ml/min. An Acquity BEH C18, 1.7 μm, 1.0 × 50 mm column was used with column temperature maintained at 65°C. Compounds were dissolved in DMSO at a nominal concentration of 1 mg/ml, and 0.25 μl of this solution was injected.</p><div id="ml229.fu2" class="figure"><div class="graphic"><img src="/books/NBK98918/bin/ml229fu19.jpg" alt="Image ml229fu19" /></div></div><p><b>Step 1. Preparation of 2-chloro-1-(pyrrolidin-1-yl)ethanone (7):</b> Finely-ground potassium carbonate (6.9 g, 50 mmol, 3.8 equiv) was suspended in anhydrous tetrahydrofuran (13 ml) while under nitrogen and cooled to 0 °C before adding 2-chloroacetyl chloride (1.0 ml, 13 mmol, 1.0 equiv). A solution of pyrrolidine (1.0 ml, 13 mmol, 1.0 equiv) in tetrahydrofuran (26 ml) was then added dropwise via syringe. The reaction was removed from the ice bath and stirred for 17 hours at room temperature. At this point, the suspension was filtered through Celite with additional tetrahydrofuran. The filtrate was concentrated under reduced pressure to approximately 5 ml, and this solution was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 0/100), yielding the title compound as a white solid (590 mg, 32% yield).</p><p><b><sup>1</sup>H NMR (300 MHz, CDCl<sub>3</sub>):</b> δ 4.03 (s, 2H), 3.52 (apparent q, <i>J</i> = 6.4, 4H), 1.98 (m, 4H); <b>MS (ESI<sup>+</sup>):</b> 149.9.</p><div id="ml229.fu3" class="figure"><div class="graphic"><img src="/books/NBK98918/bin/ml229fu20.jpg" alt="Image ml229fu20" /></div></div><p><b>Step 2. Preparation of 6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3-dihydrothiazolo-[3′,2′:1,2]-pyrimido-[5,4-</b><b><i>b</i></b><b>]-indol-5(6</b><b><i>H</i></b><b>)-one (8):</b> 2,3-dihydrothiazolo-[3′,2′:1,2]-pyrimido-[5,4-<i>b</i>]-indol-5(6<i>H</i>)-one <b>6</b> (Vitas-M Laboratory, Ltd.; Catalog No. STK780784, 31 mg, 0.13 mmol, 1.0 equiv) and powdered potassium hydroxide (11 mg, 0.19 mmol, 1.5 equiv) was added to a vial with stir bar. The vial was sealed with a septum cap and flushed with nitrogen, before anhydrous dimethyl sulfoxide (600 μl) was added. The mixture was stirred for 30 minutes at room temperature, then a solution of 2-chloro-1-(pyrrolidin-1-yl)ethanone <b>7</b> (30 mg, 0.20 mmol, 1.5 equiv) in dimethyl sulfoxide (0.3 ml) was added via syringe. An additional 0.3 ml of dimethyl sulfoxide was used to ensure complete transfer of <b>7</b>. The reaction was stirred at room temperature for 14 hours, generating a fine, white precipitate. Water (0.5 ml) was added to the vial, and the reaction was thoroughly mixed. The fine precipitate was filtered out through a cotton plug with additional water (1 ml). The collected solid was then dissolved with 1:1 (v/v) methanol/dichloromethane (approximately 3 ml) and adsorbed on silica gel before being purified by column chromatography over silica gel (methanol/dichloromethane: 0/100 to 10/90) to give the title compound as a white solid (33 mg, 74% yield).</p><p><b><sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>):</b> δ 8.10 (d, <i>J</i> = 8.0, 1H), 7.48 (t, <i>J</i> = 7.7, 1H), 7.36 (d, <i>J</i> = 8.4, 1H), 7.25 (t, <i>J</i> = 5.0, 1H), 5.42 (s, 2H), 4.54 (t, <i>J</i> = 7.4, 2H), 3.59 (t, <i>J</i> = 6.8, 2H), 3.52 (t, <i>J</i> = 6.3, 2H), 3.49 (t, <i>J</i> = 6.3, 2H), 2.08 (apparent dt, <i>J</i> = 6.8, 6.8, 2H), 1.92 (apparent dt, <i>J</i> = 6.9, 6.9,2H); <b><sup>13</sup>C NMR (125 MHz, CDCl<sub>3</sub>):</b> δ 165.8, 155.4, 155.0, 141.0, 140.5, 127.9, 121.2, 120.8, 120.5, 119.0, 110.0, 48.2, 46.7, 46.2, 45.7, 27.4, 26.3, 24.0; <b>HRMS (ESI):</b> calculated mass for C<sub>18</sub>H<sub>18</sub>N<sub>4</sub>O<sub>2</sub>S [M+H] 355.1223, found 355.1231.</p></div><div id="ml229.s31"><h3>2.4. Additional Analytical Analysis</h3><p><b>Plasma Protein Binding.</b> Plasma protein binding was determined by equilibrium dialysis using the Rapid Equilibrium Dialysis (RED) device (Pierce Biotechnology, Rockford, IL) for both human and mouse plasma. Each compound was prepared in duplicate at 5 μM in plasma (0.95% acetonitrile, 0.05% DMSO) and added to one side of the membrane (200 μl) with PBS pH 7.4 added to the other side (350 μl). Compounds were incubated at 37 °C for 5 hours in a 250-rpm orbital shaker. Following the incubation, the samples were analyzed by UPLC-MS (Waters, Milford, MA) with compounds detected by SIR detection on a single quadrupole mass spectrometer.</p><p><b>Plasma Stability.</b> Plasma stability was determined at 37 °C for 5 hours in both human and mouse plasma. Each compound was prepared in duplicate at 5 μM in plasma diluted 50/50 (v/v) with PBS pH 7.4 (0.95% acetonitrile, 0.05% DMSO). The compounds were incubated at 37 °C for 5 hours with a 250-rpm orbital shake with time points taken at 0 hours and 5 hours. The samples were analyzed by UPLC-MS (Waters, Milford, MA) with compounds detected by SIR detection on a single quadrupole mass spectrometer.</p></div></div><div id="ml229.s32"><h2 id="_ml229_s32_">3. Results</h2><div id="ml229.s33"><h3>Probe attributes</h3><ul><li class="half_rhythm"><div>Compounds that inhibit yeast growth in the presence, but not in the absence of 8 μg/ml fluconazole.</div></li><li class="half_rhythm"><div>Compounds that show at least 10-fold selectivity between the primary <i>Candida</i> test strain and mammalian cells.</div></li><li class="half_rhythm"><div>Compounds that show activity toward resistant clinical isolates at an IC<sub>50</sub> < 50 μM.</div></li><li class="half_rhythm"><div>IC<sub>50</sub> ≤ 1 μM in primary or resistant screen cell line.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml229tu2"><a href="/books/NBK98918/table/ml229.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml229tu2" rid-ob="figobml229tu2"><img class="small-thumb" src="/books/NBK98918/table/ml229.tu2/?report=thumb" src-large="/books/NBK98918/table/ml229.tu2/?report=previmg" alt="Compound Summary in PubChem." /></a><div class="icnblk_cntnt"><h4 id="ml229.tu2"><a href="/books/NBK98918/table/ml229.tu2/?report=objectonly" target="object" rid-ob="figobml229tu2">Table</a></h4><p class="float-caption no_bottom_margin">Compound Summary in PubChem. </p></div></div></div><div id="ml229.s34"><h3>3.1. Summary of Screening Results</h3><p><a class="figpopup" href="/books/NBK98918/figure/ml229.f6/?report=objectonly" target="object" rid-figpopup="figml229f6" rid-ob="figobml229f6">Figure 6</a>. displays the critical path for probe development.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml229f6" co-legend-rid="figlgndml229f6"><a href="/books/NBK98918/figure/ml229.f6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml229f6" rid-ob="figobml229f6"><img class="small-thumb" src="/books/NBK98918/bin/ml229f6.gif" src-large="/books/NBK98918/bin/ml229f6.jpg" alt="Figure 6. Critical Path for Probe Development." /></a><div class="icnblk_cntnt" id="figlgndml229f6"><h4 id="ml229.f6"><a href="/books/NBK98918/figure/ml229.f6/?report=objectonly" target="object" rid-ob="figobml229f6">Figure 6</a></h4><p class="float-caption no_bottom_margin">Critical Path for Probe Development. </p></div></div><p>A high-throughput screen (HTS) of 302,509 compounds (PubChem <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1979" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1979</a>) was performed in duplicate in the fluconazole-resistant <i>C. albicans</i> strain CaCi-2 in the presence of a sublethal concentration of fluconazole. Using a screening active cutoff of ≥75% inhibition at a screening concentration of 9.5 μM, 1893 hits were identified as <i>Candida</i> CaCi-2 growth inhibitors in the presence of fluconazole, and 1654 hits were available as cherry picks. These picked compounds were retested in dose against the <i>C. albicans</i> strain CaCi-2 to confirm their inhibitory activity and determine an IC<sub>50</sub> value. Of these, there were 622 compounds that met the criterion of inhibitory activity of less than or equal to 1 μM.</p><p>An orthogonal screen of these 1654 cherry picks against a more resistant <i>C. albicans</i> strain, CaCi-8, in the presence of a sublethal concentration of fluconazole (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2423" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2423</a>) selected for compounds that were active with an IC<sub>50</sub> value less than 50 μM. There were 836 compounds that met this criterion, and 403 of these compounds were among in the 622 actives from the CaCi-2 retest (see <a class="figpopup" href="/books/NBK98918/figure/ml229.f5/?report=objectonly" target="object" rid-figpopup="figml229f5" rid-ob="figobml229f5">Figure 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml229f5" co-legend-rid="figlgndml229f5"><a href="/books/NBK98918/figure/ml229.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml229f5" rid-ob="figobml229f5"><img class="small-thumb" src="/books/NBK98918/bin/ml229f5.gif" src-large="/books/NBK98918/bin/ml229f5.jpg" alt="Figure 5. Bar Chart of the Antifungal Screening Campaign." /></a><div class="icnblk_cntnt" id="figlgndml229f5"><h4 id="ml229.f5"><a href="/books/NBK98918/figure/ml229.f5/?report=objectonly" target="object" rid-ob="figobml229f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Bar Chart of the Antifungal Screening Campaign. Sequential results of primary, secondary, and orthogonal assays, resulting in 296 compounds that passed all criteria. </p></div></div><p>Murine 3T3 fibroblasts provided an assay for overt compound toxicity to mammalian cells. Of the 1654 cherry picks, 1012 compounds were inactive in this assay, indicating fungal selectivity, of which 350 also met the criteria in the prior CaCi-2 and CaCi-8 assays.</p><p>To eliminate cherry pick compounds that intrinsically inhibit <i>Candida</i> growth, an additional secondary screen of the 1654 cherry picks in the absence of fluconazole was included, with a 10 μM IC<sub>50</sub> cutoff. Of the 350 compounds of interest, 296 compounds met this criterion.</p><p>Two ancillary secondary assays were run to bin the remaining 296 compounds into three classes: Hsp90 inhibitors, calcineurin inhibitors, or other. The Hsp90 test used a <i>Saccharomyces cerevisiae</i> strain engineered to express beta-galactosidase driven by glucocorticoid response element. The glucocorticoid hormone receptor depends heavily on Hsp90 for function. Of the 296 compounds of interest, 17 compounds were active as defined by a 10 μM upper threshold of inhibition.</p><p>The second binning assay for calcineurin inhibition was evaluated in a yeast carrying a construct encoding calcineurin-dependent response elements (CDRE) driving expression of beta-galactosidase. Reporter activity with or without the prior addition of test compounds was measured following challenge with the stressor CaCl<sub>2</sub>. Of the 296 compounds of interest, two compounds were active as defined by a 10 μM upper threshold of inhibition. The remaining 277 compounds were binned as “Other.”</p><p>Thirty (30) compounds were chosen for initial dry powder confirmation studies from the 296 identified above by first clustering into small groups of related analogs, and then picking representative analogs from each of those families. After re-testing these dry powders in the test cascade, three compounds were chosen as potential probe candidates, and a first round of 31 analogs (plus three probe candidates) were obtained and assayed. Using the results from these assays as guidance, a second round of analogs (plus the probe candidate) was prepared for SAR analysis. <a href="#ml229.s42">Section 4.2</a> describes the mechanism of action studies and categorization of the probe (i.e., “Other” mechanism).</p></div><div id="ml229.s35"><h3>3.2. Dose Response Curves for Probe</h3><div id="ml229.f7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%207.%20Dose-dependent%20Activity%20of%20the%20Probe%20(ML229)%20Against%20Various%20Cell%20Lines.&p=BOOKS&id=98918_ml229f7.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/NBK98918/bin/ml229f7.jpg" alt="Figure 7. Dose-dependent Activity of the Probe (ML229) Against Various Cell Lines." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 7</span><span class="title">Dose-dependent Activity of the Probe (<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) Against Various Cell Lines</span></h3><div class="caption"><p><i>C.albicans</i> CaCi-2 in the presence of fluconazole (IC<sub>50</sub> = 960 nM, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504502" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504502</a>) (<i>A</i>); <i>C.albicans</i> CaCi-8 in the presence of fluconazole (IC<sub>50</sub> = 1390 nM, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504504" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504504</a>) (<i>B</i>); Murine 3T3 fibroblasts in the absence of fluconazole (inactive, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504525" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504525</a>) (<i>C</i>); <i>C.albicans</i> CaCi-2 in the absence of fluconazole (inactive, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504499" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504499</a>) (<i>D</i>).</p></div></div></div><div id="ml229.s36"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>A search of PubChem for the probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) indicated that the probe has been previously evaluated in 216 bioassays but was determined to be inactive in all of them. A structure-based search in SciFinder and Reaxys did not identify any publications or patents in which the probe appeared. There are no obvious chemical liabilities associated with the new probe compound.</p></div><div id="ml229.s37"><h3>3.4. SAR Tables</h3><p>In order to investigate the activity of this structural class, a collection of 32 structurally related analogs were synthesized and evaluated for their ability to reverse fluconazole resistance in the <i>C.albicans</i> test strains. <a class="figpopup" href="/books/NBK98918/figure/ml229.f8/?report=objectonly" target="object" rid-figpopup="figml229f8" rid-ob="figobml229f8">Figure 8</a> depicts the diversification points selected for modification. Three diversity points (highlighted in purple, blue, and green) were explored, and the number of analogs screened for each site is specified.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml229f8" co-legend-rid="figlgndml229f8"><a href="/books/NBK98918/figure/ml229.f8/?report=objectonly" target="object" title="Figure 8" class="img_link icnblk_img figpopup" rid-figpopup="figml229f8" rid-ob="figobml229f8"><img class="small-thumb" src="/books/NBK98918/bin/ml229f8.gif" src-large="/books/NBK98918/bin/ml229f8.jpg" alt="Figure 8. Summary of analogs prepared to investigate the SAR profile of the HTS hit." /></a><div class="icnblk_cntnt" id="figlgndml229f8"><h4 id="ml229.f8"><a href="/books/NBK98918/figure/ml229.f8/?report=objectonly" target="object" rid-ob="figobml229f8">Figure 8</a></h4><p class="float-caption no_bottom_margin">Summary of analogs prepared to investigate the SAR profile of the HTS hit. Key SAR findings for each site of diversification are provided in italics </p></div></div><p>The biological assay data and physical properties of these analogs are presented below in <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a> through <a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">Table 3</a>. Characterization data (<sup>1</sup>H NMR spectra and UPLC chromatograms) of these analogs are provided in <a href="#ml229.app3">Appendix C</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml229t3"><a href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml229t3" rid-ob="figobml229t3"><img class="small-thumb" src="/books/NBK98918/table/ml229.t3/?report=thumb" src-large="/books/NBK98918/table/ml229.t3/?report=previmg" alt="Table 3. Evaluation of Analogs Bearing Expanded/Truncated Tetracycle Cores (4 analogs)." /></a><div class="icnblk_cntnt"><h4 id="ml229.t3"><a href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-ob="figobml229t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Evaluation of Analogs Bearing Expanded/Truncated Tetracycle Cores (4 analogs). </p></div></div><p>The initial hit from the HTS campaign described in <a href="#ml229.s34">Section 3.1</a> was 6-(2-(4-methylpiperidin-1-yl)-2-oxoethyl)-2,3-dihydrothiazolo[3′,2′:1,2]pyrimido[5,4-<i>b</i>]indol-5(6<i>H</i>)-one (entry 1<b>,</b>
|
|
<a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). Beginning with the unsubstituted tetracycle core, a number of alternate side chains were evaluated as replacements for the 4-methylpiperidyl amide in order to improve cellular potency and PBS solubility (<a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). In the absence of the entire side chain, the parent tetracycle retained moderate activity against the less resistant CaCi-2 line, but was ineffective against the more resistant CaCi-8 isolate (entry 2, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). Converting the amide to a methyl ester did not affect potency against either strain of <i>C. albicans</i> (entry 4, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>), while the free acid was an ineffective derivative (entry 3, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>).</p><p>Additional amide analogs were prepared, and most of these compounds were active with IC<sub>50</sub> values in the low micromolar range. No change in potency was observed when the 4-methyl substituent was removed from the original hit (entry 5, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). The necessity of the piperidine moiety was further interrogated by preparing the morpholine and <i>N</i>-methyl piperazine analogs (entries 6 and 7, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). While there was a marked improvement in aqueous solubility, this was not accompanied any increase in potency. The 4,4-difluoropiperidyl amide showed a small improvement over the hit compound (CID 7693498) but was still fairly insoluble in PBS solution (entry 8, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). Replacing the piperidine with smaller cyclic amines yielded the largest increase in potency thus far. Both pyrrolidine and 2,5-dihydropyrrole exhibited nanomolar potency against CaCi-2 and low micromolar potency against CaCi-8; the pyrrolidine derivative benefited from higher PBS solubility (entries 9 and 10, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). Incorporating fluorides into the pyrrolidine scaffold diminished plasma protein binding (PPB) levels as well as its bioactivity (entry 11, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). No activity was observed when the even smaller azetidine system was examined (entry 12, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). Acyclic amides were inactive against CaCi-8, although some demonstrated activity against CaCi-2 (entries 13–15, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>). Reduction of the amide to the corresponding amine eliminated the compound’s cellular activity (entry 16, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>).</p><p>The tetracyclic core was also obtained with different substitutions at the 9-position, and a series of analogs was prepared from the 9-fluorotetracycle (<a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>). Many of these derivatives were considerably more effective against the less resistant CaCi-2 strain than their nonfluorinated counterparts. Without the side chain, the 9-fluorotetracycle demonstrated low micromolar activity (entry 1, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>), as did the methyl acetate derivative (entry 3, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>). The free acid was inactive in all cellular assays (entry 2, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>); however, all amides derived from this fluorinated tetracycle were nanomolar growth inhibitors of the CaCi-2 line (entries 4–10, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>) except for the azepine-derived amide (entry 9, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>). While not as potent as the other amides, the azepine variant was still a low micromolar chemosensitizer, lying just above the nanomolar threshold of 1.00 μM (i.e., IC<sub>50</sub> = 1.16 μM).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml229t2"><a href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml229t2" rid-ob="figobml229t2"><img class="small-thumb" src="/books/NBK98918/table/ml229.t2/?report=thumb" src-large="/books/NBK98918/table/ml229.t2/?report=previmg" alt="Table 2. Evaluation of Synthetic Analogs Bearing Substituted Tetracycle Cores (12 analogs)." /></a><div class="icnblk_cntnt"><h4 id="ml229.t2"><a href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-ob="figobml229t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Evaluation of Synthetic Analogs Bearing Substituted Tetracycle Cores (12 analogs). </p></div></div><p>Complementing the 9-fluoro derivatives, methyl ether was also incorporated into the 9-position of the tetracycle (entries 11–12, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>), but neither compound was an effective chemosensitizing agent. <a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">Table 3</a> summarizes attempts to further perturb the tetracycle core. Three analogs contained an expanded D-ring (entries 1–3, <a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">Table 3</a>), but only one of these compounds exhibited any activity in the cellular assays (entry 3, <a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">Table 3</a>). When the entire tetracycle was replaced with the more common beta-carboline scaffold, the resulting compound was unable to chemosensitize any of the tested <i>C.albicans</i> strains to fluconazole (entry 4, <a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">Table 3</a>).</p><p>The efficacy of these tetracyclic compounds against CaCi-2 was not generally reproduced when evaluated with the more resistant CaCi-8 strain. In this particular assay, several compounds demonstrated a pronounced Eagle effect (i.e<i>.,</i> at higher concentrations several agents lost their chemosensitizing properties) (<a class="bibr" href="#ml229.r11" rid="ml229.r11 ml229.r12 ml229.r13">11–13</a>), which complicated assessment of their <i>in vivo</i> potency. Data from all tested concentrations, including the higher dosages where activity diminishes, were included when calculating the IC<sub>50</sub> values reported in <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Tables 1</a>–<a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">3</a>, and compounds exhibiting the Eagle effect are noted. While some compounds in <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a> possess the characteristic parabolic dose-response curve of the Eagle effect, this phenomenon did not significantly impact the associated IC<sub>50</sub> values. However, several 9-fluoro analogs were classified as inactive in the CaCi-8 cellular assay when examined over the full range of dosages. However, if the observed Eagle effect is ignored when determining IC<sub>50</sub> values, these same compounds demonstrate nanomolar cellular activity. Because of the profound impact of the Eagle effect on the 9-fluoro compounds’ apparent potency, these analogs were not considered probe candidates. The full dose-response curves (unmasked and masked) and adjusted IC<sub>50</sub> values for compounds exhibiting this effect are provided in <a href="#ml229.app6">Appendix F</a> (<a class="figpopup" href="/books/NBK98918/figure/ml229.f10/?report=objectonly" target="object" rid-figpopup="figml229f10" rid-ob="figobml229f10">Figure A1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml229f10" co-legend-rid="figlgndml229f10"><a href="/books/NBK98918/figure/ml229.f10/?report=objectonly" target="object" title="Figure A1" class="img_link icnblk_img figpopup" rid-figpopup="figml229f10" rid-ob="figobml229f10"><img class="small-thumb" src="/books/NBK98918/bin/ml229f10a.gif" src-large="/books/NBK98918/bin/ml229f10a.jpg" alt="Figure A1. Representative Dose-Response Curves for Compounds Exhibiting the Eagle Effect." /></a><div class="icnblk_cntnt" id="figlgndml229f10"><h4 id="ml229.f10"><a href="/books/NBK98918/figure/ml229.f10/?report=objectonly" target="object" rid-ob="figobml229f10">Figure A1</a></h4><p class="float-caption no_bottom_margin">Representative Dose-Response Curves for Compounds Exhibiting the Eagle Effect. </p></div></div><p>Overall, chemistry efforts in this project led to roughly 3-fold improvement in potency and greater than 50-fold improvement in PBS solubility relative to the hit from HTS. The HTS hit (CID7693498) was 3.0 μM against CaCi-2 with 1.6 μM PBS solubility. The probe 6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3-dihydrothiazolo[3′,2′:1,2]pyrimido[5,4-<i>b</i>]indol-5(6<i>H</i>)-one (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) is 0.96 μM against CaCi-2 with 95.4 μM PBS solubility.</p></div><div id="ml229.s38"><h3>3.5. Cellular Activity</h3><p>All assays were performed in whole cells. A murine 3T3 fibroblast mammalian cell toxicity assay was also included as a secondary screen. Experimental details are provided above in <a href="#ml229.s12">Section 2.1.2</a>. The probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) clearly met the established probe criteria specified for this project (<a class="figpopup" href="/books/NBK98918/table/ml229.t4/?report=objectonly" target="object" rid-figpopup="figml229t4" rid-ob="figobml229t4">Table 4</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml229t4"><a href="/books/NBK98918/table/ml229.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml229t4" rid-ob="figobml229t4"><img class="small-thumb" src="/books/NBK98918/table/ml229.t4/?report=thumb" src-large="/books/NBK98918/table/ml229.t4/?report=previmg" alt="Table 4. Comparison of the Probe to Project Criteria." /></a><div class="icnblk_cntnt"><h4 id="ml229.t4"><a href="/books/NBK98918/table/ml229.t4/?report=objectonly" target="object" rid-ob="figobml229t4">Table 4</a></h4><p class="float-caption no_bottom_margin">Comparison of the Probe to Project Criteria. </p></div></div></div><div id="ml229.s39"><h3>3.6. Profiling Assays</h3><p>The probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) was evaluated for inhibitory activity against calcinuerin and Hsp90. Assay results indicated the probe was not an inhibitor of Hsp90 or calcinuerin. Additional details are provided in <a href="#ml229.s42">Section 4.2</a>.</p></div></div><div id="ml229.s40"><h2 id="_ml229_s40_">4. Discussion</h2><div id="ml229.s41"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>Investigation into relevant prior art entailed searching the following databases: SciFinder, Reaxys, PubChem, PubMed, US Patent and Trademark Office (USPTO), PatFT, AppFT, and World Intellectual Property Organization (WIPO). The search terms applied and hit statistics are provided in <a class="figpopup" href="/books/NBK98918/table/ml229.t5/?report=objectonly" target="object" rid-figpopup="figml229t5" rid-ob="figobml229t5">Table 5</a>. The searches were performed on and are current as of February 7, 2011.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml229t5"><a href="/books/NBK98918/table/ml229.t5/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml229t5" rid-ob="figobml229t5"><img class="small-thumb" src="/books/NBK98918/table/ml229.t5/?report=thumb" src-large="/books/NBK98918/table/ml229.t5/?report=previmg" alt="Table 5. Search Strings and Databases Employed in Prior Art Search." /></a><div class="icnblk_cntnt"><h4 id="ml229.t5"><a href="/books/NBK98918/table/ml229.t5/?report=objectonly" target="object" rid-ob="figobml229t5">Table 5</a></h4><p class="float-caption no_bottom_margin">Search Strings and Databases Employed in Prior Art Search. </p></div></div><p>Several compounds have been previously identified as chemosensitizers, increasing the susceptibility of various <i>C.albicans</i> strains to fluconazole treatment (<a class="bibr" href="#ml229.r2" rid="ml229.r2 ml229.r3 ml229.r4 ml229.r5 ml229.r6 ml229.r7">2–7</a>). Of these, the most potent belonged to a series of HDAC inhibitors reported by Mai et al. (<a class="bibr" href="#ml229.r7" rid="ml229.r7">7</a>). Depicted in <a class="figpopup" href="/books/NBK98918/figure/ml229.f9/?report=objectonly" target="object" rid-figpopup="figml229f9" rid-ob="figobml229f9">Figure 9</a>, these compounds are uracil-derived hydroxamic acids and exhibited MIC values ranging from 1.2 μM to 2.8 μM when combined with fluconazole. When tested in the absence of fluconazole, neither compound demonstrated activity against <i>C.albicans</i> at concentrations up to 368 μM. However, the potent activity of these compounds against murine HDAC1 (IC<sub>50</sub> <51 nM), combined with the antiproliferative activity of similar analogs in human cells (<a class="bibr" href="#ml229.r8" rid="ml229.r8">8</a>,<a class="bibr" href="#ml229.r9" rid="ml229.r9">9</a>), indicates they would not possess any significant species selectivity. The absence of selectivity disqualified compounds <b>4</b> and <b>5</b> as probe candidates. In addition, neither compound could be readily obtained for direct comparison to <a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml229f9" co-legend-rid="figlgndml229f9"><a href="/books/NBK98918/figure/ml229.f9/?report=objectonly" target="object" title="Figure 9" class="img_link icnblk_img figpopup" rid-figpopup="figml229f9" rid-ob="figobml229f9"><img class="small-thumb" src="/books/NBK98918/bin/ml229f9.gif" src-large="/books/NBK98918/bin/ml229f9.jpg" alt="Figure 9. Chemosensitizers for Reversing Fluconazole Resistance (MIC=1.2–2.8 μM)." /></a><div class="icnblk_cntnt" id="figlgndml229f9"><h4 id="ml229.f9"><a href="/books/NBK98918/figure/ml229.f9/?report=objectonly" target="object" rid-ob="figobml229f9">Figure 9</a></h4><p class="float-caption no_bottom_margin">Chemosensitizers for Reversing Fluconazole Resistance (MIC=1.2–2.8 μM). </p></div></div><p>The probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) has a potency of 960 nM against the <i>C.albicans</i> strain CaCi-2, and does not exhibit any effect in the absence of fluconazole or against mammalian fibroblasts.</p></div><div id="ml229.s42"><h3>4.2. Mechanism of Action Studies</h3><p>All compounds were binned into one of three categories: 1) Hsp90-inhibitors, 2) Calcineurin inhibitors, or 3) Other mechanism.</p><p>Potential inhibition of the Hsp90-based chaperone machinery was evaluated using yeast reporter assays involving the glucocorticoid hormone receptor and the tyrosine kinase, v-Src. Both of these well-established client proteins depend heavily on Hsp90 for their function. Refer to <a href="#ml229.s22">Section 2.1.4</a> for method details.</p><p>Potential inhibition of calcineurin function was evaluated in yeast carrying a construct encoding calcineurin-dependent response elements (CDRE) driving expression of a reporter enzyme. Reporter activity with or without the prior addition of test compounds was measured following challenge with the stressor CaCl<sub>2</sub>.</p><p>The probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) was classified into the “Other” categorization, showing no inhibition of calcineurin or Hsp90 pathways.</p></div><div id="ml229.s43"><h3>4.3. Planned Future Studies</h3><p>The goal of probe optimization is to generate potent, fungal-specific agents for future mechanistic studies and target identification projects. The activity of probes against drug-resistant yeast will make possible the use of the powerful genetic approaches available including genome-wide, overexpression, and deletion libraries, both in parallel arrayed format and pooled bar-coded format. To complement genetic approaches, affinity precipitation and proteomic approaches based on Stable Isotope Labeling with Amino acids in Cell culture (SILAC) technology, which are already being employed in other projects, may be used. The probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) could be studied in well-established mouse models of invasive, drug-resistant <i>Candida</i> fungemia, which are available and have been employed in the Whitehead Institute in conjunction with the laboratory of Gerald Fink. There is currently an IACUC-approved protocol in place to enable such experimentation in future work and to evaluate the therapeutic potential of probes generated by this screen.</p></div></div><div id="ml229.s44"><h2 id="_ml229_s44_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml229.r1">Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. <span><span class="ref-journal">Science. </span>2005 Sep 30;<span class="ref-vol">309</span>(5744):2185–89.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16195452" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16195452</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml229.r2">DiGirolamo JA, Li X.-C, Jacob MR, Clark AM, Ferreira D. Reversal of fluconazole resistance by sulfated sterols from the marine sponge Topsentia sp. <span><span class="ref-journal">J Nat Prod. </span>2009 Aug;<span class="ref-vol">72</span>(8):1524–28.</span> [<a href="/pmc/articles/PMC3697152/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3697152</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19653640" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19653640</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml229.r3">Cernicka J, Kozovska Z, Hnatova M, Valachovic M, Hapala I, Riedl Z, Hajós G, Subik J. Chemosensitisation of drug-resistant and drug-sensitive yeast cells to antifungals. <span><span class="ref-journal">Int J Antimicrobial Agents. </span>2007 Feb;<span class="ref-vol">29</span>(2):170–8.</span> Epub 2007 Jan 3. [<a href="https://pubmed.ncbi.nlm.nih.gov/17204400" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17204400</span></a>] [<a href="http://dx.crossref.org/10.1016/j.ijantimicag.2006.08.037" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml229.r4">Gamarra S, Rocha EM, Zhang Y.-Q, Park S, Rao R, Perlin DS. Mechanism of the synergistic effect of amiodarone and fluconazole in Candida albicans. <span><span class="ref-journal">Antimicrob Agents Chemother. </span>2010 May;<span class="ref-vol">54</span>(5):1753–61.</span> Epub 2010 Mar 1. [<a href="/pmc/articles/PMC2863688/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2863688</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20194694" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20194694</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml229.r5">Guo X.-L, Leng P, Yang Y, Yu L.-G, Lou H.-X. Plagiochin E, a botanic-derived phenolic compound, reverses fungal resistance to fluconazole relating to the efflux pump. <span><span class="ref-journal">J Appl Microbio. </span>2008 Mar;<span class="ref-vol">104</span>(3):831–38.</span> Epub 2008 Jan 9. [<a href="https://pubmed.ncbi.nlm.nih.gov/18194250" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18194250</span></a>] [<a href="http://dx.crossref.org/10.1111/j.1365-2672.2007.03617.x" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml229.r6">Courchesne WE. Characterization of a novel, broad-based fungicidal activity for the antiarrhythmic drug amiodarone. <span><span class="ref-journal">J Pharmacol Exp Ther. </span>2002 Jan 1;<span class="ref-vol">300</span>:195–99.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11752116" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11752116</span></a>] [<a href="http://dx.crossref.org/10.1124/jpet.300.1.195" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml229.r7">Mai A, Rotili D, Massa S, Brosch G, Simonetti G, Passariello C, Palamara AT. Discovery of uracil-based histone deacetylase inhibitors able to reduce acquired antifungal resistance and trailing growth in Candida albicans. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2007 Mar 1;<span class="ref-vol">17</span>(5):1221–25.</span> Epub 2006 Dec 12. [<a href="https://pubmed.ncbi.nlm.nih.gov/17196388" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17196388</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml229.r8">Mai A, Massa S, Rotili D, Pezzi R, Bottoni P, Scatena R, Meraner J, Brosch G. Exploring the connection unit in the HDAC inhibitor pharmacophore model: Novel uracil-based hydroxamates. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2005 Nov 1;<span class="ref-vol">15</span>(21):4656–61.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16165353" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16165353</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml229.r9">Mai A, Massa S, Rotili D, Simeoni S, Ragno R, Botta G, Nebbioso A, Miceli M, Altucci L, Brosch G. Synthesis and biological properties of novel, uracil-containing histone deacetylase inhibitors. <span><span class="ref-journal">J Med Chem. </span>2006 Oct 5;<span class="ref-vol">49</span>(20):6046–56.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17004718" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17004718</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml229.r10">Redding S, Smith J, Farinacci G, Rinaldi M, Fothergill A, Rhine-Chalberg J, Pfaller M. Resistance of <em>Candida albicans</em> to fluconazole during treatment of oropharyngeal candidiasis in a patient with AIDS: documentation by in vitro susceptibility testing and DNA subtype analysis. <span><span class="ref-journal">Clin Infect Dis. </span>1994 Feb 1;<span class="ref-vol">18</span>(2):240–42.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8161633" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8161633</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml229.r11">Eagle H, Musselman AD. The rate of bactericidal action of penicillin in vitro as a function of its concentration, and its paradoxically reduced activity at high concentrations against certain organisms. <span><span class="ref-journal">J Exp Med. </span>1948 July 1;<span class="ref-vol">88</span>(1):99–131.</span> [<a href="/pmc/articles/PMC2135799/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2135799</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18871882" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18871882</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml229.r12">Fleischhacker M, Radecke C, Schulz B, Ruhnke M. Paradoxical growth effects of the echinocandins caspofungin and micafungin, but not of anidulafungin, on clinical isolates of Candida albicans and C. dubliniensis. <span><span class="ref-journal">Eur J Clin Microbiol Infect Dis. </span>2008 Feb;<span class="ref-vol">27</span>(2):127–31.</span> Epub 2007 Dec 4. [<a href="https://pubmed.ncbi.nlm.nih.gov/18057972" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18057972</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml229.r13">Wiederhold NP. Attenuation of echinocandin activity at elevated concentrations: a review of the paradoxical effect. <span><span class="ref-journal">Curr Opin Infect Dis. </span>2007 Dec;<span class="ref-vol">20</span>(6):574–78.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17975406" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17975406</span></a>]</div></dd></dl></dl></div><div id="ml229.app1"><h2 id="_ml229_app1_">Appendix A. Assay Summary Table</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml229t6"><a href="/books/NBK98918/table/ml229.t6/?report=objectonly" target="object" title="Table A1" class="img_link icnblk_img figpopup" rid-figpopup="figml229t6" rid-ob="figobml229t6"><img class="small-thumb" src="/books/NBK98918/table/ml229.t6/?report=thumb" src-large="/books/NBK98918/table/ml229.t6/?report=previmg" alt="Table A1. Summary of Completed Assays and AIDs." /></a><div class="icnblk_cntnt"><h4 id="ml229.t6"><a href="/books/NBK98918/table/ml229.t6/?report=objectonly" target="object" rid-ob="figobml229t6">Table A1</a></h4><p class="float-caption no_bottom_margin">Summary of Completed Assays and AIDs. </p></div></div></div><div id="ml229.app2"><h2 id="_ml229_app2_">Appendix B. Detailed Assay Protocols</h2><div id="ml229.s45"><h3>Primary CaCi-2 (AID no. <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1979" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1979</a>) and CaCi-2 Dose-Response Retest (AID nos. <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2467" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2467</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488836</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493081" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493081</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493150" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493150</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504502" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504502</a>)</h3><div id="ml229.s46"><h4>Materials and Reagents</h4><p>Clear, flat bottom, black, 384-well plates (Corning Catalog no. 3712BC; Lot no. 35808016);Geldanamycin (AG Scientific, Catalog no. G-1047) 15 mM stock solution in DMSO; Fluconazole (Sequoia Research Products Ltd) 2 mg/ml stock solution in PBS; Pen/Strep (Gibco Catalog no.10378-016; Lot no. 21040170) 100X in PBS; Alamar Blue (AG Scientific Catalog no. DAL 1100; Lot no.151016SA); PBS without Calcium and Magnesium (Cellgro Catalog no. 21-040-CV)</p><div id="ml229.s47"><h5>Synthetic Defined Growth Medium</h5><p>RPMI 1640 medium, (powder without sodium bicarbonate; Invitrogen Catalog no. 31800-089; Lot no. 648072); Uridine 8 mg/ml in water (Sigma Catalog no. U3750; Lot no. 028KO760); Glucose 40% (w/v) in water (Sigma Catalog no. G-5400); MOPS Buffer (Sigma Catalog no. M-1254; Lot no. 098K0033)</p><ol><li class="half_rhythm"><div>Prepare 1X RPMI medium by dissolving 10.4 grams powdered medium in 800 ml water.</div></li><li class="half_rhythm"><div>Add 34.52 g MOPS. While stirring, adjust pH to 7.0 with 10 N NaOH.</div></li><li class="half_rhythm"><div>Add 10 ml uridine solution, 50 ml glucose solution, adjust final volume to 1000 ml. Filter sterilize.</div></li></ol></div><div id="ml229.s48"><h5>Fungal Inoculum</h5><p>Test Strain: <i>C. albicans</i> CaCi-2</p><ol><li class="half_rhythm"><div>Inoculate 500 μl of strain from cryopreserved stock into a 250 ml shaker flask containing 30 ml growth medium. Shake at 30 °C overnight.</div></li><li class="half_rhythm"><div>Read OD 600 of 1 ml fungal culture in a cuvette using a standard optical density reader (Eppendorf BioPhotometer Plus), with growth medium as a background blank.</div></li><li class="half_rhythm"><div>Dilute to desired volume of fungal inoculums according to the following formula: (1/OD measured) X (Desired Final Volume of Inoculum) X 0.3 = Volume of fungal culture (μl) to add to desired volume of growth medium. When added to media in wells, this yields a calculated starting OD of the fungal inoculum of 0.00015.</div></li></ol></div></div><div id="ml229.s49"><h4>Procedures</h4><ol><li class="half_rhythm"><div>Add fluconazole stock solution to fungal inoculum to achieve a final concentration of 8 μg/ml.</div></li><li class="half_rhythm"><div>Add Pen/Strep at 0.1 ml per 10 ml media (1% v/v).</div></li><li class="half_rhythm"><div>Use a Thermo Combi nL to dispense 20 μl/well of assay media into all wells.</div></li><li class="half_rhythm"><div>Pin 25 nl test compound from compound plates into assay plates using CyBi-Well pin tool.</div></li><li class="half_rhythm"><div>Dispense 20 μl/well of culture into the assay media in all wells.</div></li><li class="half_rhythm"><div>Incubate plates in a humidified (90% humidity) Liconic incubator at 37 °C without agitation for 48 hours.</div></li><li class="half_rhythm"><div>Dilute Alamar Blue Reagent 1:40 in Ca/Mg-free PBS.</div></li><li class="half_rhythm"><div>To all plates, add 5 μl/well of the diluted Alamar to a final dilution factor of 1:200.</div></li><li class="half_rhythm"><div>Incubate the plates for an additional 2 hours.</div></li><li class="half_rhythm"><div>Read the Relative Fluorescence Intensity (RFU) of wells on a standard plate reader as a measure of relative fungal growth. EnVision (Perkin Elmer) plate reader set-up: Ex 544 nm, Em 590 nm, Bandwidth 12 nm, Top read.</div></li></ol></div></div><div id="ml229.s50"><h3>Orthogonal Resistant Strain Dose Response (AID nos. <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2423" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2423</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488807" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488807</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493082" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493082</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493149" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493149</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504504" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504504</a>)</h3><div id="ml229.s51"><h4>Materials and Reagents</h4><p>Clear, flat-bottom, black, 384-well plates (Corning Catalog no. 3712BC; Lot no. 35808016); Geldanamycin (AG Scientific Catalog no. G-1047) 15 mM stock solution in DMSO; Pen/Strep (Gibco Catalog no.10378-016;Lot no.21040170) 100X in PBS; Fluconazole (Sigma Catalog no.F829-100MG;Lot no. 098K4715) 2 mg/ml stock solution in PBS; Alamar Blue (AG Scientific Catalog no. DAL1100; Lot no.151016SA); PBS w/o Calcium and Magnesium (Cellgro Catalog no. 21-040-CV)</p><div id="ml229.s52"><h5>Synthetic Defined Growth Medium</h5><p>RPMI 1640 medium, (powder without sodium bicarbonate; Invitrogen Catalog no. 31800-089, Lot no.648072); Uridine 8 mg/ml in water (Sigma Catalog no. U3750; Lot no. 028K0760); Glucose 40% (w/v) in water (Sigma Catalog no. G-5400); MOPS Buffer (Sigma Catalog no. M-1254; Lot no. 098K0033)</p><ol><li class="half_rhythm"><div>Prepare 1X RPMI medium by dissolving 10.4 g powdered medium in 800 ml water.</div></li><li class="half_rhythm"><div>Add 34.52 g MOPS. While stirring, adjust pH to 7.0 with 10N NaOH.</div></li><li class="half_rhythm"><div>Add 10 ml uridine solution, 50 ml glucose solution, adjust final volume to 1000 ml. Filter sterilize</div></li></ol></div><div id="ml229.s53"><h5>Fungal Inoculum</h5><p>Test Strain: <i>C. albicans</i> CaCi8 (<a class="bibr" href="#ml229.r10" rid="ml229.r10">10</a>)</p><ol><li class="half_rhythm"><div>Inoculate 500 μl of strain from cryopreserved stock into a 250 ml shaker flask containing 30 ml growth medium. Shake at 30 °C overnight (16 hours).</div></li><li class="half_rhythm"><div>Read OD 600 of 1 ml of fungal culture in a cuvette using a standard optical density reader (Eppendorf BioPhotometer Plus), with growth medium as a background blank.</div></li><li class="half_rhythm"><div>Dilute to a desired volume of fungal inoculum according to following formula: (1/OD measured) X (Desired Final Volume of Inoculum) X 0.3 = Volume of fungal culture (μl) to add to desired volume of growth medium. When added to media in wells, this yields a calculated starting OD of the fungal inoculum of 0.00015.</div></li></ol></div></div><div id="ml229.s54"><h4>Procedures</h4><ol><li class="half_rhythm"><div>Add fluconazole stock solution to fungal inoculum to achieve 8 μg/ml.</div></li><li class="half_rhythm"><div>Add Pen/Strep to media to 1% concentration.</div></li><li class="half_rhythm"><div>Use a Thermo Combi nL to dispense 20 μl/well of assay media into all wells.</div></li><li class="half_rhythm"><div>Dispense geldanamycin in positive control wells using Thermo Combi nL for a final concentration of 3 μM.</div></li><li class="half_rhythm"><div>Then, pin 100 nl of test compound from compound plates into assay plates using a CyBi-Well pin tool.</div></li><li class="half_rhythm"><div>Dispense 20 μl/well of culture into the assay media in all wells.</div></li><li class="half_rhythm"><div>Incubate the plates were incubated in a humidified (90% humidity) Liconic incubator at 37 °C without agitation for 48 hours.</div></li><li class="half_rhythm"><div>Dilute Alamar Blue 1:40 in Ca/Mg-free PBS.</div></li><li class="half_rhythm"><div>To all plates, add 5 μl/well of the diluted Alamar Blue to plates to a final dilution factor of 1:200.</div></li><li class="half_rhythm"><div>Incubate the plates for 2 hours.</div></li><li class="half_rhythm"><div>Read the Relative Fluorescence Intensity (RFU) of wells on a standard plate reader as a measure of relative fungal growth. EnVision (Perkin Elmer) plate reader set-up: Ex 544 nm, Em 590 nm, Bandwidth 12 nm, Top read.</div></li></ol></div></div><div id="ml229.s55"><h3>Counterscreen Mammalian Cell Toxicity Dose Response (AID Nos. <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2327" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2327</a>,<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493147" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493147</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504525" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504525</a>)</h3><div id="ml229.s56"><h4>Materials and Reagents</h4><p>Clear, flat-bottom, black, 384-well plates (Corning Catalog no. 3712BC Lot no. 35808016); Geldanamycin (AG Scientific Catalog no. G-1047) 15 mM stock solution in DMSO; Fluconazole (Sequoia Research Ltd.) 2 mg/ml stock solution in PBS; Alamar Blue (AG Scientific Catalog no. DAL1100, Lot no. 151016SA); PBS w/o Calcium and Magnesium (Cellgro Catalog no. 21-040-CV)</p><div id="ml229.s57"><h5>Assay Medium</h5><p>Optimem medium (Invitrogen Catalog no. 31985-070; Lot no. 548536); 2.5% (v/v) Fetal Bovine Serum (Hyclone Catalog no.30071.03; Lot no. <a href="/protein/1178747184/?report=GenPept" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=genpept">ARF26748</a>); 1% (v/v) Pen/Strep solution (Invitrogen Catalog no.15140-122; Lot no. 529891)</p></div><div id="ml229.s58"><h5>Cell Inoculum</h5><p>Test Strain: NIH-3T3 mammalian fibroblasts (ATCC CRL No. 1658)</p><ol><li class="half_rhythm"><div>Plate cells in 384-well plates at 6,000 cells/well in 20 μl assay medium.</div></li><li class="half_rhythm"><div>Incubate plates overnight at 37 °C under 5% CO<sub>2</sub>.</div></li></ol></div></div><div id="ml229.s59"><h4>Procedures</h4><ol><li class="half_rhythm"><div>After overnight culture, pin compounds into wells at 100 nl/well using the CyBio CyBi-Well pinning instrument.</div></li><li class="half_rhythm"><div>After pinning compounds, add 20 μl of assay medium supplemented with fluconazole to each well. To a final nominal concentration of 8 μg/ml fluconazole.</div></li><li class="half_rhythm"><div>Return the plates to the tissue culture incubator and incubate the culture for an additional 48 hours at 37 °C under 5% CO<sub>2</sub>.</div></li><li class="half_rhythm"><div>At the completion of this incubation, add Alamar Blue solution diluted 1:40 in PBS to each well (10 μl/well) to achieve a final dilution of 1:200.</div></li><li class="half_rhythm"><div>Incubate the plates for an additional 2–3 hours at 37 °C under 5% CO<sub>2</sub>.</div></li><li class="half_rhythm"><div>Read the Relative Fluorescence Intensity (RFU) of wells was read on a standard plate reader as a measure of relative cell growth. EnVision (Perkin Elmer) plate reader set-up: Ex 544 nm, Em 590 m, Bandwidth 12 nm, Top read.</div></li></ol></div></div><div id="ml229.s60"><h3>Secondary Single Agent (No Fluconazole) Activity Assay Protocol (AID Nos. <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2387" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2387</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488802" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488802</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493134" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493134</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493157" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493157</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504499" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504499</a>)</h3><div id="ml229.s61"><h4>Materials and Reagents</h4><p>Clear, flat-bottom, black 384-well plates (Corning Catalog no. 3712BC; Lot no. 35808016);Geldanamycin (AG Scientific Catalog no. G-1047) 15 mM stock solution in DMSO; Pen/Strep (Gibco Catalog no. 10378-016; Lot no21040170) 100X in PBS; Fluconazole (Sigma Catalog no. F829-100MG; Lot no. 098K4715) 2 mg/ml stock solution in PBS; Alamar Blue (AG Scientific Catalog no. DAL1100; Lot no.151016SA);PBS w/o Calcium and Magnesium (Cellgro Catalog no. 21-040-CV)</p><div id="ml229.s62"><h5>Synthetic Defined Growth Medium</h5><p>RPMI 1640 medium, (powder without sodium bicarbonate; Invitrogen 31800-089, Lot 648072); Uridine 8 mg/ml in water (Sigma Catgalog no. U3750; Lot no. 028K0760); Glucose 40% (w/v) in water (Sigma Catalog no. G-5400); MOPS Buffer (Sigma Catalog no. M-1254; Lot no. 098K0033)</p><ol><li class="half_rhythm"><div>Prepare 1X RPMI medium by dissolving 10.4 g powdered medium in 800 ml water.</div></li><li class="half_rhythm"><div>Add 34.52 g MOPS. While stirring, adjust pH to 7.0 with 10N NaOH.</div></li><li class="half_rhythm"><div>Add 10 ml uridine solution, 50 ml glucose solution, adjust final volume to 1000 ml. Filter sterilize.</div></li></ol></div><div id="ml229.s63"><h5>Fungal Inoculum</h5><p>Test Strain: <i>C. albicans</i> CaCi-2 (<a class="bibr" href="#ml229.r10" rid="ml229.r10">10</a>)</p><ol><li class="half_rhythm"><div>Inoculate 500 μl of yeast from cryopreserved stock into a 250 ml shaker flask containing 30 ml growth medium. Shake at 30 °C overnight (16 hours).</div></li><li class="half_rhythm"><div>Read OD 600 of 1 ml of fungal culture in a cuvette using a standard optical density reader (Eppendorf BioPhotometer Plus), with growth medium as a background blank.</div></li><li class="half_rhythm"><div>Dilute to desired volume of fungal inoculum according to following formula: (1/OD measured) X (Desired Final Volume of Inoculum) X 0.3 = Volume of fungal culture (μl) to add to desired volume of growth medium. When added to media in wells, this yields a calculated starting OD of the fungal inoculum of 0.00015.</div></li></ol></div></div><div id="ml229.s64"><h4>Procedures</h4><ol><li class="half_rhythm"><div>Add Pen/Strep to the media to a final 1% concentration.</div></li><li class="half_rhythm"><div>Use a Thermo Combi nL to dispense 20 μl/well of assay media into all wells.</div></li><li class="half_rhythm"><div>Mix geldanamycin and fluconazole for positive control.</div></li><li class="half_rhythm"><div>Dispense positive control solution into the positive control wells using Thermo Combi nL for a final concentration of 3 μM geldanamycin, and 8 μg/ml fluconazole.</div></li><li class="half_rhythm"><div>Then, pin 100 nl of test compound from compound plates into assay plates using a CyBi-Well pin tool.</div></li><li class="half_rhythm"><div>Dispense 20 μl/well of culture into the assay media in all wells.</div></li><li class="half_rhythm"><div>Incubate the plates in a humidified (90% humidity) Liconic incubator at 37 °C without agitation for 48 hours.</div></li><li class="half_rhythm"><div>Dilute Alamar Blue 1:40 in Ca/Mg-free PBS.</div></li><li class="half_rhythm"><div>To all plates, add 5 μl/well of the diluted Alamar Blue to the plates to a final dilution factor 1:200.</div></li><li class="half_rhythm"><div>Incubate the plates for 2 hours.</div></li><li class="half_rhythm"><div>Read Relative Fluorescence Intensity (RFU) of wells was read on a standard plate reader as measure of relative fungal growth. EnVision (Perkin Elmer) plate reader settings: Ex 544 nm, Em 590 nm, Bandwidth 12 nm, Top read.</div></li></ol></div></div><div id="ml229.s65"><h3>Hsp90 Binning (AID Nos.<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2400" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2400</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504390" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504390</a>)</h3><div id="ml229.s66"><h4>Materials and Reagents</h4><p>White, 384-well plate (Corning Catalog no. 8867BC, Lot no. 22609019); Radicicol (Sigma Catalog no. R2146);Tropix Gal-Screen (Applied Biosystems Catalog no. T2359, Lot no. 0903044)</p><div id="ml229.s67"><h5>Assay media</h5><div id="ml229.s68"><h5>SD-ADE Yeast nitrogen base w/o ammonium sulfate, minus adenine</h5><p>SD Growth Media (MP Biomedical Catalog no. 4027-012; Lot no. 119458); Dextrose 20%;Complete supplement minus adenine (Sunrise Science Catalog no. 1029-100; Lot no. 070409<b>)</b></p><ol><li class="half_rhythm"><div>To 100 ml SD Growth Media, add 100 ml 20% dextrose and 780 mg Complete Supplement.</div></li><li class="half_rhythm"><div>Add water to 1 liter. Filter and sterilize.</div></li></ol></div><div id="ml229.s69"><h5>DOC media</h5><p>SD-ADE (see above); DOC steroid (Sigma Catalog no. D7000)</p><ol><li class="half_rhythm"><div>To 100 ml SD-ADE media, add 1 ml DOC.</div></li></ol></div></div><div id="ml229.s70"><h5>Cell Inoculum</h5><p>Test Strain: ATCC 201238 <i>Saccharomyces cerevisiae</i> W303 reporter strain</p><ol><li class="half_rhythm"><div>Inoculate reporter <i>Saccharomyces</i> strain (ATCC Catalog no. 201238) from cryopreserved stock into a 250 ml shaker flask containing 20 ml SD-ADE media.</div></li><li class="half_rhythm"><div>Incubate the flask overnight (16 hours) at 37 °C and 150 RPM.</div></li></ol></div></div><div id="ml229.s71"><h4>Procedures</h4><ol><li class="half_rhythm"><div>Read OD 600 of 1 ml of culture in a cuvette using a standard optical density reader (Eppendorf BioPhotometer Plus), with growth medium as a background blank.</div></li><li class="half_rhythm"><div>Dilute cells to OD = 0.04 in SD-ADE media.</div></li><li class="half_rhythm"><div>To each 384-well white plate, add 20 μl of diluted culture using a Thermo Combi.</div></li><li class="half_rhythm"><div>Then, pin 100 nl compounds into plates with a CyBi-Well pin tool.</div></li><li class="half_rhythm"><div>Next, add 5 μM radicicol as a positive control in control wells, dispensing with Thermo Combi NL.</div></li><li class="half_rhythm"><div>With Combi, dispense 20 μl of 20 μM DOC (steroid) in SD-ADE media in pinned plates.</div></li><li class="half_rhythm"><div>Incubate the plates at 30 °C for 75 minutes with agitation.</div></li><li class="half_rhythm"><div>Using Combi, dispense 40 μl Gal-Screen reagent.</div></li><li class="half_rhythm"><div>Incubate the plates at 30 °C for 25 minutes.</div></li><li class="half_rhythm"><div>Read the luminescence of wells on a standard plate reader as measure of relative fungal growth. EnVision (Perkin Elmer) plate reader set-up: Top read; Luminescence filter (560 nm) at 0.1 second</div></li></ol></div></div></div><div id="ml229.app3"><h2 id="_ml229_app3_">Appendix C. NMR and LC Data of Probe and Analogs</h2><p id="ml229.fu4"><a href="/books/NBK98918/figure/ml229.fu4/?report=objectonly" target="object" rid-ob="figobml229fu4" class="figpopup"><sup>1</sup>H NMR Spectrum (500 MHz, CDCl<sub>3</sub>) of the Probe (CID7694069/ML229)</a></p><p id="ml229.fu5"><a href="/books/NBK98918/figure/ml229.fu5/?report=objectonly" target="object" rid-ob="figobml229fu5" class="figpopup"><sup>13</sup>C NMR Spectrum (125 MHz, CDCl<sub>3</sub>) of the Probe (CID7694069/ML229)</a></p><p id="ml229.fu6"><a href="/books/NBK98918/figure/ml229.fu6/?report=objectonly" target="object" rid-ob="figobml229fu6" class="figpopup">UPLC Chromatogram of the Probe (CID7694069/ML229)</a></p><p id="ml229.fu7"><a href="/books/NBK98918/figure/ml229.fu7/?report=objectonly" target="object" rid-ob="figobml229fu7" class="figpopup">HRMS (ESI) of the Probe (CID7694069/ML229)</a></p><div id="ml229.s72"><h3>Spectroscopic Data for SAR Analogs</h3><p id="ml229.fu8"><a href="/books/NBK98918/figure/ml229.fu8/?report=objectonly" target="object" rid-ob="figobml229fu8" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 7693498 (Entry 1, Table 1)</a></p><p id="ml229.fu9"><a href="/books/NBK98918/figure/ml229.fu9/?report=objectonly" target="object" rid-ob="figobml229fu9" class="figpopup">UPLC-MS Chromatogram of Analog CID 7693498</a></p><p id="ml229.fu10"><a href="/books/NBK98918/figure/ml229.fu10/?report=objectonly" target="object" rid-ob="figobml229fu10" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 1508416 (Entry 2, Table 1)</a></p><p id="ml229.fu11"><a href="/books/NBK98918/figure/ml229.fu11/?report=objectonly" target="object" rid-ob="figobml229fu11" class="figpopup">UPLC-MS Chromatogram of Analog CID 1508416</a></p><p id="ml229.fu12"><a href="/books/NBK98918/figure/ml229.fu12/?report=objectonly" target="object" rid-ob="figobml229fu12" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49843149 (Entry 3, Table 1)</a></p><p id="ml229.fu13"><a href="/books/NBK98918/figure/ml229.fu13/?report=objectonly" target="object" rid-ob="figobml229fu13" class="figpopup">UPLC-MS Chromatogram of Analog CID 49843149</a></p><p id="ml229.fu14"><a href="/books/NBK98918/figure/ml229.fu14/?report=objectonly" target="object" rid-ob="figobml229fu14" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49835884 (Entry 4, Table 1)</a></p><p id="ml229.fu15"><a href="/books/NBK98918/figure/ml229.fu15/?report=objectonly" target="object" rid-ob="figobml229fu15" class="figpopup">UPLC-MS Chromatogram of Analog CID 49835884</a></p><p id="ml229.fu16"><a href="/books/NBK98918/figure/ml229.fu16/?report=objectonly" target="object" rid-ob="figobml229fu16" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766519 (Entry 5, Table 1)</a></p><p id="ml229.fu17"><a href="/books/NBK98918/figure/ml229.fu17/?report=objectonly" target="object" rid-ob="figobml229fu17" class="figpopup">UPLC-MS Chromatogram of Analog CID 49766519</a></p><p id="ml229.fu18"><a href="/books/NBK98918/figure/ml229.fu18/?report=objectonly" target="object" rid-ob="figobml229fu18" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766513 (Entry 6, Table 1)</a></p><p id="ml229.fu19"><a href="/books/NBK98918/figure/ml229.fu19/?report=objectonly" target="object" rid-ob="figobml229fu19" class="figpopup">UPLC-MS Chromatogram of Analog CID 49766513</a></p><p id="ml229.fu20"><a href="/books/NBK98918/figure/ml229.fu20/?report=objectonly" target="object" rid-ob="figobml229fu20" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, Acetone-d<sub>6</sub>) of Analog CID 49843308 (Entry 7, Table 1)</a></p><p id="ml229.fu21"><a href="/books/NBK98918/figure/ml229.fu21/?report=objectonly" target="object" rid-ob="figobml229fu21" class="figpopup">UPLC-MS Chromatogram of Analog CID 49843308</a></p><p id="ml229.fu22"><a href="/books/NBK98918/figure/ml229.fu22/?report=objectonly" target="object" rid-ob="figobml229fu22" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49842942 (Entry 8, Table 1)</a></p><p id="ml229.fu23"><a href="/books/NBK98918/figure/ml229.fu23/?report=objectonly" target="object" rid-ob="figobml229fu23" class="figpopup">UPLC-MS Chromatogram of Analog CID 49842942</a></p><p id="ml229.fu24"><a href="/books/NBK98918/figure/ml229.fu24/?report=objectonly" target="object" rid-ob="figobml229fu24" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49843324 (Entry 10, Table 1)</a></p><p id="ml229.fu25"><a href="/books/NBK98918/figure/ml229.fu25/?report=objectonly" target="object" rid-ob="figobml229fu25" class="figpopup">UPLC-MS Chromatogram of Analog CID 49843324</a></p><p id="ml229.fu26"><a href="/books/NBK98918/figure/ml229.fu26/?report=objectonly" target="object" rid-ob="figobml229fu26" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49843090 (Entry 11, Table 1)</a></p><p id="ml229.fu27"><a href="/books/NBK98918/figure/ml229.fu27/?report=objectonly" target="object" rid-ob="figobml229fu27" class="figpopup">UPLC-MS Chromatogram of Analog CID 49843090</a></p><p id="ml229.fu28"><a href="/books/NBK98918/figure/ml229.fu28/?report=objectonly" target="object" rid-ob="figobml229fu28" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49843065 (Entry 12, Table 1)</a></p><p id="ml229.fu29"><a href="/books/NBK98918/figure/ml229.fu29/?report=objectonly" target="object" rid-ob="figobml229fu29" class="figpopup">UPLC-MS Chromatogram of Analog CID 49843065</a></p><p id="ml229.fu30"><a href="/books/NBK98918/figure/ml229.fu30/?report=objectonly" target="object" rid-ob="figobml229fu30" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 1507946 (Entry 13, Table 1)</a></p><p id="ml229.fu31"><a href="/books/NBK98918/figure/ml229.fu31/?report=objectonly" target="object" rid-ob="figobml229fu31" class="figpopup">UPLC-MS Chromatogram of Analog CID 1507946</a></p><p id="ml229.fu32"><a href="/books/NBK98918/figure/ml229.fu32/?report=objectonly" target="object" rid-ob="figobml229fu32" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 1507368 (Entry 14, Table 1)</a></p><p id="ml229.fu33"><a href="/books/NBK98918/figure/ml229.fu33/?report=objectonly" target="object" rid-ob="figobml229fu33" class="figpopup">UPLC-MS Chromatogram of Analog CID 1507368</a></p><p id="ml229.fu34"><a href="/books/NBK98918/figure/ml229.fu34/?report=objectonly" target="object" rid-ob="figobml229fu34" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 17581618 (Entry 15, Table 1)</a></p><p id="ml229.fu35"><a href="/books/NBK98918/figure/ml229.fu35/?report=objectonly" target="object" rid-ob="figobml229fu35" class="figpopup">UPLC-MS Chromatogram of Analog CID 17581618</a></p><p id="ml229.fu36"><a href="/books/NBK98918/figure/ml229.fu36/?report=objectonly" target="object" rid-ob="figobml229fu36" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CD<sub>3</sub>OD) of Analog CID 49868641 (Entry 16, Table 1)</a></p><p id="ml229.fu37"><a href="/books/NBK98918/figure/ml229.fu37/?report=objectonly" target="object" rid-ob="figobml229fu37" class="figpopup">UPLC-MS Chromatogram of Analog CID 49868641</a></p><p id="ml229.fu38"><a href="/books/NBK98918/figure/ml229.fu38/?report=objectonly" target="object" rid-ob="figobml229fu38" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 1508612 (Entry 1, Table 2)</a></p><p id="ml229.fu39"><a href="/books/NBK98918/figure/ml229.fu39/?report=objectonly" target="object" rid-ob="figobml229fu39" class="figpopup">UPLC-MS Chromatogram of Analog CID 1508612</a></p><p id="ml229.fu40"><a href="/books/NBK98918/figure/ml229.fu40/?report=objectonly" target="object" rid-ob="figobml229fu40" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49868642 (Entry 2, Table 2)</a></p><p id="ml229.fu41"><a href="/books/NBK98918/figure/ml229.fu41/?report=objectonly" target="object" rid-ob="figobml229fu41" class="figpopup">UPLC-MS Chromatogram of Analog CID 49868642</a></p><p id="ml229.fu42"><a href="/books/NBK98918/figure/ml229.fu42/?report=objectonly" target="object" rid-ob="figobml229fu42" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49868637 (Entry 3, Table 2)</a></p><p id="ml229.fu43"><a href="/books/NBK98918/figure/ml229.fu43/?report=objectonly" target="object" rid-ob="figobml229fu43" class="figpopup">UPLC-MS Chromatogram of Analog CID 49868637</a></p><p id="ml229.fu44"><a href="/books/NBK98918/figure/ml229.fu44/?report=objectonly" target="object" rid-ob="figobml229fu44" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 6498438 (Entry 4, Table 2)</a></p><p id="ml229.fu45"><a href="/books/NBK98918/figure/ml229.fu45/?report=objectonly" target="object" rid-ob="figobml229fu45" class="figpopup">UPLC-MS Chromatogram of Analog CID 6498438</a></p><p id="ml229.fu46"><a href="/books/NBK98918/figure/ml229.fu46/?report=objectonly" target="object" rid-ob="figobml229fu46" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49868634 (Entry 5, Table 2)</a></p><p id="ml229.fu47"><a href="/books/NBK98918/figure/ml229.fu47/?report=objectonly" target="object" rid-ob="figobml229fu47" class="figpopup">UPLC-MS Chromatogram of Analog CID 49868634</a></p><p id="ml229.fu48"><a href="/books/NBK98918/figure/ml229.fu48/?report=objectonly" target="object" rid-ob="figobml229fu48" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49868635 (Entry 6, Table 2)</a></p><p id="ml229.fu49"><a href="/books/NBK98918/figure/ml229.fu49/?report=objectonly" target="object" rid-ob="figobml229fu49" class="figpopup">UPLC-MS Chromatogram of Analog CID 49868635</a></p><p id="ml229.fu50"><a href="/books/NBK98918/figure/ml229.fu50/?report=objectonly" target="object" rid-ob="figobml229fu50" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766545 (Entry 7, Table 2)</a></p><p id="ml229.fu51"><a href="/books/NBK98918/figure/ml229.fu51/?report=objectonly" target="object" rid-ob="figobml229fu51" class="figpopup">UPLC-MS Chromatogram of Analog CID 49766545</a></p><p id="ml229.fu52"><a href="/books/NBK98918/figure/ml229.fu52/?report=objectonly" target="object" rid-ob="figobml229fu52" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49868641 (Entry 8, Table 2)</a></p><p id="ml229.fu53"><a href="/books/NBK98918/figure/ml229.fu53/?report=objectonly" target="object" rid-ob="figobml229fu53" class="figpopup">UPLC-MS Chromatogram of Analog CID 49868641</a></p><p id="ml229.fu54"><a href="/books/NBK98918/figure/ml229.fu54/?report=objectonly" target="object" rid-ob="figobml229fu54" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 7708613 (Entry 9, Table 2)</a></p><p id="ml229.fu55"><a href="/books/NBK98918/figure/ml229.fu55/?report=objectonly" target="object" rid-ob="figobml229fu55" class="figpopup">UPLC-MS Chromatogram of Analog CID 7708613</a></p><p id="ml229.fu56"><a href="/books/NBK98918/figure/ml229.fu56/?report=objectonly" target="object" rid-ob="figobml229fu56" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 1508304 (Entry 10, Table 2)</a></p><p id="ml229.fu57"><a href="/books/NBK98918/figure/ml229.fu57/?report=objectonly" target="object" rid-ob="figobml229fu57" class="figpopup">UPLC-MS Chromatogram of Analog CID 1508304</a></p><p id="ml229.fu58"><a href="/books/NBK98918/figure/ml229.fu58/?report=objectonly" target="object" rid-ob="figobml229fu58" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 7708097 (Entry 11, Table 2)</a></p><p id="ml229.fu59"><a href="/books/NBK98918/figure/ml229.fu59/?report=objectonly" target="object" rid-ob="figobml229fu59" class="figpopup">UPLC-MS Chromatogram of Analog CID 7708097</a></p><p id="ml229.fu60"><a href="/books/NBK98918/figure/ml229.fu60/?report=objectonly" target="object" rid-ob="figobml229fu60" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 17581348 (Entry 12, Table 2)</a></p><p id="ml229.fu61"><a href="/books/NBK98918/figure/ml229.fu61/?report=objectonly" target="object" rid-ob="figobml229fu61" class="figpopup">UPLC-MS Chromatogram of Analog CID 17581348</a></p><p id="ml229.fu62"><a href="/books/NBK98918/figure/ml229.fu62/?report=objectonly" target="object" rid-ob="figobml229fu62" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 7708820 (Entry 1, Table 3)</a></p><p id="ml229.fu63"><a href="/books/NBK98918/figure/ml229.fu63/?report=objectonly" target="object" rid-ob="figobml229fu63" class="figpopup">UPLC-MS Chromatogram of Analog CID 7708820</a></p><p id="ml229.fu64"><a href="/books/NBK98918/figure/ml229.fu64/?report=objectonly" target="object" rid-ob="figobml229fu64" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 1508322 (Entry 2, Table 3)</a></p><p id="ml229.fu65"><a href="/books/NBK98918/figure/ml229.fu65/?report=objectonly" target="object" rid-ob="figobml229fu65" class="figpopup">UPLC-MS Chromatogram of Analog CID 1508322</a></p><p id="ml229.fu66"><a href="/books/NBK98918/figure/ml229.fu66/?report=objectonly" target="object" rid-ob="figobml229fu66" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 7693333 (Entry 3, Table 3)</a></p><p id="ml229.fu67"><a href="/books/NBK98918/figure/ml229.fu67/?report=objectonly" target="object" rid-ob="figobml229fu67" class="figpopup">UPLC-MS Chromatogram of Analog CID 7693333</a></p><p id="ml229.fu68"><a href="/books/NBK98918/figure/ml229.fu68/?report=objectonly" target="object" rid-ob="figobml229fu68" class="figpopup"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766506 (Entry 4, Table 3)</a></p><p id="ml229.fu69"><a href="/books/NBK98918/figure/ml229.fu69/?report=objectonly" target="object" rid-ob="figobml229fu69" class="figpopup">UPLC-MS Chromatogram of Analog CID 49766506</a></p></div></div><div id="ml229.app4"><h2 id="_ml229_app4_">Appendix D. X-Ray Crystal Structure of CID 49835884</h2><div id="ml229.fu70" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=X-Ray%20Crystal%20Structure%20of%20CID%2049835884%20(Entry%204%2C%20Table%201).&p=BOOKS&id=98918_ml229fu104.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/NBK98918/bin/ml229fu104.jpg" alt="X-Ray Crystal Structure of CID 49835884 (Entry 4, Table 1)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title">X-Ray Crystal Structure of CID 49835884 (Entry 4, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3><div class="caption"><p>The associated CIF will be deposited with the Cambridge Crystallographic Data Centre (CCDC).</p></div></div></div><div id="ml229.app5"><h2 id="_ml229_app5_">Appendix E. Compounds Submitted to BioFocus</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml229t7"><a href="/books/NBK98918/table/ml229.t7/?report=objectonly" target="object" title="Table A2" class="img_link icnblk_img figpopup" rid-figpopup="figml229t7" rid-ob="figobml229t7"><img class="small-thumb" src="/books/NBK98918/table/ml229.t7/?report=thumb" src-large="/books/NBK98918/table/ml229.t7/?report=previmg" alt="Table A2. Probe and Analog Information." /></a><div class="icnblk_cntnt"><h4 id="ml229.t7"><a href="/books/NBK98918/table/ml229.t7/?report=objectonly" target="object" rid-ob="figobml229t7">Table A2</a></h4><p class="float-caption no_bottom_margin">Probe and Analog Information. </p></div></div></div><div id="ml229.app6"><h2 id="_ml229_app6_">Appendix F. Eagle Effect Dose-Response Curves</h2><p>The Eagle effect is a documented phenomenon in which drug-resistant bacteria or fungal strains show dose-response inhibition up to a median dose then lose this sensitivity at higher dosages (<a class="bibr" href="#ml229.r11" rid="ml229.r11 ml229.r12 ml229.r13">11–13</a>). A possible explanation for this phenomenon is that at exposure to higher drug concentrations, a different coping mechanism is activated (e.g., efflux pumping), which manifests as decreased inhibition. This effect was observed in the probe and several analogs to varying degrees when tested against the orthogonal <i>Candida</i> CaCi-8 resistant strain. The less resistant <i>Candida</i> CaCi-2 primary screening strain did not demonstrate this phenomenon.</p><p>The full dose-response curves (unmasked and masked) and associated IC<sub>50</sub> values for compounds exhibiting the Eagle effect are reproduced in <a class="figpopup" href="/books/NBK98918/figure/ml229.f10/?report=objectonly" target="object" rid-figpopup="figml229f10" rid-ob="figobml229f10">Figure A1</a>. Data from both the primary CaCi-2 and orthogonal CaCi-8 strains are provided. In order to visualize the Eagle effect in the CaCi-8 strain, the higher dosages were ignored and a new dose-response curve was generated and is presented in <a class="figpopup" href="/books/NBK98918/figure/ml229.f10/?report=objectonly" target="object" rid-figpopup="figml229f10" rid-ob="figobml229f10">Figure A1</a>. An IC<sub>50</sub> value was then calculated from this new curve. For several compounds, the Eagle effect did not impact the calculated IC<sub>50</sub> values despite being readily apparent in the dose-response curves. However, the data for the 9-fluoro analogs showed significant perturbation. When all dosages were considered, these substances were classified as inactive against CaCi-8. By removing the ineffective higher dosages, the dose-response curves were adjusted accordingly. These compounds now exhibited almost nanomolar potency against CaCi-8.</p><p>The data reported above in <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Tables 1</a>–<a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">3</a> (<i>cf.</i>
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<a href="#ml229.s37">Section 3.4</a>) were calculated from all dosages tested, including the higher concentrations where activity diminishes.</p></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK98918_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Cathy L Hartland</span>,<sup>1</sup> <span itemprop="author">Willmen Youngsaye</span>,<sup>1</sup> <span itemprop="author">Chris Dockendorff</span>,<sup>1</sup> <span itemprop="author">Stephen Johnston</span>,<sup>1</sup> <span itemprop="author">Joshua Bittker</span>,<sup>1</sup> <span itemprop="author">Benjamin Vincent</span>,<sup>2</sup> <span itemprop="author">Luke Whitesell</span>,<sup>2</sup> <span itemprop="author">Sivaraman Dandapani</span>,<sup>1</sup> <span itemprop="author">Lawrence MacPherson</span>,<sup>1</sup> <span itemprop="author">Benito Munoz</span>,<sup>1</sup> <span itemprop="author">Michelle Palmer</span>,<sup>1</sup> <span itemprop="author">Susan Lindquist</span>,<sup>2</sup> and <span itemprop="author">Stuart L Schreiber</span><sup>1</sup>.<sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup></p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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The Broad Institute Probe Development Center, Cambridge, MA;</div><div class="affiliation"><sup>2</sup>
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The Whitehead Institute, Cambridge, MA</div><div class="affiliation"><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>Corresponding author email:
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<a href="mailto:dev@null" data-email="gro.etutitsnidaorb@dnaltrah" class="oemail">gro.etutitsnidaorb@dnaltrah</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">March 31, 2011</span>; Last Update: <span itemprop="dateModified">November 21, 2011</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>Hartland CL, Youngsaye W, Dockendorff C, et al. Identification of Small Molecules that Selectively Inhibit Fluconazole-Resistant Candida Albicans in the Presence of Fluconazole but not in its Absence - Probe 3. 2011 Mar 31 [Updated 2011 Nov 21]. 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/ml230/?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/ml228/?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="figobml229fu1"><div id="ml229.fu1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu1.jpg" alt="ML229." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a></span></h3></div></article><article data-type="table-wrap" id="figobml229tu1"><div id="ml229.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98918/table/ml229.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml229.tu1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml229.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID/ML No.</th><th id="hd_h_ml229.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target Name</th><th id="hd_h_ml229.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml229.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-Target Names</th><th id="hd_h_ml229.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml229.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fold Selective<sup>*</sup></th><th id="hd_h_ml229.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay(s) IC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml229.tu1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">229</a></td><td headers="hd_h_ml229.tu1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.tu1_1_1_1_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">960 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023254</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504502" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504502</a>]</td><td headers="hd_h_ml229.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fibroblast toxicity</td><td headers="hd_h_ml229.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>26,000 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023254</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504525" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504525</a>]</td><td headers="hd_h_ml229.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">27</td><td headers="hd_h_ml229.tu1_1_1_1_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-8 growth inhibition 1390 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023254</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504504" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504504</a></td></tr><tr><td headers="hd_h_ml229.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Activity without fluconazole</td><td headers="hd_h_ml229.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>26,000 nM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023254</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504499" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504499</a>]</td><td headers="hd_h_ml229.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">27</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml229.tfn1"><p class="no_margin">Selectivity = Anti-target IC<sub>50</sub>/Target IC<sub>50</sub></p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml229f1"><div id="ml229.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f1.jpg" alt="Figure 1. Chemosensitizing Agents for Reversing Fluconazole Resistance." /></div><h3><span class="label">Figure 1</span><span class="title">Chemosensitizing Agents for Reversing Fluconazole Resistance</span></h3></div></article><article data-type="fig" id="figobml229f2"><div id="ml229.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f2.jpg" alt="Figure 2. Uracil-derived HDAC Inhibitors Capable of Reversing Antifungal Drug Resistance." /></div><h3><span class="label">Figure 2</span><span class="title">Uracil-derived HDAC Inhibitors Capable of Reversing Antifungal Drug Resistance</span></h3></div></article><article data-type="fig" id="figobml229f3"><div id="ml229.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f3.jpg" alt="Figure 3. Positive Controls for Biological Assays." /></div><h3><span class="label">Figure 3</span><span class="title">Positive Controls for Biological Assays</span></h3></div></article><article data-type="fig" id="figobml229f4"><div id="ml229.f4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f4.jpg" alt="Figure 4. Stability of the Probe (CID7694069/ML229) in PBS at 23 °C." /></div><h3><span class="label">Figure 4</span><span class="title">Stability of the Probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) in PBS at 23 °C</span></h3></div></article><article data-type="table-wrap" id="figobml229t1"><div id="ml229.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Evaluation of 16 Synthetic Ester and Amide Analogs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml229.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml229.t1_1_1_1_1" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">SAR Analysis</th><th id="hd_h_ml229.t1_1_1_1_2" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">Structure<br />
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu2.jpg" alt="Image ml229fu2.jpg" /></div></th><th id="hd_h_ml229.t1_1_1_1_3" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Target Potency (μM)<br />Mean ± S.E.M</th><th id="hd_h_ml229.t1_1_1_1_4" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">Anti-target Potency(μM)<br />Mean ± S.E.M</th></tr><tr><th headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" id="hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Entry No.</th><th headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" id="hd_h_ml229.t1_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" id="hd_h_ml229.t1_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" id="hd_h_ml229.t1_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">Broad ID</th><th headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" id="hd_h_ml229.t1_1_1_2_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" id="hd_h_ml229.t1_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>1</sub></th><th headers="hd_h_ml229.t1_1_1_1_3" id="hd_h_ml229.t1_1_1_2_7" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">CaCi-2<sup>a</sup></th><th headers="hd_h_ml229.t1_1_1_1_3" id="hd_h_ml229.t1_1_1_2_8" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">CaCi-2<sup>b</sup></th><th headers="hd_h_ml229.t1_1_1_1_3" id="hd_h_ml229.t1_1_1_2_9" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">CaCi-8<sup>a</sup></th><th headers="hd_h_ml229.t1_1_1_1_4" id="hd_h_ml229.t1_1_1_2_10" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">Fibroblasts<sup>b</sup></th></tr><tr><th headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7" id="hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7" id="hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8" id="hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8" id="hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9" id="hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9" id="hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10" id="hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10" id="hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10" id="hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><sup>**</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7693498</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99245563" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99245563</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K34322692</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu3.jpg" alt="Image ml229fu3.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.02 ± 1.49</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.62 ± 3.30</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 1.6 μM</i> <i>Plasma Protein Binding: 94%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1508416</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99245556" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99245556</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K06098735</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu4.jpg" alt="Image ml229fu4.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.22 ±3.84</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 5.0 μM</i> <i>Plasma Protein Binding: 96%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49843149</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104170287" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104170287</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K20884688</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu5.jpg" alt="Image ml229fu5.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12.0</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 515.2 μM</i> <i>Plasma Protein Binding: 95%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 97%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49835884</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/103910837" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103910837</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K73397422</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu6.jpg" alt="Image ml229fu6.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.84 ± 0.22</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.51 ± 0.89</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.67</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.69</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 12.3 μM</i> <i>Plasma Protein Binding: 91%</i> <i>Plasma Stability: 86%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766519</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023252" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023252</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K07703560</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu7.jpg" alt="Image ml229fu7.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.52 ± 0.74</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.65 ± 1.38<sup>†</sup></td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 0.8 μM</i> <i>Plasma Protein Binding: 92%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766513</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023251" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023251</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K52907439</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu8.jpg" alt="Image ml229fu8.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.61 ± 0.98</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.20 ± 1.42</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 20.8 μM</i> <i>Plasma Protein Binding: 78%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49843308</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104170294" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104170294</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K03555780</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu9.jpg" alt="Image ml229fu9.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.74</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">39.3</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 456.0 μM</i> <i>Plasma Protein Binding: 83%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49842942</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104170286" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104170286</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K72004749</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu10.jpg" alt="Image ml229fu10.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.47</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA<sup>†</sup></td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 3.8 μM</i> <i>Plasma Protein Binding: 88%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 99%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">9</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7694069</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023254" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023254</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K67778494</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu11.jpg" alt="Image ml229fu11.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.96 ± 0.13</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.39 ± 1.00<sup>†</sup></td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 95.4 μM</i> <i>Plasma Protein Binding: 87%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 98%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49843324</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104170298" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104170298</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K53064056</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu12.jpg" alt="Image ml229fu12.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.82</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.02<sup>†</sup></td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 3.9 μM</i> <i>Plasma Protein Binding: 92%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49843090</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104170297" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104170297</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K58565700</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu13.jpg" alt="Image ml229fu13.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.71</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.69</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 6.7 μM</i> <i>Plasma Protein Binding: 57%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 98%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">12</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49843065</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104170296" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104170296</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K61818633</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu14.jpg" alt="Image ml229fu14.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 494.8 μM</i> <i>Plasma Protein Binding: 67%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 92%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">13</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1507946</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023259" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023259</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K40151202</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu15.jpg" alt="Image ml229fu15.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.61 ± 3.30</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 82.9 μM</i> <i>Plasma Protein Binding: 84%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">14</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1507368</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99245573" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99245573</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K44412801</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu16.jpg" alt="Image ml229fu16.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.56 ± 0.76</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: <1.0 μM</i> <i>Plasma Protein Binding: 95%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">15</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17581618</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99245568" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99245568</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K76132250</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu17.jpg" alt="Image ml229fu17.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: <1.0 μM</i> <i>Plasma Protein Binding: 97%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 98%</i></td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">16</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49868641</td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104543579" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104543579</a></td><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K26118965</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu18.jpg" alt="Image ml229fu18.jpg" /></div></td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t1_1_1_1_1 hd_h_ml229.t1_1_1_2_2 hd_h_ml229.t1_1_1_2_3 hd_h_ml229.t1_1_1_2_4 hd_h_ml229.t1_1_1_1_2 hd_h_ml229.t1_1_1_2_5 hd_h_ml229.t1_1_1_2_6 hd_h_ml229.t1_1_1_1_3 hd_h_ml229.t1_1_1_2_7 hd_h_ml229.t1_1_1_3_1 hd_h_ml229.t1_1_1_3_2 hd_h_ml229.t1_1_1_2_8 hd_h_ml229.t1_1_1_3_3 hd_h_ml229.t1_1_1_3_4 hd_h_ml229.t1_1_1_2_9 hd_h_ml229.t1_1_1_3_5 hd_h_ml229.t1_1_1_3_6 hd_h_ml229.t1_1_1_1_4 hd_h_ml229.t1_1_1_2_10 hd_h_ml229.t1_1_1_3_7 hd_h_ml229.t1_1_1_3_8 hd_h_ml229.t1_1_1_3_9" colspan="14" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 320.8 μM</i> <i>Plasma Protein Binding: 94%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 97%</i></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="ml229.tfn2"><p class="no_margin">IA = Inactive; ND = Not determined</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml229.tfn3"><p class="no_margin">S = synthesized; P = purchased</p></div></dd></dl><dl class="bkr_refwrap"><dt>**</dt><dd><div id="ml229.tfn4"><p class="no_margin">CaCi-2 to anti-target fold selectivity</p></div></dd></dl><dl class="bkr_refwrap"><dt>†</dt><dd><div id="ml229.tfn5"><p class="no_margin">This compound exhibited an Eagle effect. See <a href="#ml229.app6">Appendix F</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml229.tfn6"><p class="no_margin">In the presence of fluconazole</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml229.tfn7"><p class="no_margin">In the absence of fluconazole</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml229.tfn8"><p class="no_margin">Number of replicates</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml229f11"><div id="ml229.f11" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f11.jpg" alt="Scheme 1. Synthesis of Probe (CID7694069/ML229)." /></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of Probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu2"><div id="ml229.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu19.jpg" alt="Image ml229fu19" /></div></div></article><article data-type="fig" id="figobml229fu3"><div id="ml229.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu20.jpg" alt="Image ml229fu20" /></div></div></article><article data-type="table-wrap" id="figobml229tu2"><div id="ml229.tu2" class="table"><h3><span class="title">Compound Summary in PubChem</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98918/table/ml229.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml229.tu2_lrgtbl__"><table class="no_top_margin"><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">IUPAC Chemical Name</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3- dihydrothiazolo[3′,2′:1,2]pyrimido[5,4-<i>b</i>]indol-5(6<i>H</i>)-one</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PubChem CID</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7694069</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Weight</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">354.43 g/mol</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Formula</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">C<sub>18</sub>H<sub>18</sub>N<sub>4</sub>O<sub>2</sub>S</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">XLogP3-AA</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Donor</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Acceptor</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bond Count</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exact Mass</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">354.1150</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Topological Polar Surface Area</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">83.2</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml229f6"><div id="ml229.f6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%206.%20Critical%20Path%20for%20Probe%20Development.&p=BOOKS&id=98918_ml229f6.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/NBK98918/bin/ml229f6.jpg" alt="Figure 6. Critical Path for Probe Development." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 6</span><span class="title">Critical Path for Probe Development</span></h3></div></article><article data-type="fig" id="figobml229f5"><div id="ml229.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f5.jpg" alt="Figure 5. Bar Chart of the Antifungal Screening Campaign." /></div><h3><span class="label">Figure 5</span><span class="title">Bar Chart of the Antifungal Screening Campaign</span></h3><div class="caption"><p>Sequential results of primary, secondary, and orthogonal assays, resulting in 296 compounds that passed all criteria.</p></div></div></article><article data-type="fig" id="figobml229f7"><div id="ml229.f7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%207.%20Dose-dependent%20Activity%20of%20the%20Probe%20(ML229)%20Against%20Various%20Cell%20Lines.&p=BOOKS&id=98918_ml229f7.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/NBK98918/bin/ml229f7.jpg" alt="Figure 7. Dose-dependent Activity of the Probe (ML229) Against Various Cell Lines." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 7</span><span class="title">Dose-dependent Activity of the Probe (<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>) Against Various Cell Lines</span></h3><div class="caption"><p><i>C.albicans</i> CaCi-2 in the presence of fluconazole (IC<sub>50</sub> = 960 nM, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504502" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504502</a>) (<i>A</i>); <i>C.albicans</i> CaCi-8 in the presence of fluconazole (IC<sub>50</sub> = 1390 nM, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504504" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504504</a>) (<i>B</i>); Murine 3T3 fibroblasts in the absence of fluconazole (inactive, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504525" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504525</a>) (<i>C</i>); <i>C.albicans</i> CaCi-2 in the absence of fluconazole (inactive, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504499" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504499</a>) (<i>D</i>).</p></div></div></article><article data-type="fig" id="figobml229f8"><div id="ml229.f8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f8.jpg" alt="Figure 8. Summary of analogs prepared to investigate the SAR profile of the HTS hit." /></div><h3><span class="label">Figure 8</span><span class="title">Summary of analogs prepared to investigate the SAR profile of the HTS hit</span></h3><div class="caption"><p>Key SAR findings for each site of diversification are provided in italics</p></div></div></article><article data-type="table-wrap" id="figobml229t2"><div id="ml229.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Evaluation of Synthetic Analogs Bearing Substituted Tetracycle Cores (12 analogs)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml229.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml229.t2_1_1_1_1" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">SAR Analysis</th><th id="hd_h_ml229.t2_1_1_1_2" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">Structure<br />
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu21.jpg" alt="Image ml229fu21.jpg" /></div></th><th id="hd_h_ml229.t2_1_1_1_3" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Target Potency (μM)<br />Mean ± S.E.M</th><th id="hd_h_ml229.t2_1_1_1_4" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">Anti-target Potency (μM)<br />Mean ± S.E.M</th></tr><tr><th headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" id="hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Entry No.</th><th headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" id="hd_h_ml229.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" id="hd_h_ml229.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" id="hd_h_ml229.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Broad ID</th><th headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" id="hd_h_ml229.t2_1_1_2_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" id="hd_h_ml229.t2_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>1</sub></th><th headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" id="hd_h_ml229.t2_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>2</sub></th><th headers="hd_h_ml229.t2_1_1_1_3" id="hd_h_ml229.t2_1_1_2_8" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">CaCi-2<sup>a</sup></th><th headers="hd_h_ml229.t2_1_1_1_3" id="hd_h_ml229.t2_1_1_2_9" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">CaCi-2<sup>b</sup></th><th headers="hd_h_ml229.t2_1_1_1_3" id="hd_h_ml229.t2_1_1_2_10" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">CaCi-8<sup>a</sup></th><th headers="hd_h_ml229.t2_1_1_1_4" id="hd_h_ml229.t2_1_1_2_11" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">Fibroblasts<sup>b</sup></th></tr><tr><th headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8" id="hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8" id="hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9" id="hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9" id="hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10" id="hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10" id="hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11" id="hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11" id="hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11" id="hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><sup>**</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1508612</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99245560" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99245560</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K85540032</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu22.jpg" alt="Image ml229fu22.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.48 ± 0.56</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.89 ± 6.35</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 1.0 μM</i> <i>Plasma Protein Binding: 96%</i> <i>Plasma Stability: 98%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49868642</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104543578" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104543578</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K56067899</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu23.jpg" alt="Image ml229fu23.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 514.2 μM</i> <i>Plasma Protein Binding: 88%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 99%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49868637</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104543577" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104543577</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K61166434</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu24.jpg" alt="Image ml229fu24.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.08</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">19.5</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.99</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 2.0 μM</i> <i>Plasma Protein Binding: 95%</i> <i>Plasma Stability: 86%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6498438</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023255" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023255</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K88745214</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu25.jpg" alt="Image ml229fu25.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.50 ± 0.14</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA<sup>†</sup></td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 5.1 μM</i> <i>Plasma Protein Binding: 80%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49868634</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104543581" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104543581</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K06197956</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu26.jpg" alt="Image ml229fu26.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.28</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA<sup>†</sup></td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 61.0 μM</i> <i>Plasma Protein Binding: 84%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49868635</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104543580" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104543580</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K89228848</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu27.jpg" alt="Image ml229fu27.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.72</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA<sup>†</sup></td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 1.6 μM</i> <i>Plasma Protein Binding: 83%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 98%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766545</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023253" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023253</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K57680310</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu28.jpg" alt="Image ml229fu28.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.48 ± 0.13</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 0.3 μM</i> <i>Plasma Protein Binding: 87%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">8</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49868641</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104543579" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104543579</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K27712477</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu29.jpg" alt="Image ml229fu29.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.39</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 1.9 μM</i> <i>Plasma Protein Binding: 87%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 98%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">9</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7708613</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023258" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023258</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K54763634</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu30.jpg" alt="Image ml229fu30.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.16 ± 0.46</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: <1.0 μM</i> <i>Plasma Protein Binding: 91%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1508304</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023257" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023257</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K19587545</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu31.jpg" alt="Image ml229fu31.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.47 ± 0.35</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 20.9 μM</i> <i>Plasma Protein Binding: 82%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 98%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">11</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7708097</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99245541" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99245541</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K90274651</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">OMe</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu32.jpg" alt="Image ml229fu32.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.04 ± 4.54</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 7.0 μM</i> <i>Plasma Protein Binding: ND</i> <i>Plasma Stability: ND</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">12</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17581348</td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99245534" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99245534</a></td><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K53923665</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">OMe</td><td headers="hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu33.jpg" alt="Image ml229fu33.jpg" /></div></td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t2_1_1_1_1 hd_h_ml229.t2_1_1_2_2 hd_h_ml229.t2_1_1_2_3 hd_h_ml229.t2_1_1_2_4 hd_h_ml229.t2_1_1_1_2 hd_h_ml229.t2_1_1_2_5 hd_h_ml229.t2_1_1_2_6 hd_h_ml229.t2_1_1_2_7 hd_h_ml229.t2_1_1_1_3 hd_h_ml229.t2_1_1_2_8 hd_h_ml229.t2_1_1_3_1 hd_h_ml229.t2_1_1_3_2 hd_h_ml229.t2_1_1_2_9 hd_h_ml229.t2_1_1_3_3 hd_h_ml229.t2_1_1_3_4 hd_h_ml229.t2_1_1_2_10 hd_h_ml229.t2_1_1_3_5 hd_h_ml229.t2_1_1_3_6 hd_h_ml229.t2_1_1_1_4 hd_h_ml229.t2_1_1_2_11 hd_h_ml229.t2_1_1_3_7 hd_h_ml229.t2_1_1_3_8 hd_h_ml229.t2_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: <1.0 μM</i> <i>Plasma Protein Binding: 91%</i> <i>Plasma Stability: 95%</i> <i>Purity (UPLC): 99%</i></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="ml229.tfn9"><p class="no_margin">IA = Inactive; ND = Not determined</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml229.tfn10"><p class="no_margin">S = synthesized; P = purchased</p></div></dd></dl><dl class="bkr_refwrap"><dt>**</dt><dd><div id="ml229.tfn11"><p class="no_margin">CaCi-2 to anti-target fold selectivity</p></div></dd></dl><dl class="bkr_refwrap"><dt>†</dt><dd><div id="ml229.tfn12"><p class="no_margin">This compound exhibited an Eagle effect. See <a href="#ml229.app6">Appendix F</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml229.tfn13"><p class="no_margin">In the presence of fluconazole</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml229.tfn14"><p class="no_margin">In the absence of fluconazole</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml229.tfn15"><p class="no_margin">Number of replicates</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml229t3"><div id="ml229.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Evaluation of Analogs Bearing Expanded/Truncated Tetracycle Cores (4 analogs)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml229.t3_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml229.t3_1_1_1_1" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">SAR Analysis</th><th id="hd_h_ml229.t3_1_1_1_2" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">Structure<br />
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu34.jpg" alt="Image ml229fu34.jpg" /></div></th><th id="hd_h_ml229.t3_1_1_1_3" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Target Potency (μM)<br />Mean ± S.E.M</th><th id="hd_h_ml229.t3_1_1_1_4" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">Anti-target Potency (μM)<br />Mean ± S.E.M</th></tr><tr><th headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_1" id="hd_h_ml229.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Entry No.</th><th headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_2" id="hd_h_ml229.t3_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_3" id="hd_h_ml229.t3_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_4" id="hd_h_ml229.t3_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Broad ID</th><th headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_5" id="hd_h_ml229.t3_1_1_2_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><sup>*</sup></th><th headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_6" id="hd_h_ml229.t3_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>1</sub></th><th headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_7" id="hd_h_ml229.t3_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>2</sub></th><th headers="hd_h_ml229.t3_1_1_1_3" id="hd_h_ml229.t3_1_1_2_8" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">CaCi-2<sup>a</sup></th><th headers="hd_h_ml229.t3_1_1_1_3" id="hd_h_ml229.t3_1_1_2_9" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">CaCi-2<sup>b</sup></th><th headers="hd_h_ml229.t3_1_1_1_3" id="hd_h_ml229.t3_1_1_2_10" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">CaCi-8<sup>a</sup></th><th headers="hd_h_ml229.t3_1_1_1_4" id="hd_h_ml229.t3_1_1_2_11" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">Fibroblasts<sup>b</sup></th></tr><tr><th headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8" id="hd_h_ml229.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8" id="hd_h_ml229.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_9" id="hd_h_ml229.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_9" id="hd_h_ml229.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_10" id="hd_h_ml229.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_10" id="hd_h_ml229.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11" id="hd_h_ml229.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>c</sup></th><th headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11" id="hd_h_ml229.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub></th><th headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11" id="hd_h_ml229.t3_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><sup>**</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7708820</td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99245546" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99245546</a></td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K37127624</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu35.jpg" alt="Image ml229fu35.jpg" /></div></td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_2 hd_h_ml229.t3_1_1_2_3 hd_h_ml229.t3_1_1_2_4 hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_5 hd_h_ml229.t3_1_1_2_6 hd_h_ml229.t3_1_1_2_7 hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_1 hd_h_ml229.t3_1_1_3_2 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_3 hd_h_ml229.t3_1_1_3_4 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_5 hd_h_ml229.t3_1_1_3_6 hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_7 hd_h_ml229.t3_1_1_3_8 hd_h_ml229.t3_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: <1.0 μM</i> <i>Plasma Protein Binding: 93%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): 99%</i></td></tr><tr><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1508322</td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99245550" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99245550</a></td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K42282238</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu36.jpg" alt="Image ml229fu36.jpg" /></div></td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_2 hd_h_ml229.t3_1_1_2_3 hd_h_ml229.t3_1_1_2_4 hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_5 hd_h_ml229.t3_1_1_2_6 hd_h_ml229.t3_1_1_2_7 hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_1 hd_h_ml229.t3_1_1_3_2 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_3 hd_h_ml229.t3_1_1_3_4 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_5 hd_h_ml229.t3_1_1_3_6 hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_7 hd_h_ml229.t3_1_1_3_8 hd_h_ml229.t3_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: <1.0 μM</i> <i>Plasma Protein Binding: 90%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7693333</td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99245562" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99245562</a></td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K76357752</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu35.jpg" alt="Image ml229fu35.jpg" /></div></td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.79 ± 0.77</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_2 hd_h_ml229.t3_1_1_2_3 hd_h_ml229.t3_1_1_2_4 hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_5 hd_h_ml229.t3_1_1_2_6 hd_h_ml229.t3_1_1_2_7 hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_1 hd_h_ml229.t3_1_1_3_2 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_3 hd_h_ml229.t3_1_1_3_4 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_5 hd_h_ml229.t3_1_1_3_6 hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_7 hd_h_ml229.t3_1_1_3_8 hd_h_ml229.t3_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: <1.0 μM</i> <i>Plasma Protein Binding: 90%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr><tr><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49766506</td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/103023256" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">103023256</a></td><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K67144305</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_6 hd_h_ml229.t3_1_1_2_7" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98918/bin/ml229fu37.jpg" alt="Image ml229fu37.jpg" /></div></td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IA</td><td headers="hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml229.t3_1_1_1_1 hd_h_ml229.t3_1_1_2_2 hd_h_ml229.t3_1_1_2_3 hd_h_ml229.t3_1_1_2_4 hd_h_ml229.t3_1_1_1_2 hd_h_ml229.t3_1_1_2_5 hd_h_ml229.t3_1_1_2_6 hd_h_ml229.t3_1_1_2_7 hd_h_ml229.t3_1_1_1_3 hd_h_ml229.t3_1_1_2_8 hd_h_ml229.t3_1_1_3_1 hd_h_ml229.t3_1_1_3_2 hd_h_ml229.t3_1_1_2_9 hd_h_ml229.t3_1_1_3_3 hd_h_ml229.t3_1_1_3_4 hd_h_ml229.t3_1_1_2_10 hd_h_ml229.t3_1_1_3_5 hd_h_ml229.t3_1_1_3_6 hd_h_ml229.t3_1_1_1_4 hd_h_ml229.t3_1_1_2_11 hd_h_ml229.t3_1_1_3_7 hd_h_ml229.t3_1_1_3_8 hd_h_ml229.t3_1_1_3_9" colspan="15" rowspan="1" style="text-align:center;vertical-align:middle;"><i>PBS Solubility: 397.0 μM</i> <i>Plasma Protein Binding: 88%</i> <i>Plasma Stability: >99%</i> <i>Purity (UPLC): >99%</i></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="ml229.tfn16"><p class="no_margin">IA = Inactive; ND = Not determined</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml229.tfn17"><p class="no_margin">S = synthesized; P = purchased</p></div></dd></dl><dl class="bkr_refwrap"><dt>**</dt><dd><div id="ml229.tfn18"><p class="no_margin">CaCi-2 to anti-target fold selectivity</p></div></dd></dl><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml229.tfn19"><p class="no_margin">In the presence of fluconazole</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml229.tfn20"><p class="no_margin">In the absence of fluconazole</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml229.tfn21"><p class="no_margin">Number of replicates</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml229t4"><div id="ml229.t4" class="table"><h3><span class="label">Table 4</span><span class="title">Comparison of the Probe to Project Criteria</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98918/table/ml229.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml229.t4_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml229.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">No.</th><th id="hd_h_ml229.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Property</th><th id="hd_h_ml229.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Requirement</th><th id="hd_h_ml229.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe</th></tr></thead><tbody><tr><td headers="hd_h_ml229.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td><td headers="hd_h_ml229.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CaCi-2 IC<sub>50</sub> with 8 μg/ml fluconazole</td><td headers="hd_h_ml229.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Less than 1 μM</td><td headers="hd_h_ml229.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.96 μM</td></tr><tr><td headers="hd_h_ml229.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml229.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CaCi-8 IC<sub>50</sub> with 8 μg/ml fluconazole</td><td headers="hd_h_ml229.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Less than 50 μM</td><td headers="hd_h_ml229.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.39 μM</td></tr><tr><td headers="hd_h_ml229.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td><td headers="hd_h_ml229.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CaCi-2 IC<sub>50</sub> without fluconazole</td><td headers="hd_h_ml229.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Greater than 10 μM</td><td headers="hd_h_ml229.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>26 μM</td></tr><tr><td headers="hd_h_ml229.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td><td headers="hd_h_ml229.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Mammalian fibroblast IC<sub>50</sub></td><td headers="hd_h_ml229.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">At least 10-fold greater than (<a class="bibr" href="#ml229.r1" rid="ml229.r1">1</a>)</td><td headers="hd_h_ml229.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>27-fold</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml229t5"><div id="ml229.t5" class="table"><h3><span class="label">Table 5</span><span class="title">Search Strings and Databases Employed in Prior Art Search</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98918/table/ml229.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml229.t5_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Search String</th><th id="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Database</th><th id="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Hits Found</th></tr></thead><tbody><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole resistance”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SciFinder</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3071</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole sensitivity”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SciFinder</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">702</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole chemosensitizer”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SciFinder</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole resistance”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Reaxys</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">162</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole AND sensitivity”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Reaxys</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole AND chemosensitize”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Reaxys</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole resistance”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem Bioassay</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">250</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole sensitivity”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem Bioassay</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">34</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole chemosensitize”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem Bioassay</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole resistance”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubMed</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1923</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole sensitivity”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubMed</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2153</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole chemosensitize”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubMed</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole resistance”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">USPTO PatFT</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole resistance”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">USPTO AppFT</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">28</td></tr><tr><td headers="hd_h_ml229.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“fluconazole sensitivity”</td><td headers="hd_h_ml229.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">WIPO</td><td headers="hd_h_ml229.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1225</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml229f9"><div id="ml229.f9" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f9.jpg" alt="Figure 9. Chemosensitizers for Reversing Fluconazole Resistance (MIC=1.2–2.8 μM)." /></div><h3><span class="label">Figure 9</span><span class="title">Chemosensitizers for Reversing Fluconazole Resistance (MIC=1.2–2.8 μM)</span></h3></div></article><article data-type="table-wrap" id="figobml229t6"><div id="ml229.t6" class="table"><h3><span class="label">Table A1</span><span class="title">Summary of Completed Assays and AIDs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98918/table/ml229.t6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml229.t6_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem AID Nos.</th><th id="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Type</th><th id="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target</th><th id="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Concentration Range (μM)</th><th id="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Samples Tested</th></tr></thead><tbody><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1979" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1979</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Primary</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.5</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">302509</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2467" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2467</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Confirmatory</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.8 – 0.03</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1654</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488836</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Confirmatory (powder)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">30</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493081" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493081</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analogs 1</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12 – 0.05</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">29</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493150" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493150</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analogs 2</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12 – 0.05</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">33</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504502" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504502</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analogs 3</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12 – 0.05</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">28</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2327" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2327</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fibroblast toxicity</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16 – 0.12</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1654</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488809" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488809</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen (powder)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fibroblast toxicity</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493147" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493147</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen (analogs)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fibroblast toxicity</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6 – 0.05</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">108</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504525" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504525</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen (analogs 2)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fibroblast toxicity</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6 – 0.05</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">28</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2423" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2423</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Orthogonal</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-8 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16 – 0.12</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1654</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488807" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488807</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Orthogonal (powder)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-8 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493082" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493082</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Orthogonal (analogs)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-8 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">29</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493149" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493149</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Orthogonal (analogs 2)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-8 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">33</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504504" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504504</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Orthogonal (analogs 3)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-8 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">28</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2387" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2387</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16 – 0.12</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">350</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488802" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488802</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary (powder)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">30</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493157" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493157</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary (analogs)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">29</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504499" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504499</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary (analogs2)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">28</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493134" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493134</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary (analogs3)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CaCi-2 growth inhibition</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">33</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2400" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2400</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Hsp90</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16 – 0.12</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">350</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504390" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504390</a></b></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary (analogs)</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Hsp90</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26 – 0.1</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">18</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2388" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2388</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Calcineurin</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16 – 0.12</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">350</td></tr><tr><td headers="hd_h_ml229.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2007" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2007</a></td><td headers="hd_h_ml229.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Summary</td><td headers="hd_h_ml229.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td><td headers="hd_h_ml229.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td><td headers="hd_h_ml229.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml229fu4"><div id="ml229.fu4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu38.jpg" alt="1H NMR Spectrum (500 MHz, CDCl3) of the Probe (CID7694069/ML229)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (500 MHz, CDCl<sub>3</sub>) of the Probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu5"><div id="ml229.fu5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu39.jpg" alt="13C NMR Spectrum (125 MHz, CDCl3) of the Probe (CID7694069/ML229)." /></div><h3><span class="title"><sup>13</sup>C NMR Spectrum (125 MHz, CDCl<sub>3</sub>) of the Probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu6"><div id="ml229.fu6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu40.jpg" alt="UPLC Chromatogram of the Probe (CID7694069/ML229)." /></div><h3><span class="title">UPLC Chromatogram of the Probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu7"><div id="ml229.fu7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu41.jpg" alt="HRMS (ESI) of the Probe (CID7694069/ML229)." /></div><h3><span class="title">HRMS (ESI) of the Probe (CID7694069/<a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML229</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu8"><div id="ml229.fu8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu42.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 7693498 (Entry 1, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 7693498 (Entry 1, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu9"><div id="ml229.fu9" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu43.jpg" alt="UPLC-MS Chromatogram of Analog CID 7693498." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 7693498</span></h3></div></article><article data-type="fig" id="figobml229fu10"><div id="ml229.fu10" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu44.jpg" alt="1H NMR Spectrum (300 MHz, DMSO-d6) of Analog CID 1508416 (Entry 2, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 1508416 (Entry 2, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu11"><div id="ml229.fu11" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu45.jpg" alt="UPLC-MS Chromatogram of Analog CID 1508416." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 1508416</span></h3></div></article><article data-type="fig" id="figobml229fu12"><div id="ml229.fu12" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu46.jpg" alt="1H NMR Spectrum (300 MHz, DMSO-d6) of Analog CID 49843149 (Entry 3, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49843149 (Entry 3, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu13"><div id="ml229.fu13" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu47.jpg" alt="UPLC-MS Chromatogram of Analog CID 49843149." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49843149</span></h3></div></article><article data-type="fig" id="figobml229fu14"><div id="ml229.fu14" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu48.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 49835884 (Entry 4, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49835884 (Entry 4, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu15"><div id="ml229.fu15" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu49.jpg" alt="UPLC-MS Chromatogram of Analog CID 49835884." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49835884</span></h3></div></article><article data-type="fig" id="figobml229fu16"><div id="ml229.fu16" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu50.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 49766519 (Entry 5, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766519 (Entry 5, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu17"><div id="ml229.fu17" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu51.jpg" alt="UPLC-MS Chromatogram of Analog CID 49766519." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49766519</span></h3></div></article><article data-type="fig" id="figobml229fu18"><div id="ml229.fu18" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu52.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 49766513 (Entry 6, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766513 (Entry 6, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu19"><div id="ml229.fu19" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu53.jpg" alt="UPLC-MS Chromatogram of Analog CID 49766513." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49766513</span></h3></div></article><article data-type="fig" id="figobml229fu20"><div id="ml229.fu20" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu54.jpg" alt="1H NMR Spectrum (300 MHz, Acetone-d6) of Analog CID 49843308 (Entry 7, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, Acetone-d<sub>6</sub>) of Analog CID 49843308 (Entry 7, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu21"><div id="ml229.fu21" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu55.jpg" alt="UPLC-MS Chromatogram of Analog CID 49843308." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49843308</span></h3></div></article><article data-type="fig" id="figobml229fu22"><div id="ml229.fu22" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu56.jpg" alt="1H NMR Spectrum (300 MHz, DMSO-d6) of Analog CID 49842942 (Entry 8, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49842942 (Entry 8, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu23"><div id="ml229.fu23" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu57.jpg" alt="UPLC-MS Chromatogram of Analog CID 49842942." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49842942</span></h3></div></article><article data-type="fig" id="figobml229fu24"><div id="ml229.fu24" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu58.jpg" alt="1H NMR Spectrum (300 MHz, DMSO-d6) of Analog CID 49843324 (Entry 10, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49843324 (Entry 10, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu25"><div id="ml229.fu25" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu59.jpg" alt="UPLC-MS Chromatogram of Analog CID 49843324." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49843324</span></h3></div></article><article data-type="fig" id="figobml229fu26"><div id="ml229.fu26" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu60.jpg" alt="1H NMR Spectrum (300 MHz, DMSO-d6) of Analog CID 49843090 (Entry 11, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49843090 (Entry 11, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu27"><div id="ml229.fu27" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu61.jpg" alt="UPLC-MS Chromatogram of Analog CID 49843090." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49843090</span></h3></div></article><article data-type="fig" id="figobml229fu28"><div id="ml229.fu28" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu62.jpg" alt="1H NMR Spectrum (300 MHz, DMSO-d6) of Analog CID 49843065 (Entry 12, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49843065 (Entry 12, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu29"><div id="ml229.fu29" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu63.jpg" alt="UPLC-MS Chromatogram of Analog CID 49843065." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49843065</span></h3></div></article><article data-type="fig" id="figobml229fu30"><div id="ml229.fu30" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu64.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 1507946 (Entry 13, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 1507946 (Entry 13, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu31"><div id="ml229.fu31" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu65.jpg" alt="UPLC-MS Chromatogram of Analog CID 1507946." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 1507946</span></h3></div></article><article data-type="fig" id="figobml229fu32"><div id="ml229.fu32" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu66.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 1507368 (Entry 14, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 1507368 (Entry 14, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu33"><div id="ml229.fu33" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu67.jpg" alt="UPLC-MS Chromatogram of Analog CID 1507368." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 1507368</span></h3></div></article><article data-type="fig" id="figobml229fu34"><div id="ml229.fu34" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu68.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 17581618 (Entry 15, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 17581618 (Entry 15, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu35"><div id="ml229.fu35" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu69.jpg" alt="UPLC-MS Chromatogram of Analog CID 17581618." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 17581618</span></h3></div></article><article data-type="fig" id="figobml229fu36"><div id="ml229.fu36" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu70.jpg" alt="1H NMR Spectrum (300 MHz, CD3OD) of Analog CID 49868641 (Entry 16, Table 1)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CD<sub>3</sub>OD) of Analog CID 49868641 (Entry 16, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu37"><div id="ml229.fu37" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu71.jpg" alt="UPLC-MS Chromatogram of Analog CID 49868641." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49868641</span></h3></div></article><article data-type="fig" id="figobml229fu38"><div id="ml229.fu38" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu72.jpg" alt="1H NMR Spectrum (300 MHz, DMSO-d6) of Analog CID 1508612 (Entry 1, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 1508612 (Entry 1, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu39"><div id="ml229.fu39" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu73.jpg" alt="UPLC-MS Chromatogram of Analog CID 1508612." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 1508612</span></h3></div></article><article data-type="fig" id="figobml229fu40"><div id="ml229.fu40" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu74.jpg" alt="1H NMR Spectrum (300 MHz, DMSO-d6) of Analog CID 49868642 (Entry 2, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49868642 (Entry 2, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu41"><div id="ml229.fu41" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu75.jpg" alt="UPLC-MS Chromatogram of Analog CID 49868642." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49868642</span></h3></div></article><article data-type="fig" id="figobml229fu42"><div id="ml229.fu42" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu76.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 49868637 (Entry 3, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49868637 (Entry 3, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu43"><div id="ml229.fu43" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu77.jpg" alt="UPLC-MS Chromatogram of Analog CID 49868637." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49868637</span></h3></div></article><article data-type="fig" id="figobml229fu44"><div id="ml229.fu44" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu78.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 6498438 (Entry 4, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 6498438 (Entry 4, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu45"><div id="ml229.fu45" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu79.jpg" alt="UPLC-MS Chromatogram of Analog CID 6498438." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 6498438</span></h3></div></article><article data-type="fig" id="figobml229fu46"><div id="ml229.fu46" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu80.jpg" alt="1H NMR Spectrum (300 MHz, DMSO-d6) of Analog CID 49868634 (Entry 5, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, DMSO-d<sub>6</sub>) of Analog CID 49868634 (Entry 5, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu47"><div id="ml229.fu47" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu81.jpg" alt="UPLC-MS Chromatogram of Analog CID 49868634." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49868634</span></h3></div></article><article data-type="fig" id="figobml229fu48"><div id="ml229.fu48" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu82.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 49868635 (Entry 6, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49868635 (Entry 6, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu49"><div id="ml229.fu49" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu83.jpg" alt="UPLC-MS Chromatogram of Analog CID 49868635." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49868635</span></h3></div></article><article data-type="fig" id="figobml229fu50"><div id="ml229.fu50" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu84.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 49766545 (Entry 7, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766545 (Entry 7, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu51"><div id="ml229.fu51" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu85.jpg" alt="UPLC-MS Chromatogram of Analog CID 49766545." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49766545</span></h3></div></article><article data-type="fig" id="figobml229fu52"><div id="ml229.fu52" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu86.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 49868641 (Entry 8, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49868641 (Entry 8, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu53"><div id="ml229.fu53" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu87.jpg" alt="UPLC-MS Chromatogram of Analog CID 49868641." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49868641</span></h3></div></article><article data-type="fig" id="figobml229fu54"><div id="ml229.fu54" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu88.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 7708613 (Entry 9, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 7708613 (Entry 9, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu55"><div id="ml229.fu55" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu89.jpg" alt="UPLC-MS Chromatogram of Analog CID 7708613." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 7708613</span></h3></div></article><article data-type="fig" id="figobml229fu56"><div id="ml229.fu56" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu90.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 1508304 (Entry 10, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 1508304 (Entry 10, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu57"><div id="ml229.fu57" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu91.jpg" alt="UPLC-MS Chromatogram of Analog CID 1508304." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 1508304</span></h3></div></article><article data-type="fig" id="figobml229fu58"><div id="ml229.fu58" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu92.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 7708097 (Entry 11, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 7708097 (Entry 11, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu59"><div id="ml229.fu59" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu93.jpg" alt="UPLC-MS Chromatogram of Analog CID 7708097." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 7708097</span></h3></div></article><article data-type="fig" id="figobml229fu60"><div id="ml229.fu60" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu94.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 17581348 (Entry 12, Table 2)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 17581348 (Entry 12, <a class="figpopup" href="/books/NBK98918/table/ml229.t2/?report=objectonly" target="object" rid-figpopup="figml229t2" rid-ob="figobml229t2">Table 2</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu61"><div id="ml229.fu61" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu95.jpg" alt="UPLC-MS Chromatogram of Analog CID 17581348." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 17581348</span></h3></div></article><article data-type="fig" id="figobml229fu62"><div id="ml229.fu62" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu96.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 7708820 (Entry 1, Table 3)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 7708820 (Entry 1, <a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">Table 3</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu63"><div id="ml229.fu63" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu97.jpg" alt="UPLC-MS Chromatogram of Analog CID 7708820." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 7708820</span></h3></div></article><article data-type="fig" id="figobml229fu64"><div id="ml229.fu64" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu98.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 1508322 (Entry 2, Table 3)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 1508322 (Entry 2, <a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">Table 3</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu65"><div id="ml229.fu65" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu99.jpg" alt="UPLC-MS Chromatogram of Analog CID 1508322." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 1508322</span></h3></div></article><article data-type="fig" id="figobml229fu66"><div id="ml229.fu66" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu100.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 7693333 (Entry 3, Table 3)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 7693333 (Entry 3, <a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">Table 3</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu67"><div id="ml229.fu67" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu101.jpg" alt="UPLC-MS Chromatogram of Analog CID 7693333." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 7693333</span></h3></div></article><article data-type="fig" id="figobml229fu68"><div id="ml229.fu68" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu102.jpg" alt="1H NMR Spectrum (300 MHz, CDCl3) of Analog CID 49766506 (Entry 4, Table 3)." /></div><h3><span class="title"><sup>1</sup>H NMR Spectrum (300 MHz, CDCl<sub>3</sub>) of Analog CID 49766506 (Entry 4, <a class="figpopup" href="/books/NBK98918/table/ml229.t3/?report=objectonly" target="object" rid-figpopup="figml229t3" rid-ob="figobml229t3">Table 3</a>)</span></h3></div></article><article data-type="fig" id="figobml229fu69"><div id="ml229.fu69" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229fu103.jpg" alt="UPLC-MS Chromatogram of Analog CID 49766506." /></div><h3><span class="title">UPLC-MS Chromatogram of Analog CID 49766506</span></h3></div></article><article data-type="fig" id="figobml229fu70"><div id="ml229.fu70" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=X-Ray%20Crystal%20Structure%20of%20CID%2049835884%20(Entry%204%2C%20Table%201).&p=BOOKS&id=98918_ml229fu104.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/NBK98918/bin/ml229fu104.jpg" alt="X-Ray Crystal Structure of CID 49835884 (Entry 4, Table 1)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title">X-Ray Crystal Structure of CID 49835884 (Entry 4, <a class="figpopup" href="/books/NBK98918/table/ml229.t1/?report=objectonly" target="object" rid-figpopup="figml229t1" rid-ob="figobml229t1">Table 1</a>)</span></h3><div class="caption"><p>The associated CIF will be deposited with the Cambridge Crystallographic Data Centre (CCDC).</p></div></div></article><article data-type="table-wrap" id="figobml229t7"><div id="ml229.t7" class="table"><h3><span class="label">Table A2</span><span class="title">Probe and Analog Information</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98918/table/ml229.t7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml229.t7_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml229.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD</th><th id="hd_h_ml229.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th id="hd_h_ml229.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th id="hd_h_ml229.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P/A</th><th id="hd_h_ml229.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLSID</th><th id="hd_h_ml229.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ML</th></tr></thead><tbody><tr><td headers="hd_h_ml229.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K67778494-001-07-4</td><td headers="hd_h_ml229.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/112378965" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">112378965</a></td><td headers="hd_h_ml229.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7694069</td><td headers="hd_h_ml229.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml229.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">003390980</td><td headers="hd_h_ml229.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="/pcsubstance/?term=ML229[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">229</a></td></tr><tr><td headers="hd_h_ml229.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K37127624-001-05-8</td><td headers="hd_h_ml229.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/112378962" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">112378962</a></td><td headers="hd_h_ml229.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7708820</td><td headers="hd_h_ml229.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml229.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">003390983</td><td headers="hd_h_ml229.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml229.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K40151202-001-03-8</td><td headers="hd_h_ml229.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/112378963" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">112378963</a></td><td headers="hd_h_ml229.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1507946</td><td headers="hd_h_ml229.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml229.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">003390982</td><td headers="hd_h_ml229.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml229.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K53923665-001-02-6</td><td headers="hd_h_ml229.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/112378964" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">112378964</a></td><td headers="hd_h_ml229.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17581348</td><td headers="hd_h_ml229.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml229.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">003390984</td><td headers="hd_h_ml229.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml229.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K76132250-001-02-8</td><td headers="hd_h_ml229.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/112378966" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">112378966</a></td><td headers="hd_h_ml229.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17581618</td><td headers="hd_h_ml229.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml229.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">003390981</td><td headers="hd_h_ml229.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr><tr><td headers="hd_h_ml229.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BRD-K76357752-001-05-7</td><td headers="hd_h_ml229.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/112378967" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">112378967</a></td><td headers="hd_h_ml229.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7693333</td><td headers="hd_h_ml229.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml229.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">003390979</td><td headers="hd_h_ml229.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NA</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="ml229.tfn22"><p class="no_margin">A = analog; NA= not applicable; P = probe</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml229f10"><div id="ml229.f10" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f10a.jpg" alt="Figure A1. Representative Dose-Response Curves for Compounds Exhibiting the Eagle Effect." /></div><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f10b.jpg" alt="Figure A1. Representative Dose-Response Curves for Compounds Exhibiting the Eagle Effect." /></div><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f10c.jpg" alt="Figure A1. Representative Dose-Response Curves for Compounds Exhibiting the Eagle Effect." /></div><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f10d.jpg" alt="Figure A1. Representative Dose-Response Curves for Compounds Exhibiting the Eagle Effect." /></div><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f10e.jpg" alt="Figure A1. Representative Dose-Response Curves for Compounds Exhibiting the Eagle Effect." /></div><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f10f.jpg" alt="Figure A1. Representative Dose-Response Curves for Compounds Exhibiting the Eagle Effect." /></div><div class="graphic"><img data-src="/books/NBK98918/bin/ml229f10g.jpg" alt="Figure A1. Representative Dose-Response Curves for Compounds Exhibiting the Eagle Effect." /></div><h3><span class="label">Figure A1</span><span class="title">Representative Dose-Response Curves for Compounds Exhibiting the Eagle Effect</span></h3></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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