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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Optimization and Characterization of an Inhibitor for NADPH Oxidase 1 (NOX-1) - 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="Optimization and Characterization of an Inhibitor for NADPH Oxidase 1 (NOX-1)">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2011/12/12">
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<meta name="citation_author" content="D Gianni">
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<meta name="citation_author" content="N Nicolas">
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<meta name="citation_author" content="H Zhang">
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<meta name="citation_author" content="C Der Mardirossian">
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<meta name="citation_author" content="J Kister">
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<meta name="citation_author" content="L Martinez">
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<meta name="citation_author" content="J Ferguson">
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<meta name="citation_author" content="WR Roush">
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<meta name="citation_author" content="SJ Brown">
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<meta name="citation_author" content="GM Bokoch">
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<meta name="citation_author" content="P Hodder">
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<meta name="citation_author" content="H Rosen">
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<meta name="citation_pmid" content="22834042">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK98925/">
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<meta name="DC.Title" content="Optimization and Characterization of an Inhibitor for NADPH Oxidase 1 (NOX-1)">
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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="D Gianni">
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<meta name="DC.Contributor" content="N Nicolas">
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<meta name="DC.Contributor" content="H Zhang">
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<meta name="DC.Contributor" content="C Der Mardirossian">
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<meta name="DC.Contributor" content="J Kister">
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<meta name="DC.Contributor" content="L Martinez">
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<meta name="DC.Contributor" content="J Ferguson">
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<meta name="DC.Contributor" content="WR Roush">
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<meta name="DC.Contributor" content="SJ Brown">
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<meta name="DC.Contributor" content="GM Bokoch">
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<meta name="DC.Contributor" content="P Hodder">
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<meta name="DC.Contributor" content="H Rosen">
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<meta name="DC.Date" content="2011/12/12">
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<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK98925/">
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<meta name="description" content="The NADPH oxidase (NOX) family catalyzes the regulated formation of reactive oxygen species (ROS). ROS generated via NOX1 have been reported to play a role in a growing number of diseases, including cancer, atherosclerosis, hypertension, neurological disorders and inflammation. Since ROS are also produced by other cellular enzymes, the ability to selectively inhibit NOX1 can be expected to provide reversible, mechanistic insights into these cellular processes with which it is involved. The Scripps Research Institute Molecular Screening Center (SRIMSC), part of the Molecular Libraries Probe Production Centers Network (MLPCN), identified a potent and selective phenothiazine NOX1 inhibitor probe, ML171, by high-throughput screening using a cell-based luminescence assay. ML171 is a potent and selective inhibitor of NOX1, with an IC50 of 129–156 nM in cell-based assays. ML171 is not cytotoxic, and is selective among NOX family members NOX2, NOX3, and NOX4, as well as against xanthine oxidase, another cellular source of ROS. In addition, ML171 is highly effective in inhibiting the cellular production of invadopodia in a human colon cancer cell line. These results elucidate the relevance of NOX1-dependent ROS generation in mechanisms of cancer invasion, and define compound ML171 as a powerful NOX1 chemical probe and a potential therapeutic agent for treatment of this pathology.">
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<meta name="og:title" content="Optimization and Characterization of an Inhibitor for NADPH Oxidase 1 (NOX-1)">
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<meta name="og:description" content="The NADPH oxidase (NOX) family catalyzes the regulated formation of reactive oxygen species (ROS). ROS generated via NOX1 have been reported to play a role in a growing number of diseases, including cancer, atherosclerosis, hypertension, neurological disorders and inflammation. Since ROS are also produced by other cellular enzymes, the ability to selectively inhibit NOX1 can be expected to provide reversible, mechanistic insights into these cellular processes with which it is involved. The Scripps Research Institute Molecular Screening Center (SRIMSC), part of the Molecular Libraries Probe Production Centers Network (MLPCN), identified a potent and selective phenothiazine NOX1 inhibitor probe, ML171, by high-throughput screening using a cell-based luminescence assay. ML171 is a potent and selective inhibitor of NOX1, with an IC50 of 129–156 nM in cell-based assays. ML171 is not cytotoxic, and is selective among NOX family members NOX2, NOX3, and NOX4, as well as against xanthine oxidase, another cellular source of ROS. In addition, ML171 is highly effective in inhibiting the cellular production of invadopodia in a human colon cancer cell line. These results elucidate the relevance of NOX1-dependent ROS generation in mechanisms of cancer invasion, and define compound ML171 as a powerful NOX1 chemical probe and a potential therapeutic agent for treatment of this pathology.">
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id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK98925_"><span class="title" itemprop="name">Optimization and Characterization of an Inhibitor for NADPH Oxidase 1
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(NOX-1)</span></h1><p class="contribs">Gianni D, Nicolas N, Zhang H, et al.</p><p class="fm-aai"><a href="#_NBK98925_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 NADPH oxidase (NOX) family catalyzes the regulated formation of reactive oxygen
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species (ROS). ROS generated via NOX1 have been reported to play a role in a growing
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number of diseases, including cancer, atherosclerosis, hypertension, neurological
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disorders and inflammation. Since ROS are also produced by other cellular enzymes,
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the ability to selectively inhibit NOX1 can be expected to provide reversible,
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mechanistic insights into these cellular processes with which it is involved. The
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Scripps Research Institute Molecular Screening Center (SRIMSC), part of the
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Molecular Libraries Probe Production Centers Network (MLPCN), identified a potent
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and selective phenothiazine NOX1 inhibitor probe, <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a>, by high-throughput screening using a cell-based luminescence
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assay. <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> is a potent and selective inhibitor of
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NOX1, with an IC<sub>50</sub> of 129–156 nM in cell-based assays. <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> is not cytotoxic, and is selective among NOX family members
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NOX2, NOX3, and NOX4, as well as against xanthine oxidase, another cellular source
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of ROS. In addition, <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> is highly effective in inhibiting the
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cellular production of invadopodia in a human colon cancer cell line. These results
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elucidate the relevance of NOX1-dependent ROS generation in mechanisms of cancer
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invasion, and define compound <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> as a powerful NOX1
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chemical probe and a potential therapeutic agent for treatment of this
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pathology.</p></div><div class="h2"></div><p>Assigned Assay Grant #: 1 R03 MH083264-01A1</p><p>Screening Center Name & PI: Scripps Research Institute Molecular Screening Center (SRIMSC), Hugh Rosen</p><p>Chemistry Center Name & PI: SRIMSC, Hugh Rosen</p><p>Assay Submitter & Institution: Gary M. Bokoch, The Scripps Research Institute</p><p>PubChem Summary Bioassay Identifier (AID): <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1796" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1796</a></p><div id="ml171.s1"><h2 id="_ml171_s1_">Probe Structure & Characteristics</h2><div id="ml171.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK98925/bin/ml171fu1.jpg" alt="ML171." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a></span></h3></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml171tu1"><a href="/books/NBK98925/table/ml171.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml171tu1" rid-ob="figobml171tu1"><img class="small-thumb" src="/books/NBK98925/table/ml171.tu1/?report=thumb" src-large="/books/NBK98925/table/ml171.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml171.tu1"><a href="/books/NBK98925/table/ml171.tu1/?report=objectonly" target="object" rid-ob="figobml171tu1">Table</a></h4></div></div></div><div id="ml171.s2"><h2 id="_ml171_s2_">Recommendations for scientific use of the probe</h2><p>The NADPH oxidase (NOX) family catalyzes the regulated formation of reactive oxygen species (ROS) [<a class="bibr" href="#ml171.r1" rid="ml171.r1">1</a>]. ROS generated via NOX1 have been reported to play a role in a growing number of diseases, including cancer, atherosclerosis, hypertension, neurological disorders and inflammation [<a class="bibr" href="#ml171.r2" rid="ml171.r2 ml171.r3 ml171.r4 ml171.r5 ml171.r6 ml171.r7">2–7</a>]. A few non-specific NOX1 inhibitors have been reported in the literature [<a class="bibr" href="#ml171.r8" rid="ml171.r8 ml171.r9 ml171.r10 ml171.r11">8–11</a>]. Our first NOX1 inhibitor probe (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>, CID 616479), based on a quinoxaline scaffold, is the first specific NOX inhibitor to be described [<a class="bibr" href="#ml171.r12" rid="ml171.r12">12</a>]. Since ROS are also produced by other cellular enzymes, the ability to selectively inhibit NOX1 can be expected to provide reversible, mechanistic insights into these cellular processes with which it is involved. The results reported here demonstrate the identification of a subset of phenothiazines as nanomolar, cell-active and specific NOX1 inhibitors that potently block NOX1-dependent ROS generation, with only marginal activity on other cellular ROS-producing enzymes and receptors including the other NOX isoforms. The probe compound <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> reported here also blocks the ROS-dependent formation of ECM-degrading invadopodia in colon cancer cells. These results elucidate the relevance of NOX1-dependent ROS generation in mechanisms of cancer invasion, and define probe compound <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> as a powerful NOX1 chemical probe and a potential therapeutic agent for treatment of this pathology. Interestingly, Dr. Brent Stockwell from Columbia has recently successfully used compound <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> to protect against erastin-induced cell death (personal communication to Dr. Hugh Rosen), confirming the rapid uptake of this probe by the research community and the value of this compound.</p></div><div id="ml171.s3"><h2 id="_ml171_s3_">1. Introduction</h2><p>The NADPH oxidase (NOX) family, consisting of the homologous enzymes NOX1-4 and the more distantly related NOX5, Duox1 and Duox2, catalyzes the regulated formation of reactive oxygen species (ROS) [<a class="bibr" href="#ml171.r1" rid="ml171.r1">1</a>]. Among all seven NOX isoforms, the NOX1-4 enzymes share the highest level of structural similarities [<a class="bibr" href="#ml171.r13" rid="ml171.r13">13</a>]. All NOX enzymes have been implicated in physiological and pathophysiological processes [<a class="bibr" href="#ml171.r14" rid="ml171.r14">14</a>]. Particularly, NOX1-dependent ROS generation has been shown to play a pivotal role in cell signaling, cell growth, angiogenesis, motility and blood pressure regulation [<a class="bibr" href="#ml171.r15" rid="ml171.r15 ml171.r16 ml171.r17 ml171.r18 ml171.r19">15–19</a>]. ROS generated via NOX1 have been reported to contribute to a growing number of diseases, including cancer, atherosclerosis, hypertension, neurological disorders and inflammation [<a class="bibr" href="#ml171.r2" rid="ml171.r2 ml171.r3 ml171.r4 ml171.r5 ml171.r6 ml171.r7">2–7</a>]. There appear to be significant differences between human and mouse NOX1 [<a class="bibr" href="#ml171.r20" rid="ml171.r20">20</a>].</p><p>Consistent with a role of NOX1 in colon cancer, Gianni et al have recently shown that in human colon cancer cells NOX1-derived ROS are necessary for the formation of extracellular matrix (ECM)-degrading, actin-rich cellular structures known as invadopodia [<a class="bibr" href="#ml171.r21" rid="ml171.r21">21</a>], whose presence directly correlates with the ability of cells to invade the surrounding tissues [<a class="bibr" href="#ml171.r22" rid="ml171.r22">22</a>,<a class="bibr" href="#ml171.r23" rid="ml171.r23">23</a>].</p><p>Since it has been reported that ROS can also be produced by other cellular enzymes such as xanthine oxidase (XO), cytochrome P450, and mitochondrial oxidases [<a class="bibr" href="#ml171.r23" rid="ml171.r23 ml171.r24 ml171.r25 ml171.r26">23–26</a>], dissecting the contribution to these pathophysiological conditions of NOX1-derived ROS in contrast to those of other ROS generators has been complicated by the lack of potent, selective and specific NOX1 inhibitors. Selective inhibition of NOX1 can be expected to provide reversible, mechanistic insights into these cellular processes, in contrast to other non-NOX1 mechanisms for scavenging or inhibiting ROS production.</p><p>Currently, only a few non-specific inhibitors, such as diphenylene iodonium (DPI) and apocynin have been reported in the literature [<a class="bibr" href="#ml171.r8" rid="ml171.r8">8</a>]. Issues of selectivity, specificity, potency and toxicity have been raised against the use of these compounds as NOX1 inhibitors both as research and clinical tools [<a class="bibr" href="#ml171.r9" rid="ml171.r9 ml171.r10 ml171.r11">9–11</a>]. DPI, the most widely used NOX inhibitor, rapidly and irreversibly blocks not only all NOX isoforms but also many other flavin-dependent enzymes such as xanthine oxidase because of its chemical mechanism of inhibition which involves accepting an electron from flavin, followed by covalently reacting with the enzymes or its prosthetic group [<a class="bibr" href="#ml171.r8" rid="ml171.r8">8</a>].</p><p>Apocynin (CID 2214) is another non-selective NADPH oxidase inhibitor [<a class="bibr" href="#ml171.r8" rid="ml171.r8">8</a>] that reduces levels of gp91<sup>phox</sup>, p22<sup>phox</sup>, p47<sup>phox</sup> and p67<sup>phox</sup> NADPH oxidase subunits <i>in vivo</i> [<a class="bibr" href="#ml171.r27" rid="ml171.r27">27</a>,<a class="bibr" href="#ml171.r28" rid="ml171.r28">28</a>]. High throughput screening efforts have identified VAS2870 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine; Vasopharm Biotech GmbH, Würzburg, Germany) as a novel NADPH oxidase inhibitor, which was shown to dose-dependently inhibit NADPH oxidase activity in both cell-free assays (IC<sub>50</sub> = 10 μM) and in PMA-stimulated HL-60 cells (IC<sub>50</sub> = 2 μM) [<a class="bibr" href="#ml171.r29" rid="ml171.r29">29</a>]. VAS2870 (5 μM) did not alter levels of NOX4 mRNA in human endothelial cells [<a class="bibr" href="#ml171.r30" rid="ml171.r30">30</a>]. No data on NOX1 was presented in these studies. Both intracellular ROS and NADPH oxidase activity were inhibited by the antioxidants tiron and N-acetylcysteine in human pancreatic adenocarcinoma cell lines [<a class="bibr" href="#ml171.r31" rid="ml171.r31">31</a>].</p><p>Our first NOX1 inhibitor probe (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>, CID 616479), based on a quinoxaline scaffold, is the first specific NOX inhibitor to be described [<a class="bibr" href="#ml171.r12" rid="ml171.r12">12</a>]. It has a target IC<sub>50</sub> of 360 nM in a HEK293 transfection format (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2532" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2532</a>) and antitarget IC<sub>50</sub>s of >10 μM against NOX2, NOX3, and NOX4 (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2539" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2539</a>), and 3.5 μM against xanthine oxidase (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2556" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2556</a>). Currently, no other specific NOX inhibitors have been reported in the literature.</p><div id="ml171.fu2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK98925/bin/ml171fu2.jpg" alt="ML090 CID 616479 SID 23535836." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a><br />CID 616479<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/23535836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 23535836</a></span></h3></div><p>A search of patents posted on the US Patent and Trademark Office web site on September 15, 2010, returned no results for NOX1-specific inhibitors.</p><p>The results reported here demonstrate the identification of a subset of phenothiazines as nanomolar, cell-active and specific NOX1 inhibitors that potently block NOX1-dependent ROS generation, with only marginal activity on other cellular ROS-producing enzymes and receptors including the other NOX isoforms. The probe compound <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> reported here also blocks the ROS-dependent formation of ECM-degrading invadopodia in colon cancer cells. These results elucidate the relevance of NOX1-dependent ROS generation in mechanisms of cancer invasion, and define probe compound <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> as a powerful NOX1 chemical probe and a potential therapeutic agent for treatment of this pathology.</p></div><div id="ml171.s4"><h2 id="_ml171_s4_">2. Materials and Methods</h2><p>The following reagents were purchased from Sigma: 2-Acetylphenothiazine (175226), chlorpromazine (C0982), DPI (D2926), horseradish peroxidase (HRP) (77330), fMet- Leu-Phe (fMLP) (F3506), NADPH (N5130), FAD (F6625), cytochrome c (105201) and luminol (09253) H<sub>2</sub>O<sub>2</sub> (95321), rotenone (R8875), xanthine oxidase (X4376), hypoxanthine (HX) (H9377). Cell culture medium, fetal bovine serum, supplements Hank’s Balanced Salt Solution, and lipofectamine were from Invitrogen. NOX1, NOXA1, NOXO1 and Rac1-Q61L expression plasmids were provided by Dr. Gary M. Bokoch. Plasmids for transfection were purified using the Qiagen Qiafilter system. DLD1 and HT29 colonic adenocarcinoma cells (Cat# CCL-221 and HTB-38) were purchased from ATCC. <sup>35</sup>S-GTPγS (Cat# NEG030H) was obtained from Perkin Elmer. 2-(Trifluoromethyl)- phenothiazine (CID 7082, product code JFD03930), compound library (HitFinder version 4, Maybridge) and other positive hits from primary assay were purchased from Maybridge. 2-acetylphenothiazine (CID 81131, product code STK301831) was purchased from Vitas-M Laboratories. Mouse monoclonal cortactin antibody 4F10 was purchased from Millipore, and anti-mouse Alexa-Fluor-568 and Alexa-Fluor-568 phalloidin antibodies were purchased from Molecular Probes. Reagents used by the NIMH Psychoactive Drug Screening Program (PDSP) were provided by the PDSP.</p><div id="ml171.s5"><h3>2.1. Assays</h3><div id="ml171.s6"><h4>LC-MS/MS</h4><p>All analytical methods were in MRM mode where the parent ion was selected in Q1 of the mass spectrometer. The parent ion was fragmented and a characteristic fragment ion monitored in Q3. MRM mass spectroscopy methods are particularly sensitive because additional time is spent monitoring the desired ions and not sweeping a large mass range. Methods were rapidly set up using Automaton<sup>®</sup> (Applied Biosystems), where the compounds were listed with their name and mass in an Excel datasheet. Compounds were submitted in a 96-well plate to the HPLC autosampler and slowly injected without a column present. A narrow range centered on the indicated mass was scanned to detect the parent ion. The software then evaluated a few pre-selected parameters to determine conditions that maximized the signal for the parent ion. The molecule was then fragmented in the collision cell of the mass spectrometer and fragments with m/z larger than 70 but smaller than the parent mass were determined. Three separate collision energies were evaluated to fragment the parent ion and the largest three ions were selected. Each of these three fragment ions was further optimized and the best fragment was chosen. The software then inserted the optimized masses and parameters into a template method and saved it with a unique name that indicated the individual compound being optimized. Spectra for the parent ion and the fragmentation pattern were saved and reviewable later.</p></div><div id="ml171.s7"><h4>Solubility</h4><p>The solubility of compounds was tested in phosphate buffered saline, pH 7.4. Compounds were inverted for 24 hours in test tubes containing 1–2 mg of compound with 1 mL of PBS. The samples were centrifuged and analyzed by HPLC (Agilent 1100 with diode-array detector). Peak area was compared to a standard of known concentration. In cases when the concentration was too low for UV analysis or when the compound did not possess a good chromophore, LC-MS/MS analysis was used.</p></div><div id="ml171.s8"><h4>Stability</h4><p>Demonstration of stability in PBS was conducted under conditions likely to be experienced in a laboratory setting. The compound was dissolved in 1 mL of PBS at a concentration of 10 μM, unless its maximum solubility was insufficient to achieve this concentration. Low solubility compounds were tested between ten and fifty percent of their solubility limit. The solution was immediately aliquoted into seven standard polypropylene microcentrifuge tubes which were stored at ambient temperature in a block microcentrifuge tube holder. Individual tubes were frozen at −80°C at 0, 1, 2, 4, 8, 24, and 48 hours. The frozen samples were thawed in a room temperature and an equal volume of acetonitrile was added prior to determination of concentration by LC-MS/MS.</p></div><div id="ml171.s9"><h4>Determination of glutathione reactivity</h4><p>One μL of a 10 mM compound stock solution was added to 1 mL of a freshly prepared solution of 100 μM reduced glutathione. Final compound concentration was 10 μM unless solubility limited. The solution was allowed to incubate at 37°C for two hours prior to being directly analyzed for glutathione adduct formation. LC-MS/MS analysis of GSH adducts was performed on an API 4000 Q-TrapTM mass spectrometer equipped with a Turboionspray source (Applied Biosystems, Foster City, CA). Two methodologies were utilized—a negative precursor ion (PI) scan of m/z 272, corresponding to GSH fragmenting at the thioether bond, and a neutral loss scan of −129 AMU to detect GSH adducts. This triggered positive ion enhanced resolution and enhanced product ion scans [<a class="bibr" href="#ml171.r32" rid="ml171.r32">32</a>,<a class="bibr" href="#ml171.r33" rid="ml171.r33">33</a>].</p></div><div id="ml171.s10"><h4>Primary screen to identify NOX1 inhibitors (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1792" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1792</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2541" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2541</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2538" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2538</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2664" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2664</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2752" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2752</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2773" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2773</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2808" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2808</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2819</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434997" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">434997</a>)</h4><p><b>Assay Overview:</b> The purpose of this cell-based assay was to identify compounds in the Maybridge collection that inhibit NOX1 activity. This chemiluminescence assay employs a luminol probe to monitor intracellular ROS in the HT29 transformed colonic epithelial cell line. HT29 cells express high endogenous levels of known NOX1 components and no other NOX family members. In this assay, the cells are incubated with test compounds, cell permeable luminol, and horseradish peroxidase. The interaction of luminol with NOX1-generated ROS/superoxide inside cells yields an unstable endoperoxide that generates light, leading to increased well luminescence. As designed, compounds that inhibit cellular NOX1 activity will reduce intracellular ROS and endoperoxide levels, leading to reduced luminol-ROS interactions, reduced endoperoxide production, reduced light emission, and reduced well luminescence. Test compounds were assayed in singlicate at a final nominal concentration of 6.7 μM (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1792" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1792</a>), in triplicate at a final nominal concentration of 3.3 μM (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2541" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2541</a>), in triplicate using a dilution series starting at a maximum concentration of 10 μM (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2538" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2538</a>), in triplicate using a dilution series starting at a maximum concentration of 20 μM (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2808" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2808</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2819</a>), in triplicate using a dilution series starting at a maximum concentration of 25 μM (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2773" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2773</a>), or in triplicate using a dilution series starting at a maximum concentration of 50 μM (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2664" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2664</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2752" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2752</a>).</p><p><b>Protocol Summary:</b> HT29 cells were routinely cultured in 150 mm dishes at 37 °C and 95% relative humidity (RH). The growth media consisted of Dulbecco’s Modified Eagle’s Media supplemented with 10% v/v fetal bovine serum, 2 mM L-Glutamine, and 100U/mL penicillin and streptomycin. Prior to the start of the assay, cells were suspended to a concentration of 2.25 million cells/mL in Hank’s Balanced Salt Solution. 30 μL of cell suspension (67,500 cells) were dispensed into each well of 384-well tissue culture-treated microtiter plates and the plates were centrifuged briefly. The assay was started by dispensing 100 nL of test compound in DMSO, diphenylene iodonium (DPI) in DMSO, or DMSO alone (0.33% final concentration) to the appropriate wells. The plates were incubated for 1 hour at 37 °C, 5% CO<sub>2</sub> and 95% RH, followed by the addition of 20 μL of a solution containing 400U/mL horseradish peroxidase and 50 mM luminol mix to all wells. The plates were centrifuged briefly and incubated for 10 minutes at 37 °C (5% CO<sub>2</sub>, 95% RH). Well luminescence was measured on the EnVision plate reader (Perkin Elmer). <b>Assay Cutoff:</b> 1) compounds that inhibited NOX1 ≥ 75% [(<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1792" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1792</a>); 2) compounds with ≥ 50% inhibitory activity (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2541" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2541</a>); 3) compounds with an IC<sub>50</sub> < 20 μM (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2538" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2538</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2664" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2664</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2752" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2752</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2773" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2773</a>); and 4) compounds with an IC<sub>50</sub> ≤ 17 μM (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2808" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2808</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2819</a>) were declared active.</p></div><div id="ml171.s11"><h4>Maybridge library uHTS counterscreen to identify inhibitors of luminol (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1823" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1823</a>)</h4><p><b>Assay Overview:</b> The purpose of this biochemical assay was to identify compounds in the Maybridge collection that directly inhibit luminescence generated by luminol in the peroxide reaction. This assay served as a counterscreen for a previous set of experiments entitled, “Luminescence-based primary cell-based high throughput screening assay to identify inhibitors of NADPH oxidase 1 (NOX1): Maybridge Library” (PubChem <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1792" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1792</a>). In this assay, compounds are incubated with hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), horseradish peroxidase (HRP), and luminol. The interaction between luminol and H<sub>2</sub>O<sub>2</sub> yields unstable peroxide radicals that generate light that can be detected by a luminometer. As designed, compounds that inhibit this reaction will reduce luminol interactions with H<sub>2</sub>O<sub>2</sub> and production of the unstable peroxide, leading to reduced light emission and well luminescence. Test compounds were assayed in singlicate at a final nominal concentration of 6.7 μM.</p><p><b>Protocol Summary:</b> Prior to the start of the assay, H<sub>2</sub>O<sub>2</sub> was diluted to a concentration of 88 μM in Hank’s Balanced Salt Solution. 30 μL of the diluted H<sub>2</sub>O<sub>2</sub> were dispensed into each well of 384-well tissue culture-treated microtiter plates and the plates were centrifuged briefly. The assay was started by dispensing 100 nL of test compound in DMSO, N-acetyl cysteine (NAC; 2.5 mM final concentration) in DMSO, or DMSO alone (0.33% final concentration) to the appropriate wells. The plates were incubated for 30 minutes at 25 °C, followed by the addition of 20 μL of a solution containing 400U/mL horseradish peroxidase and 50 mM luminol mix to all wells. The plates were centrifuged briefly and incubated for 10 minutes at 25 °C. Well luminescence was measured on the EnVision plate reader (Perkin Elmer). <b>Assay Cutoff:</b> compounds that inhibited luminol ≥ 25% were declared active.</p></div><div id="ml171.s12"><h4>Dose response assay to identify inhibitors of NOX1 in a human embryonic kidney (HEK) 293 transfection format (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2532" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2532</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2545" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2545</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">435002</a>)</h4><p><b>Assay Overview:</b> The purpose of this cell-based assay is to determine the potency of selected compounds identified as active in previous assays in a HEK293 transfection format. This chemiluminescence assay employs a luminol probe to monitor intracellular ROS in HEK293 cells. In this assay, HEK293 cells seeded into 6-well plates were cotransfected with expression vectors for NOX1, NOXA1, NOXO1 and constitutive active RAC1. After 16 hours, test or control compounds were added, followed 2 hours later by luminol and horseradish peroxidase. NOX activity was determined by chemiluminescence as described above (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1792" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1792</a>). Test compounds were assayed in triplicate using a 4-point 1:3 dilution series starting at a maximum concentration of 10 μM.</p><p><b>Protocol Summary:</b> HEK293 cells were maintained in DMEM containing 10% heat-inactivated fetal bovine serum, 2 mM glutamine, and antibiotics (100 U/ml penicillin and 100 g/ml streptomycin) at 37°C in 5% CO<sub>2</sub>. 500,000 HEK293 cells were seeded into 6-well plates in media without antibiotics the day before transfection. Cells were transfected with pRK5-Myc-NOX1, -NOXO1, -NOXA1, and pRK5-myc-Rac1CAQ61L using Lipofectamine 2000. 16 hours after transfection, 50,000 HEK293 cells in 30 μL HBSS were dispensed into each well of a white 384-well plate. The assay was started by dispensing 50 nL of test compound in DMSO, diphenylene iodonium (DPI) in DMSO, or DMSO alone (0.33% final concentration) to the appropriate wells. The plates were incubated for 1 hour at 37 °C, 5% CO<sub>2</sub> and 95% RH, followed by the addition of 20 μL of a mixture of 1 mM luminol plus 8 units of HRP in HBSS and luminescence quantified using a 384-well plate luminometer (EnVision). Chemiluminescence was measured for 30 minutes. <b>Assay Cutoff:</b> compounds with an IC<sub>50</sub> ≤ 10 μM were declared active.</p></div><div id="ml171.s13"><h4>Dose response assay to identify inhibitors of NOX2, NOX3, or NOX4 in a human embryonic kidney (HEK)/293 transfection format (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2539" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2539</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435013" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">435013</a>)</h4><p><b>Assay Overview:</b> The purpose of this family selectivity cell-based assay was to evaluate the ability of compounds identified as active in previous assays to inhibit NOX2, NOX3, or NOX4 activity in a HEK293 transfection format. This chemiluminescence assay employs a luminol probe to monitor intracellular ROS in HEK293 cells. HEK293 cells seeded into 6-well plates were cotransfected with the appropriate expression vectors for each NOX subtype. NOX activity was determined by chemiluminescence as described above (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1792" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1792</a>).</p><p><b>Protocol Summary:</b> HEK293 cells were maintained as described above (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435002</a>). HEK293 cells seeded into 6-well plates were cotransfected with the appropriate expression vectors for each NOX subtype. For the NOX2 assay (Assay 1), cells were transfected with pRK5-Myc- NOX2, pRK5-p67phox, pRK5-p47phox and pRK5-myc-Rac1CA-Q61L. For the NOX-3 assay (Assay 2), cells were transfected with pRK5-Myc-NOX3, pRK5-NOXO1, pRK5-NOXA1and pRK5-myc- Rac1CA-Q61L. For the NOX-4 assay (Assay 3), cells were transfected with pRK5-Myc-NOX4 and pRK5-p22phox. After 16 hours, cells were dispensed into wells of a 384-well plate, test or control compounds were added, and NOX activity was determined by chemiluminescence as described above (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435002</a>). <b>Assay Cutoff:</b> compounds with an IC<sub>50</sub> ≤ 10 μM were declared active.</p></div><div id="ml171.s14"><h4>Dose response assay to identify inhibitors of xanthine oxidase (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2556" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2556</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435009" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">435009</a>)</h4><p><b>Assay Overview:</b> The purpose of this cell-free assay was to evaluate the ability of compounds identified as active in previous assays to inhibit ROS production by another cellular source, xanthine oxidase. This chemiluminescence assay employs a luminol probe to monitor ROS production. In this assay, xanthine oxidase was dispensed to all wells of a 96-well plate followed by test or control compounds. Hypoxanthine was dispensed to all wells, followed by the addition of horseradish peroxide and luminal and reading luminescence. The interaction of luminol with xanthine oxidase-generated ROS/superoxide inside cells yields an unstable endoperoxide that generates light, leading to increased well luminescence. As designed, compounds that inhibit cellular xanthine oxidase activity will reduce intracellular ROS and endoperoxide levels, leading to reduced luminol-ROS interactions, reduced endoperoxide production, reduced light emission, and reduced well luminescence. Test compounds were assayed in triplicate using a 7-point dilution series starting at a maximum concentration of 10 μM.</p><p><b>Protocol Summary:</b> 25 μL of freshly-prepared 0.25 U/ml xanthine oxidase were dispensed into a 384-well plate (white Corning) by FlexDrop. 50 nL of DPI, DMSO or library compounds were dispensed by Biomek FX into each individual well. Upon 10 minutes of incubation at room temperature, 20 μL of 1 mM luminol plus 8 units of HRP in HBSS was added and luminescence was quantified using a 384-well plate luminometer (EnVision). <b>Assay Cutoff:</b> Compounds with an IC<sub>50</sub> ≤ 10 μM were declared active.</p></div><div id="ml171.s15"><h4>Dose response cytotoxicity assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434992" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434992</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/463255" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">463255</a>)</h4><p><b>Assay Overview:</b> The purpose of this assay was to eliminate cytotoxic compounds. In this assay, HT29 cells were incubated with test compounds, followed by determination of cell viability. The assay utilizes the CellTiter-Glo luminescent reagent to measure intracellular ATP in viable cells. Luciferase present in the reagent catalyzes the oxidation of beetle luciferin to oxyluciferin and light in the presence of cellular ATP. Well luminescence is directly proportional to ATP levels and cell viability. As designed, compounds that reduce cell viability will reduce ATP levels, luciferin oxidation and light production, resulting in decreased well luminescence. Compounds were tested in triplicate in a 10-point 1:3 dilution series starting at a nominal test concentration of 40 μM.</p><p><b>Protocol Summary:</b> Prior to the start of the assay 50,000 HT29 cells in 20 μL HBSS were dispensed into each well of 384-well tissue culture-treated microtiter plates. The assay was started by immediately dispensing 50 nL of test compound in DMSO, DMSO alone, or rotenone as a positive control (150 μM final concentration) to the appropriate wells. The plates were then incubated for 1 hour at 37 °C. The assay was stopped by dispensing 20 μL of CellTiter-Glo reagent to each well, followed by incubation at room temperature for 15 minutes. Well luminescence was measured on the ViewLux plate reader. <b>Assay Cutoff:</b> compounds with a CC<sub>50</sub> ≤ 10 μM were declared active.</p></div><div id="ml171.s16"><h4>Microscopic assay to identify inhibitors of invadopodia formation (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434993</a>)</h4><p><b>Assay Overview:</b> The purpose of this assay was to determine whether a compound that inhibits NOX1 can block invadopodia formation in DLD1 human colon cancer cells. In this assay, cells were transfected with tyrosine kinase c-Src, which is required for the formation of functional invadopodia. Cells were then treated with test or control compounds, then stained with invadopodia markers phalloidin or cortactin, and then prepared for confocal and epifluorescence microscopy. As designed, a compound that inhibits NOX1 will inhibit invadopodia formation and result in fewer phalloidin- and contactin-positive structures.</p><p><b>Protocol Summary:</b> Human DLD1 cells were maintained in Dulbecco’s modified Eagle’s medium containing 10% heat-inactivated fetal bovine serum, 2 mM glutamine, and antibiotics (100 units/ml penicillin and 100 g/ml streptomycin) at 37 °C in 5% CO<sub>2</sub>. DLD1 cells were plated on glass coverslips and after 24 hours cells were transfected with active SrcYF or empty vector (mock) in the presence of Lipofectamine 2000. 48 hours after transfection, cells were treated for 1 hour with 10 μM test compound, DMSO, or 10 μM DPI. Afterwards, cells were fixed in 4% paraformaldehyde at room temperature for 10 minutes. Successively, cells were permeabilized in 0.5% Triton for 10 minutes, then blocked in 2% BSA in PBS for 45 minutes at room temperature. Cells were then immunolabeled with appropriate primary and Alexa-Fluor 568-conjugated secondary antibodies. F-actin was detected by using Alexa-Fluor 568-conjugated phalloidin. Cells were mounted on slides with Mowiol mounting medium (Calbiochem) according to the manufacturer’s instructions. Epifluorescence images of fixed cells were acquired on an inverted microscope (Eclipse TE 2000-U, Nikon) equipped with an electronically controlled shutter, filter wheels, and a 14-bit cooled CCD camera (Cool SNAP HQ, Photometrics) controlled by MetaMorph software (Universal Imaging Corp.) by using a 60x/1.4 NA Plan Apo DIC or a 40x/1.4 NA Plan Apo Ph3 objective lens (Nikon). Confocal images were acquired on a spinning disk confocal microscope system, equipped with a CoolSnapHQ camera and 100x/1.4 NA Plan Apo or a 60x/1.4 NA Plan Apo objective lens (Nikon). Invadopodia structures in typical fields were counted. Data were collected from three independent experiments. <b>Assay Cutoff:</b> compounds that exhibited a SEM of p < 0.05 compared to the DMSO control were declared active.</p></div><div id="ml171.s17"><h4>Microscopic assay to identify inhibitors of extracellular matrix (ECM) degradation (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488778" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488778</a>)</h4><p><b>Assay Overview:</b> The purpose of this assay was to determine whether a NOX1 inhibitor compound that was shown to block invadopodia formation in DLD1 human colon cancer cells in a previous assay, “Late-stage microscopic assay to identify inhibitors of NADPH oxidase 1 (NOX1): Inhibition of invadopodia formation” (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434993</a>), can block the ability of DLD1 cells to degrade ECM. This assay also tests whether NOX1 overexpression restores the capacity of the DLD1 cells to degrade ECM in the presence of NOX1 inhibitor compound. In this assay, cells are transfected with empty vector, tyrosine kinase c-Src (SrcYF), which is required for the formation of functional invadopodia, or SrcYF plus a NOX1 expression plasmid. After transfection, cells are plated on fluorescently labeled gelatin-coated coverslips. Cells are treated with test compound or control, then stained with invadopodia marker phalloidin (that stains actin), and then prepared for epifluorescence microscopy. As designed, a compound that inhibits NOX1 will inhibit the NOX1-mediated formation of functional invadopodia and reduce the ability of c-Src-transfected DLD1 cells to degrade the ECM</p><p><b>Protocol Summary:</b> Human DLD1 cells were maintained as described above (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434993</a>). DLD1 cells were transfected with empty vector, vector with constitutive active Src (SrcYF), or SrcYF plus a NOX1 expresssion plasmid, in the presence of Lipofectamine 2000. 24 hrs after transfection, cells were trypsinized and plated on FITC-labeled gelatin-coated coverslips. After 2 hours, cells were treated with test compound, DPI (positive control), or DMSO (negative control) for 1.5 hours. 24 hours later, cells were fixed in 4% paraformaldehyde at room temperature for 10 minutes. Successively, cells were permeabilized in 0.5% Triton for 10 minutes and blocked in 2% BSA in PBS for 45 minutes at room temperature. Cells were then immunolabeled with Alexa-Fluor 568-conjugated phalloidin and visualized by epifluorescence microscopy (60X) as described above (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434993</a>). Quantification from three independent biological experiments is reported for each condition. <b>Assay Cutoff:</b> compounds that exhibited a SEM of p < 0.05 compared to the DMSO control were declared active.</p></div><div id="ml171.s18"><h4>NIMH Psychoactive Drug Screening Program (PDSP) primary assay (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434974" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">434974</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504381" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504381</a>)</h4><p><b>Assay Overview:</b> The purpose of this panel of radioligand binding assays performed by the NIMH PDSP was to identify a subset of potential receptors, transporters, or ion channels for which the test compound displays affinity. In this assay, test compounds are incubated with radioligand and receptor-containing crude membrane fractions. Bound radioactivity is isolated by filtration onto filter mats and counted. As designed, membrane fractions to which test compound bind will bind less radioligand and decrease the radioactivity measured in the assay.</p><p><b>Protocol Summary:</b> Test and reference compounds were diluted to 5X final assay concentration (50 μM for a final assay concentration of 10 μM) in the appropriate radioligand binding buffer. 50 μL aliquots of buffer (negative control), test compound, and reference compound (positive control) were added in quadruplicate to the wells of a 96-well plate, each of which contained 50 μL 5X radioligand and 100 μL buffer. Receptor-containing, crude membrane fractions were resuspended in an appropriate volume of buffer and dispensed (50 μL per well) into the 96-well plate. Radioligand binding was allowed to equilibrate for 1.5 hours at room temperature, and then bound radioactivity was isolated by filtration onto 0.3% polyethyleneimine-treated, 96-well filter mats using a 96-well Filtermate harverster. The filter mats were dried, scintillant was melted onto the filters, and the radioactivity retained on the filters was counted in a Microbeta scintillation counter. Test compound was tested in quadruplicate. <b>Assay Cutoff:</b> inhibition of > 50% for a particular target was considered active.</p></div><div id="ml171.s19"><h4>NIMH Psychoactive Drug Screening Program (PDSP) secondary assay (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434953" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">434953</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504410" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504410</a>)</h4><p><b>Assay Overview:</b> The purpose of this panel of radioligand binding assays performed by the NIMH PDSP was to determine Ki values for test compounds in selected assays from the PDSP primary assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434974" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434974</a>). In this assay, test compounds are incubated with radioligand and receptor-containing crude membrane fractions. Bound radioactivity is isolated by filtration onto Whatman glass fiber filters and counted. As designed, membrane fractions to which test compound binds will bind less radioligand and decrease the radioactivity measured in the assay. Compounds were tested in duplicate in an 11-point dilution series starting at a nominal test concentration of 50 μM.</p><p><b>Protocol Summary:</b> A solution of the compound to be tested was prepared as a 1 mg/ml stock in buffer or DMSO according to its solubility. A similar stock of a reference compound (positive control) was also prepared. Eleven dilutions (5X assay concentration) of the test and reference compounds were prepared by serial dilution: 0.05 nM, 0.5 nM, 1.5 nM, 5 nM, 15 nM, 50 nM, 150 nM, 500 nM, 1.5 μM, 5 μM, 50 μM (thus, the corresponding assay concentrations span from 10 pM to 10 μM and include semilog points in the range where high-to-moderate affinity ligands compete with radioligand for binding sites). Radioligand was dispensed into the wells of a 96-well plate. (Typically, the assay concentration of radioligand is a value between one half the KD and the KD of a particular radioligand at its target). Duplicate 50 μL aliquots of the test and reference compound dilutions are added. Then, crude membrane fractions of cells expressing recombinant receptor are dispensed into each well. The 250 μL reactions are incubated at room temperature and shielded from light (to prevent photolysis of light-sensitive ligands), then harvested by rapid filtration onto Whatman glass fiber filters. Filters are placed in scintillation tubes and allowed to dry overnight. The next day scintillation cocktail is added to each tube. The tubes are capped, labeled, and counted by liquid scintillation counting. <b>Assay Cutoff:</b> compounds with a Ki of ≤ 10 μM are considered active.</p><p><a class="figpopup" href="/books/NBK98925/table/ml171.t1/?report=objectonly" target="object" rid-figpopup="figml171t1" rid-ob="figobml171t1">Table 1</a> gives an overview of the PubChem assays associated with the NOX1 inhibitor project and indicates which are associated with the current probe development effort for <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml171t1"><a href="/books/NBK98925/table/ml171.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml171t1" rid-ob="figobml171t1"><img class="small-thumb" src="/books/NBK98925/table/ml171.t1/?report=thumb" src-large="/books/NBK98925/table/ml171.t1/?report=previmg" alt="Table 1. Overview of PubChem assays for NOX1 inhibitor project." /></a><div class="icnblk_cntnt"><h4 id="ml171.t1"><a href="/books/NBK98925/table/ml171.t1/?report=objectonly" target="object" rid-ob="figobml171t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Overview of PubChem assays for NOX1 inhibitor project. </p></div></div></div></div><div id="ml171.s20"><h3>2.2. Probe Chemical Characterization</h3><div id="ml171.fu3" class="figure bk_fig"><div class="graphic"><img src="/books/NBK98925/bin/ml171fu3.jpg" alt="CID 81131 SID57287864 ML171." /></div><h3><span class="title">CID 81131<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID57287864</a><br /><a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a></span></h3></div><p>The probe structure was verified by NMR and high resolution MS (<a class="figpopup" href="/books/NBK98925/figure/ml171.f1/?report=objectonly" target="object" rid-figpopup="figml171f1" rid-ob="figobml171f1">Figures 1</a> and <a class="figpopup" href="/books/NBK98925/figure/ml171.f2/?report=objectonly" target="object" rid-figpopup="figml171f2" rid-ob="figobml171f2">2</a>):</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml171f1" co-legend-rid="figlgndml171f1"><a href="/books/NBK98925/figure/ml171.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml171f1" rid-ob="figobml171f1"><img class="small-thumb" src="/books/NBK98925/bin/ml171f1.gif" src-large="/books/NBK98925/bin/ml171f1.jpg" alt="Figure 1. LC-MS of probe ML178." /></a><div class="icnblk_cntnt" id="figlgndml171f1"><h4 id="ml171.f1"><a href="/books/NBK98925/figure/ml171.f1/?report=objectonly" target="object" rid-ob="figobml171f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">LC-MS of probe ML178. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml171f2" co-legend-rid="figlgndml171f2"><a href="/books/NBK98925/figure/ml171.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml171f2" rid-ob="figobml171f2"><img class="small-thumb" src="/books/NBK98925/bin/ml171f2.gif" src-large="/books/NBK98925/bin/ml171f2.jpg" alt="Figure 2. LRMS of probe ML178." /></a><div class="icnblk_cntnt" id="figlgndml171f2"><h4 id="ml171.f2"><a href="/books/NBK98925/figure/ml171.f2/?report=objectonly" target="object" rid-ob="figobml171f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">LRMS of probe ML178. </p></div></div><p><sup>1</sup> H NMR (400 MHz, DMSO-d<sub>6</sub>) d 8.75 (s, 1H), 7.32 (dd, <i>J</i> = 8.0, 2.0 Hz, 1H), 7.18 (d, <i>J</i> = 1.6 Hz, 1H), 7.01 (d, <i>J</i> = 7.6 Hz, 1H), 6.99 (td, <i>J</i> = 7.6, 1.6 Hz, 1H), 6.89 (dd, <i>J</i> = 7.6, 0.8 Hz, 1H), 6.75 (td, <i>J</i> = 7.6, 1.2 Hz, 1H), 6.65 (dd, <i>J</i> = 8.0, 1.2 Hz, 1H), 2.47 (s, 3H); <sup>13</sup>C NMR (100 MHz, DMSO-d6) d 196.7, 142.0, 141.2, 136.1, 127.9, 126.2, 126.1, 123.2, 122.10, 122.06, 115.2, 114.5, 112.7, 26.4; IR (neat) 3346, 2255, 1667, 1026. LRMS (EI): <i>m/z</i> for C<sub>14</sub>H<sub>11</sub>NOS [M]+ calcd 241.06, found 241.1</p><p>Solubility in PBS (137 mM NaCl, 2.7 mM KCl, 10 mM sodium phosphate dibasic, 2 mM potassium phosphate monobasic, pH 7.4) at room temperature (23 °C) was determined to be 1.2 μM. The probe has a half-life of > 48 hours in PBS at room temperature (84% compound remaining at 48 hours) (<a class="figpopup" href="/books/NBK98925/figure/ml171.f3/?report=objectonly" target="object" rid-figpopup="figml171f3" rid-ob="figobml171f3">Figure 3</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml171f3" co-legend-rid="figlgndml171f3"><a href="/books/NBK98925/figure/ml171.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml171f3" rid-ob="figobml171f3"><img class="small-thumb" src="/books/NBK98925/bin/ml171f3.gif" src-large="/books/NBK98925/bin/ml171f3.jpg" alt="Figure 3. Stability of Probe ML171 in PBS." /></a><div class="icnblk_cntnt" id="figlgndml171f3"><h4 id="ml171.f3"><a href="/books/NBK98925/figure/ml171.f3/?report=objectonly" target="object" rid-ob="figobml171f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Stability of Probe ML171 in PBS. </p></div></div><p>No Michael acceptor adducts were observed when a sample of the probe was incubated with 100 μM glutathione and analyzed by LC-MS.</p><p>The compounds in <a class="figpopup" href="/books/NBK98925/table/ml171.t2/?report=objectonly" target="object" rid-figpopup="figml171t2" rid-ob="figobml171t2">Table 2</a> have been submitted to the SMR collection. Compound numbers refer to the SAR Table.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml171t2"><a href="/books/NBK98925/table/ml171.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml171t2" rid-ob="figobml171t2"><img class="small-thumb" src="/books/NBK98925/table/ml171.t2/?report=thumb" src-large="/books/NBK98925/table/ml171.t2/?report=previmg" alt="Table 2. Compounds Submitted to the MLSMR." /></a><div class="icnblk_cntnt"><h4 id="ml171.t2"><a href="/books/NBK98925/table/ml171.t2/?report=objectonly" target="object" rid-ob="figobml171t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Compounds Submitted to the MLSMR. </p></div></div></div><div id="ml171.s21"><h3>2.3. Probe Preparation</h3><p>In our SAR analysis for this project, compounds were tested for inhibitory activity in the primary assay for two rounds of SAR by purchase (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2808" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2808</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2819</a>) and three rounds of SAR by synthesis (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2664" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2664</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2752" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2752</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2773" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2773</a>). The probe we chose was a purchased compound (compound <b>1</b> in the <a class="figpopup" href="/books/NBK98925/table/ml171.t3/?report=objectonly" target="object" rid-figpopup="figml171t3" rid-ob="figobml171t3">Table 3</a>). The structure of the purchased compound was verified by NMR (<a class="figpopup" href="/books/NBK98925/figure/ml171.f2/?report=objectonly" target="object" rid-figpopup="figml171f2" rid-ob="figobml171f2">Figure 2</a>) and LC-MS (<a class="figpopup" href="/books/NBK98925/figure/ml171.f1/?report=objectonly" target="object" rid-figpopup="figml171f1" rid-ob="figobml171f1">Figure 1</a>). Two synthetic schemes from the literature are provided (<a class="figpopup" href="/books/NBK98925/figure/ml171.f4/?report=objectonly" target="object" rid-figpopup="figml171f4" rid-ob="figobml171f4">Figure 4</a>) [<a class="bibr" href="#ml171.r34" rid="ml171.r34">34</a>,<a class="bibr" href="#ml171.r35" rid="ml171.r35">35</a>].</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml171f4" co-legend-rid="figlgndml171f4"><a href="/books/NBK98925/figure/ml171.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml171f4" rid-ob="figobml171f4"><img class="small-thumb" src="/books/NBK98925/bin/ml171f4.gif" src-large="/books/NBK98925/bin/ml171f4.jpg" alt="Figure 4. Synthetic schemes for probe compound 1." /></a><div class="icnblk_cntnt" id="figlgndml171f4"><h4 id="ml171.f4"><a href="/books/NBK98925/figure/ml171.f4/?report=objectonly" target="object" rid-ob="figobml171f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Synthetic schemes for probe compound 1. </p></div></div></div></div><div id="ml171.s22"><h2 id="_ml171_s22_">3. Results</h2><p>Compound 1 (see <a class="figpopup" href="/books/NBK98925/table/ml171.t4/?report=objectonly" target="object" rid-figpopup="figml171t4" rid-ob="figobml171t4">Table 4</a>) satisfies the goals for the probe characteristics identified at the outset of the project: 1) probes should not induce cell death, 2) probes should exhibit saturable inhibitor activity, and 3) probes should exhibit inhibitory activity against NOX1 selectively or against other NOX proteins in general. We have demonstrated that probe compound <b>1</b> is a potent and selective inhibitor of NOX1. Its IC<sub>50</sub> was determined to be 129–156 nM in a cell-based assay using HT29 cells (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2808" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2808</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2538" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2538</a>), and 250 nM in a cell-based HEK293 transfection format (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435002</a>). Compound <b>1</b> is not cytotoxic (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/463255" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 463255</a>), and is selective among family members NOX2, NOX3, and NOX4 (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435013" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435013</a>), as well as against xanthine oxidase, another cellular source of ROS (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435009" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435009</a>). In order to gain mechanistic insight into the inhibition of NOX1 by compound <b>1</b>, assays were run to determine its effect on the formation of functional invadopodia and inhibition of extracellular matrix (ECM) degration in a human colon cancer cell line (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">434993</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488778" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488778</a>, respectively). Invadopodia are actin protrusions of the ventral plasma membrane and their formation in human cancer cells correlates with their invasiveness both <i>in vitro</i> and <i>in vivo</i> [<a class="bibr" href="#ml171.r36" rid="ml171.r36">36</a>]. Compound <b>1</b> was found to be highly effective at blocking invadopodia formation and reducing the ability of invadopodia to degrade the ECM in this system, supporting the validity of its use as a specific and selective NOX1 inhibitor.</p><div id="ml171.s23"><h3>3.1. Summary of Screening Results</h3><p>In the primary luminol-based chemiluminescence HTS screen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1792" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1792</a>) (see <a class="figpopup" href="/books/NBK98925/figure/ml171.f5/?report=objectonly" target="object" rid-figpopup="figml171f5" rid-ob="figobml171f5">Figure 5</a>), 16,000 compounds from the Maybridge Hitfinder library were screened. The cell line chosen for this screen was human HT29 colon cancer cells, as it had previously been shown that these cells endogenously expressed NOX1 as the only members of the NOX family and its cytosolic regulators NOXA1 and NOXO1 [<a class="bibr" href="#ml171.r37" rid="ml171.r37">37</a>]. A total of 130 compounds (0.81%) were active, passing the set threshold of 75% NOX1 inhibition. Of these 130 compounds, 100 (77%) did not exhibit H<sub>2</sub>O<sub>2</sub> scavenger activity in a luminol biochemical H<sub>2</sub>O<sub>2</sub>-based HTS counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1823" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1823</a>). In a HTS confirmation screen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2541" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2541</a>), 68 out of 96 compounds (71%) confirmed activity.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml171f5" co-legend-rid="figlgndml171f5"><a href="/books/NBK98925/figure/ml171.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml171f5" rid-ob="figobml171f5"><img class="small-thumb" src="/books/NBK98925/bin/ml171f5.gif" src-large="/books/NBK98925/bin/ml171f5.jpg" alt="Figure 5. Flow chart of HTS screening for NOX1 inhibitors." /></a><div class="icnblk_cntnt" id="figlgndml171f5"><h4 id="ml171.f5"><a href="/books/NBK98925/figure/ml171.f5/?report=objectonly" target="object" rid-ob="figobml171f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Flow chart of HTS screening for NOX1 inhibitors. </p></div></div><p>One of the hits from the primary screen, CID 616479, was tested in secondary confirmation, cytotoxicity, and selectivity assays, and found to be a potent and selective inhibitor of NOX1. It was declared a probe and a probe report was submitted in April of 2009.</p><p>A number of other compounds of interest emerged from the HTS screening, including a phenothiazine, 2-(trifluoromethyl)-phenothiazine (compound <b>3</b>). A number of these compounds were tested in a dose response NOX1 inhibition assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434997" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434997</a>), where they were found to have IC<sub>50</sub>s ranging from 230 nM to 670 nM. A set of related phenothiazine compounds from the MLSMR library was tested in a dose response assay for NOX1 inhibitory activity (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2538" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2538</a>). In this assay, two compounds of interest, compound <b>1</b> (2-acetylphenothiazine) and compound <b>2</b>, had IC<sub>50</sub>s of 156 nM and 44.5 nM, respectively.</p><p>The primary screen and follow-up assays identified several chemotypes with selective inhibition of NOX1. SAR analysis was undertaken. Initial lead expansion of these chemotypes was focused upon phenothiazines because the compounds were potent, closely related to well-known drugs, and highly selective. Compounds were tested for inhibitory activity in the primary assay for two rounds of SAR by purchase (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2808" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2808</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2819</a>) and three rounds of SAR by synthesis (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2664" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2664</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2752" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2752</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2773" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2773</a>).</p><p>Seven of the most promising lead compounds were tested for their ability to selectively block NOX1-dependent ROS generation using the HEK293-NOX1 cell system reconstituted with protein components required for ROS generation by NOX1 (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435002</a>). The most potent was compound <b>1</b>, with an IC<sub>50</sub> of 250 nM. These seven compounds, plus three purchased compounds with IC<sub>50</sub>s in the 78 nM to 517 nM range, were tested for their ability to inhibit reactive oxygen species by another cellular source, xanthine oxidase, in a biochemical assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435009" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435009</a>). Compounds <b>1</b> and <b>3</b> had IC<sub>50</sub>s for xanthine oxidase around 5 μM.</p><p>Compounds with the highest IC<sub>50</sub>s for xanthine oxidase were tested for family selectivity in a HEK293-NOX cell system reconstituted with protein components required for ROS generation by NOX2, NOX3, and NOX4 (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435013" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435013</a>). Compound <b>1</b> exhibited the greatest selectivity, with 12 to 20 fold greater activity against NOX1 in the HEK293 transfection format (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435002</a>) than against the other NOX family members (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435013" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435013</a>). Cell-based cytotoxicity assays were run to determine the cytotoxicity of compound <b>3</b> (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434992" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434992</a>) and compound <b>1</b> (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/463255" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 463255</a>). No cytotoxicity of these compounds was observed in HT29 cells at the highest concentration tested, 40 μM (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434992" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434992</a>) or 20 μM (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/463255" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 463255</a>).</p><p>In order to gain mechanistic insight into the inhibition of NOX1 by compound <b>1</b>, assays were run to determine whether this compound could block the formation of functional invadopodia (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434993</a>) and inhibit extracellular matrix (ECM) degradation (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488778" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488778</a>) in DLD1 human colon cancer cells. Invadopodia are dynamic phospho-tyrosine-rich structures with an actin core and abundant actin regulatory proteins (e.g. cortactin) capable of proteolytically degrading the ECM [<a class="bibr" href="#ml171.r38" rid="ml171.r38">38</a>]. They appear as actin protrusions of the ventral plasma membrane and their formation in human cancer cells correlates with their invasiveness both <i>in vitro</i> and <i>in vivo</i> [<a class="bibr" href="#ml171.r36" rid="ml171.r36">36</a>]. Activation of the tyrosine kinase c-Src is required for the formation of functional invadopodia [<a class="bibr" href="#ml171.r39" rid="ml171.r39">39</a>]. Evidence has recently demonstrated that NOX-mediated ROS generation is required for invadopodia formation and ECM degradation in different cancer cells. To test compound <b>1</b> in this system, DLD1 cells were transfected with empty vector or with constitutive active Src (SrcYF) to trigger the formation of invadopodia and then treated for 1hour with compound <b>1</b> (<a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a>), DMSO (negative control), or DPI (positive control). After staining with invadopodia markers phalloidin and cortactin, treatment with compound <b>1</b> (<a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a>) was found to strongly decrease SrcYF-induced invadopodia formation (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434993</a>). As shown by confocal microscopy in <a class="figpopup" href="/books/NBK98925/figure/ml171.f6/?report=objectonly" target="object" rid-figpopup="figml171f6" rid-ob="figobml171f6">Figure 6a</a> and in the quantification of three independent experiments in <a class="figpopup" href="/books/NBK98925/figure/ml171.f6/?report=objectonly" target="object" rid-figpopup="figml171f6" rid-ob="figobml171f6">Figure 6b</a>, this inhibition of invadopodia formation by compound <b>1</b> (<a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a>) was as effective as that seen after treatment with DPI.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml171f6" co-legend-rid="figlgndml171f6"><a href="/books/NBK98925/figure/ml171.f6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml171f6" rid-ob="figobml171f6"><img class="small-thumb" src="/books/NBK98925/bin/ml171f6.gif" src-large="/books/NBK98925/bin/ml171f6.jpg" alt="Figure 6. Compound 1 (ML171) treatment significantly blocks invadopodia formation in DLD1 cells." /></a><div class="icnblk_cntnt" id="figlgndml171f6"><h4 id="ml171.f6"><a href="/books/NBK98925/figure/ml171.f6/?report=objectonly" target="object" rid-ob="figobml171f6">Figure 6</a></h4><p class="float-caption no_bottom_margin">Compound 1 (ML171) treatment significantly blocks invadopodia formation in DLD1 cells. (a) Cells were stained with Alexa-Fluor-568 phalloidin (left column) or cortactin (right column) antibody, followed by Alexa-Fluor 568-conjugated secondary antibody <a href="/books/NBK98925/figure/ml171.f6/?report=objectonly" target="object" rid-ob="figobml171f6">(more...)</a></p></div></div><p>To further confirm that compound <b>1</b> blocks the ROS-dependent, NOX1- mediated formation of functional invadopodia, its effect on ECM degradation in DLD1 cells was tested (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488778" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488778</a>). SrcYF overexpression induced ECM degradation when cells were treated with DMSO control, while DPI treatment blocked this effect (<a class="figpopup" href="/books/NBK98925/figure/ml171.f6/?report=objectonly" target="object" rid-figpopup="figml171f6" rid-ob="figobml171f6">Figure 6a</a>). Treatment with compound <b>1</b> (<a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a>) strongly reduced the ability of SrcYF-transfected DLD1 cells to degrade the ECM. Importantly, the overexpression of NOX1 at least partially restored the capacity of these cells to degrade the ECM when treated with compound 1. The quantification of three independent experiments is shown in <a class="figpopup" href="/books/NBK98925/figure/ml171.f7/?report=objectonly" target="object" rid-figpopup="figml171f7" rid-ob="figobml171f7">Figure 7b</a>. These results support the validity of the use of compound <b>1</b> as a specific and selective NOX1 inhibitor.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml171f7" co-legend-rid="figlgndml171f7"><a href="/books/NBK98925/figure/ml171.f7/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figml171f7" rid-ob="figobml171f7"><img class="small-thumb" src="/books/NBK98925/bin/ml171f7.gif" src-large="/books/NBK98925/bin/ml171f7.jpg" alt="Figure 7. Treatment with compound 1 (ML171) significantly blocks ECM degradation in DLD1 cells." /></a><div class="icnblk_cntnt" id="figlgndml171f7"><h4 id="ml171.f7"><a href="/books/NBK98925/figure/ml171.f7/?report=objectonly" target="object" rid-ob="figobml171f7">Figure 7</a></h4><p class="float-caption no_bottom_margin">Treatment with compound 1 (ML171) significantly blocks ECM degradation in DLD1 cells. (a) DLD1 cells were transfected as indicated with SrcYF, empty vector (mock) or NOX1 expression plasmid. 24 hours later, cells were trypsinized and plated on FITC-labeled <a href="/books/NBK98925/figure/ml171.f7/?report=objectonly" target="object" rid-ob="figobml171f7">(more...)</a></p></div></div><p>2-(Trifluoromethyl)-phenothiazine (compound <b>3</b>) belongs to the class of phenothiazines whose structure occurs in various antipsychotic drugs [<a class="bibr" href="#ml171.r40" rid="ml171.r40">40</a>], such as chlorpromazine, promazine, and trifluperazine. With the intent of identifying related phenothiazines with higher potency in blocking NOX1-dependent ROS generation, we performed SAR analysis on several commercially available phenothiazines, including those used as anti-psychotic drugs, as well as analogs synthesized in our laboratories. These molecules were tested in HT29 cells by luminol-based CL assay for their ability to block ROS production. As summarized in <a class="figpopup" href="/books/NBK98925/table/ml171.t3/?report=objectonly" target="object" rid-figpopup="figml171t3" rid-ob="figobml171t3">Table 3</a>, we found that chlorpromazine did not inhibit ROS generation in our assay (IC<sub>50</sub> > 50 μM). Consistent with this, as indicated in <a class="figpopup" href="/books/NBK98925/table/ml171.t3/?report=objectonly" target="object" rid-figpopup="figml171t3" rid-ob="figobml171t3">Table 3</a>, we observed that other phenothiazines such as trifluperazine (compound <b>17</b>) and perphenazine (compound <b>16</b>) used as anti-psychotic drugs were additionally unable to block Nox1-dependent ROS generation. In general, all phenothiazines tested in <a class="figpopup" href="/books/NBK98925/table/ml171.t4/?report=objectonly" target="object" rid-figpopup="figml171t4" rid-ob="figobml171t4">Table 4</a> with a substituent on the ring nitrogen were devoid of NOX1 activity if the substituent in the adjacent benzene ring is meta to the ring nitrogen. However, several compounds with ring N-methyl groups possessing an additional substituent para to the ring nitrogen on the adjacent phenyl ring, such as compounds <b>21</b>, <b>25</b>, and <b>29</b>, were active. We selected the molecule with the highest potency (compound <b>1</b>) and used it for further analyses. Compound <b>1</b> strongly blocks ROS generation in HT29 cells (IC<sub>50</sub>HT29 = 0.129 μM). Consistent with this, when compound <b>1</b> was tested in a HEK293-NOX1 reconstituted cell system, we observed higher potency in blocking NOX1-dependent ROS generation compared with compound <b>3</b>. Of note, the IC<sub>50</sub> values towards NOX2 and NOX3 were also slightly decreased, while this compound was still unable to inhibit xanthine oxidase-dependent ROS generation.</p></div><div id="ml171.s24"><h3>3.2. Dose Response Curves for Probe</h3><div id="ml171.f8" class="figure bk_fig"><div class="graphic"><img src="/books/NBK98925/bin/ml171f8.jpg" alt="Figure 8. Dose response curve for probe ML171." /></div><h3><span class="label">Figure 8</span><span class="title">Dose response curve for probe <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a></span></h3></div></div><div id="ml171.s25"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>No reactive functional groups are observed in the probe molecule, which is very stable with a half life of > 48 hours.</p></div><div id="ml171.s26"><h3>3.4. SAR Tables</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml171t3"><a href="/books/NBK98925/table/ml171.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml171t3" rid-ob="figobml171t3"><img class="small-thumb" src="/books/NBK98925/table/ml171.t3/?report=thumb" src-large="/books/NBK98925/table/ml171.t3/?report=previmg" alt="Table 3. Selectivity of parent hit and probe compounds compared to that of chlorpromazine." /></a><div class="icnblk_cntnt"><h4 id="ml171.t3"><a href="/books/NBK98925/table/ml171.t3/?report=objectonly" target="object" rid-ob="figobml171t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Selectivity of parent hit and probe compounds compared to that of chlorpromazine. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml171t4"><a href="/books/NBK98925/table/ml171.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml171t4" rid-ob="figobml171t4"><img class="small-thumb" src="/books/NBK98925/table/ml171.t4/?report=thumb" src-large="/books/NBK98925/table/ml171.t4/?report=previmg" alt="Table 4. SAR Table of Phenothiazines." /></a><div class="icnblk_cntnt"><h4 id="ml171.t4"><a href="/books/NBK98925/table/ml171.t4/?report=objectonly" target="object" rid-ob="figobml171t4">Table 4</a></h4><p class="float-caption no_bottom_margin">SAR Table of Phenothiazines. Fragment point of attachment is indicated with an <sup>*</sup> </p></div></div></div><div id="ml171.s27"><h3>3.5. Cellular Activity</h3><p>The primary NOX1 inhibition assay is a cell-based assay (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1792" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1792</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2541" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2541</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2538" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2538</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2664" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2664</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2752" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2752</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2773" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2773</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2808" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2808</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2819</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434997" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">434997</a>). We also employed a HEK293 transfection format cell-based assay to determine potency of compounds (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435002</a>), and to determine family selectivity using NOX2, NOX3, and NOX4 (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435013" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435013</a>). In a cytotoxicity assay (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434992" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">434992</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/463225" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">463225</a>), no cytotoxicity was observed in HT29 cells for compound <b>1</b> or the related compound <b>3</b>. Two cell-based assays in human colon cancer cells overexpressing tyrosine kinase c-Src (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">434993</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488778" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488778</a>) showed that compound <b>1</b> strongly inhibited invadopodia formation and strongly reduced the ability of the cells to degrade ECM. In summary, we have tested compound <b>1</b> and related compounds in multiple cell-based assays, where they have proven to have potent NOX1 inhibitory activity.</p></div><div id="ml171.s28"><h3>3.6. Profiling Assays</h3><p>To date, compound <b>1</b> has been tested in 445 other bioassays deposited in PubChem, and has shown activity in 17 of those assays, giving a hit rate of 3.8%, indicating that this compound is not generally active across a broad range of cell-based and non-cell based assays.</p><p>Compound <b>1</b> was submitted to the NIMH’s Psychoactive Drug Screening Program (PDSP). The goal was to identify any potential receptors, transporters, or ion channels for which the compound displays affinity (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504381" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504381</a>). A secondary screen provided Ki values for targets identified in the primary screen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504410" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504410</a>). The results of this screening are in <a class="figpopup" href="/books/NBK98925/table/ml171.t5/?report=objectonly" target="object" rid-figpopup="figml171t5" rid-ob="figobml171t5">Table 5</a>. Compound <b>1</b> did not significantly bind most of the receptors tested in the binding assays, with the exception of serotonin 5-HT2B, dopamine D3, and opioid KOR receptors (>50% inhibition). Of note, secondary concentration-response analysis revealed Ki values in the mid-nanomolar (serotonin 5-HT2B receptor) and micromolar range (dopamine D3, and opioid KOR receptors), suggestive of low affinity of this low nanomolar NOX1 inhibitor for these GPCR receptors. These data suggest that compound <b>1</b> does not likely exert unwanted anti-psychotic effects.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml171t5"><a href="/books/NBK98925/table/ml171.t5/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml171t5" rid-ob="figobml171t5"><img class="small-thumb" src="/books/NBK98925/table/ml171.t5/?report=thumb" src-large="/books/NBK98925/table/ml171.t5/?report=previmg" alt="Table 5. NIMH’s Psychoactive Drug Screening Program results for compound 1." /></a><div class="icnblk_cntnt"><h4 id="ml171.t5"><a href="/books/NBK98925/table/ml171.t5/?report=objectonly" target="object" rid-ob="figobml171t5">Table 5</a></h4><p class="float-caption no_bottom_margin">NIMH’s Psychoactive Drug Screening Program results for compound 1. </p></div></div></div></div><div id="ml171.s29"><h2 id="_ml171_s29_">4. Discussion</h2><p>We have demonstrated that probe compound <b>1</b> is a potent and selective inhibitor of NOX1, with an IC<sub>50</sub> of 129–156 nM in a cell-based assay using HT29 cells (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2808" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2808</a>, 2538), and 250 nM in a cell-based HEK293 transfection format (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435002</a>). Compound <b>1</b> is not cytotoxic to HT29 cells (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/463255" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 463255</a>), and is selective among NOX family members NOX2, NOX3, and NOX4 (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435013" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435013</a>), as well as against xanthine oxidase, another cellular source of ROS (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435009" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435009</a>). In addition, compound <b>1</b> is highly effective in inhibiting the cellular production of invadopodia in a human colon cancer cell line (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434993</a>) These results have been published [<a class="bibr" href="#ml171.r41" rid="ml171.r41">41</a>].</p><div id="ml171.s30"><h3>4.1. Comparison to existing art and how the new probe is an improvement</h3><p>Probe <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> is potent and selective among the NOX family members NOX2, NOX3, and NOX4, (>30-fold selectivity for NOX2 and NOX4, and 20-fold selectivity for NOX3, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435013" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435013</a>) as well as xanthine oxidase (>30-fold selectivity, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435009" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435009</a>). No selective compounds have previously been reported in the literature.</p><p>Probe <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> is comparable in potency and selectivity to the first NOX1 INH probe <a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a> [<a class="bibr" href="#ml171.r12" rid="ml171.r12">12</a>], but it is chemically more tractable than was probe <a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>. <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> has a phenothiazine scaffold, which is present in many anti-psychotic drugs. The large body of knowledge about this compound class, including that it is known to be nontoxic, will facilitate studies with this compound in animals. We have shown that compound <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> is able to block the ROS-dependent formation of ECM-degrading invadopodia in colon cancer cells, a promising result that defines compound <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> as a powerful NOX1 chemical probe and a potential therapeutic agent for treatment of this pathology.</p></div><div id="ml171.s31"><h3>4.2. Mechanism of Action Studies</h3><p>We have addressed the mechanism of action of probe compound <b>1</b> in two ways. First, we tested its ability to block the formation of invadopodia, actin protrusions of the ventral plasma membrane, and invadopodia-mediated ECM degradation, in human colon cancer cells overexpressing tyrosine kinase c-Src (AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">434993</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488778" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488778</a>) and showed that it strongly inhibited invadopodia formation and strongly reduced the ability of the cells to degrade the ECM. The formation of invadopodia in human cancer cells correlates with their invasiveness both <i>in vitro</i> and <i>in vivo</i> [<a class="bibr" href="#ml171.r33" rid="ml171.r33">33</a>]. Thus, this result is highly suggestive that NOX1 is mechanistically involved in the process of cancer invasion.</p><p>Secondly, we submitted compound <b>2</b>, a close structural analog to probe compound <b>1</b>, to the NIMH’s Psychoactive Drug Screening Program. The results of this testing reveal that compound <b>2</b> did not significantly bind most of the receptors tested in the binding assays and suggest that the probe compound <b>1</b> will not likely exert unwanted anti-psychotic effects.</p></div><div id="ml171.s32"><h3>4.3. Planned Future Studies</h3><p>In the extended probe development period we plan to continue SAR studies to identify more potent compounds with increased selectivity that can be optimized for <i>in vivo</i> applications. The pharmacokinetic (PK) properties of the lead compounds will also be optimized using a series of <i>in vitro</i> and <i>in vivo</i> (mouse) PK studies to identify a compound that is suitable for use in animal studies. The most promising compounds will be tested for selectivity against the panel of off-target proteins including GPCRs and ion channels that may be implicated in antipsychotic mechanisms of the broader scaffold. We plan to develop compounds that inhibit NOX1 in human colon cancer lines implanted into the mouse, to test the role of NOX1 in the regulation of invasion and metastasis. In addition, pull-down chemical probes will also be useful for target identification in clinical specimens, and in the development of surrogate marker assays.</p></div></div><div id="ml171.s33"><h2 id="_ml171_s33_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml171.r1">Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. <span><span class="ref-journal">Physiological reviews. </span>2007;<span class="ref-vol">87</span>:245–313.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17237347" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17237347</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml171.r2">Block ML. NADPH oxidase as a therapeutic target in Alzheimer’s disease. <span><span class="ref-journal">BMC neuroscience. </span>2008;<span class="ref-vol">9</span>(Suppl 2):S8.</span> [<a href="/pmc/articles/PMC2604892/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2604892</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19090996" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19090996</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml171.r3">Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM. NADPH oxidases in cardiovascular health and disease. <span><span class="ref-journal">Antioxidants & redox signaling. </span>2006;<span class="ref-vol">8</span>:691–728.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16771662" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16771662</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml171.r4">Cifuentes ME, Pagano PJ. Targeting reactive oxygen species in hypertension. <span><span class="ref-journal">Current opinion in nephrology and hypertension. </span>2006;<span class="ref-vol">15</span>:179–186.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16481886" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16481886</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml171.r5">Nauseef WM. Nox enzymes in immune cells. <span><span class="ref-journal">Seminars in immunopathology. </span>2008;<span class="ref-vol">30</span>:195–208.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18449540" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18449540</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml171.r6">Rokutan K, Kawahara T, Kuwano Y, Tominaga K, Sekiyama A, Teshima-Kondo S. NADPH oxidases in the gastrointestinal tract: a potential role of Nox1 in innate immune response and carcinogenesis. <span><span class="ref-journal">Antioxidants & redox signaling. </span>2006;<span class="ref-vol">8</span>:1573–1582.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16987012" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16987012</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml171.r7">Ushio-Fukai M, Nakamura Y. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. <span><span class="ref-journal">Cancer letters. </span>2008;<span class="ref-vol">266</span>:37–52.</span> [<a href="/pmc/articles/PMC2673114/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2673114</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18406051" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18406051</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml171.r8">Jaquet V, Scapozza L, Clark RA, Krause KH, Lambeth JD. Small-molecule NOX inhibitors: ROS-generating NADPH oxidases as therapeutic targets. <span><span class="ref-journal">Antioxidants & redox signaling. </span>2009;<span class="ref-vol">11</span>:2535–2552.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19309261" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19309261</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml171.r9">Aldieri E, Riganti C, Polimeni M, Gazzano E, Lussiana C, Campia I, Ghigo D. Classical inhibitors of NOX NAD(P)H oxidases are not specific. <span><span class="ref-journal">Current drug metabolism. </span>2008;<span class="ref-vol">9</span>:686–696.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18855607" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18855607</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml171.r10">O’Donnell BV, Tew DG, Jones OT, England PJ. Studies on the inhibitory mechanism of iodonium compounds with special reference to neutrophil NADPH oxidase. <span><span class="ref-journal">The Biochemical journal. </span>1993;<span class="ref-vol">290</span>(Pt 1):41–49.</span> [<a href="/pmc/articles/PMC1132380/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1132380</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8439298" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8439298</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml171.r11">O’Donnell VB, Smith GC, Jones OT. Involvement of phenyl radicals in iodonium inhibition of flavoenzymes. <span><span class="ref-journal">Molecular pharmacology. </span>1994;<span class="ref-vol">46</span>:778–785.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7969060" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7969060</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml171.r12">Brown SJ, Gianni D, Bokoch G, Mercer BA, Hodder P, Rosen H. Probe report for NOX1 inhibitors. <span><span class="ref-journal">MLPCN probe report. </span>2009</span></div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml171.r13">Lambeth JD. NOX enzymes and the biology of reactive oxygen. <span><span class="ref-journal">Nature reviews. </span>2004;<span class="ref-vol">4</span>:181–189.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15039755" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15039755</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml171.r14">Lambeth JD, Krause KH, Clark RA. NOX enzymes as novel targets for drug development. <span><span class="ref-journal">Seminars in immunopathology. </span>2008;<span class="ref-vol">30</span>:339–363.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18509646" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18509646</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml171.r15">Arbiser JL, Petros J, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, Cohen C, Moses M, Kilroy S, Arnold RS, Lambeth JD. Reactive oxygen generated by Nox1 triggers the angiogenic switch. <span><span class="ref-journal">Proceedings of the National Academy of Sciences of the United States of America. </span>2002;<span class="ref-vol">99</span>:715–720.</span> [<a href="/pmc/articles/PMC117371/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC117371</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11805326" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11805326</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml171.r16">Gavazzi G, Banfi B, Deffert C, Fiette L, Schappi M, Herrmann F, Krause KH. Decreased blood pressure in NOX1-deficient mice. <span><span class="ref-journal">FEBS Lett. </span>2006;<span class="ref-vol">580</span>:497–504.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16386251" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16386251</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml171.r17">Komatsu D, Kato M, Nakayama J, Miyagawa S, Kamata T. NADPH oxidase 1 plays a critical mediating role in oncogenic Ras-induced vascular endothelial growth factor expression. <span><span class="ref-journal">Oncogene. </span>2008;<span class="ref-vol">27</span>:4724–4732.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18454179" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18454179</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml171.r18">Sadok A, Bourgarel-Rey V, Gattacceca F, Penel C, Lehmann M, Kovacic H. Nox1-dependent superoxide production controls colon adenocarcinoma cell migration. <span><span class="ref-journal">Biochimica et biophysica acta. </span>2008;<span class="ref-vol">1783</span>:23–33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18023288" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18023288</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml171.r19">Sancho P, Fabregat I. The NADPH oxidase NOX1 controls autocrine growth of liver tumor cells through up-regulation of the epidermal growth factor receptor pathway. <span><span class="ref-journal">The Journal of biological chemistry. </span></span> [<a href="/pmc/articles/PMC2915717/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2915717</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20525691" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20525691</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="ml171.r20">Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. <span><span class="ref-journal">Physiol Rev. </span>2007;<span class="ref-vol">87</span>:245–313.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17237347" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17237347</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="ml171.r21">Gianni D, Diaz B, Taulet N, Fowler B, Courtneidge SA, Bokoch GM. Novel p47(phox)-related organizers regulate localized NADPH oxidase 1 (Nox1) activity. <span><span class="ref-journal">Science signaling. </span>2009;<span class="ref-vol">2</span>:ra54.</span> [<a href="/pmc/articles/PMC2850287/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2850287</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19755710" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19755710</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="ml171.r22">Buccione R, Caldieri G, Ayala I. Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix. <span><span class="ref-journal">Cancer metastasis reviews. </span>2009;<span class="ref-vol">28</span>:137–149.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19153671" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19153671</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>23.</dt><dd><div class="bk_ref" id="ml171.r23">Linder S. The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. <span><span class="ref-journal">Trends in cell biology. </span>2007;<span class="ref-vol">17</span>:107–117.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17275303" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17275303</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="ml171.r24">Faggioni R, Gatti S, Demitri MT, Delgado R, Echtenacher B, Gnocchi P, Heremans H, Ghezzi P. Role of xanthine oxidase and reactive oxygen intermediates in LPS- and TNF-induced pulmonary edema. <span><span class="ref-journal">The Journal of laboratory and clinical medicine. </span>1994;<span class="ref-vol">123</span>:394–399.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8133151" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8133151</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="ml171.r25">Gottlieb RA. Cytochrome P450: major player in reperfusion injury. <span><span class="ref-journal">Archives of biochemistry and biophysics. </span>2003;<span class="ref-vol">420</span>:262–267.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14654065" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14654065</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>26.</dt><dd><div class="bk_ref" id="ml171.r26">Jaeschke H, Mitchell JR. Mitochondria and xanthine oxidase both generate reactive oxygen species in isolated perfused rat liver after hypoxic injury. <span><span class="ref-journal">Biochemical and biophysical research communications. </span>1989;<span class="ref-vol">160</span>:140–147.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2540741" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2540741</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>27.</dt><dd><div class="bk_ref" id="ml171.r27">Tian N, Moore RS, Phillips WE, Lin L, Braddy SJ, Pryor JS, Stockstill RL, Hughson MD, Manning RD Jr. Nadph Oxidase Contributes to Renal Damage and Dysfunction in Dahl Salt-Sensitive Hypertension. <span><span class="ref-journal">Am J Physiol Regul Integr Comp Physiol. </span>2008;<span class="ref-vol">295</span>:R1858–1865.</span> [<a href="/pmc/articles/PMC2685289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2685289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18922960" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18922960</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>28.</dt><dd><div class="bk_ref" id="ml171.r28">Yu J, Weiwer M, Linhardt RJ, Dordick JS. The role of the methoxyphenol apocynin, a vascular NADPH oxidase inhibitor, as a chemopreventative agent in the potential treatment of cardiovascular diseases. <span><span class="ref-journal">Curr Vasc Pharmacol. </span>2008;<span class="ref-vol">6</span>:204–217.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18673160" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18673160</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>29.</dt><dd><div class="bk_ref" id="ml171.r29">ten Freyhaus H, Huntgeburth M, Wingler K, Schnitker J, Baumer AT, Vantler M, Bekhite MM, Wartenberg M, Sauer H, Rosenkranz S. Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation. <span><span class="ref-journal">Cardiovasc Res. </span>2006;<span class="ref-vol">71</span>:331–341.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16545786" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16545786</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>30.</dt><dd><div class="bk_ref" id="ml171.r30">Stielow C, Catar RA, Muller G, Wingler K, Scheurer P, Schmidt HH, Morawietz H. Novel Nox inhibitor of oxLDL-induced reactive oxygen species formation in human endothelial cells. <span><span class="ref-journal">Biochem Biophys Res Commun. </span>2006;<span class="ref-vol">344</span>:200–205.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16603125" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16603125</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>31.</dt><dd><div class="bk_ref" id="ml171.r31">Vaquero EC, Edderkaoui M, Pandol SJ, Gukovsky I, Gukovskaya AS. Reactive Oxygen Species Produced by NAD(P)H Oxidase Inhibit Apoptosis in Pancreatic Cancer Cells. <span><span class="ref-journal">The Journal of biological chemistry. </span>2004;<span class="ref-vol">279</span>:34643–34654.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15155719" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15155719</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>32.</dt><dd><div class="bk_ref" id="ml171.r32">Li X, He Y, Ruiz CH, Koenig M, Cameron MD. Characterization of dasatinib and its structural analogs as CYP3A4 mechanism-based inactivators and the proposed bioactivation pathways. <span><span class="ref-journal">Drug Metab Dispos. </span>2009;<span class="ref-vol">37</span>:1242–1250.</span> [<a href="/pmc/articles/PMC3202349/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3202349</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19282395" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19282395</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>33.</dt><dd><div class="bk_ref" id="ml171.r33">Li X, Kamenecka TM, Cameron MD. Bioactivation of the epidermal growth factor receptor inhibitor gefitinib: implications for pulmonary and hepatic toxicities. <span><span class="ref-journal">Chem Res Toxicol. </span>2009;<span class="ref-vol">22</span>:1736–1742.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19803472" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19803472</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>34.</dt><dd><div class="bk_ref" id="ml171.r34">Baltzly R, Hargenist M, Webb FJ. <span><span class="ref-journal">J Am Chem Soc. </span>1946;<span class="ref-vol">68</span>:2672–2678.</span></div></dd></dl><dl class="bkr_refwrap"><dt>35.</dt><dd><div class="bk_ref" id="ml171.r35">Ma D, Geng Q, Zhang H, Jiang Y. <span><span class="ref-journal">Angew Chem Int Ed Engl. </span>2010;<span class="ref-vol">8</span>:1291–1294.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20058286" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20058286</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>36.</dt><dd><div class="bk_ref" id="ml171.r36">Weaver AM. Invadopodia: specialized cell structures for cancer invasion. <span><span class="ref-journal">Clinical & experimental metastasis. </span>2006;<span class="ref-vol">23</span>:97–105.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16830222" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16830222</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>37.</dt><dd><div class="bk_ref" id="ml171.r37">Gianni D, Bohl B, Courtneidge SA, Bokoch GM. The involvement of the tyrosine kinase c-Src in the regulation of reactive oxygen species generation mediated by NADPH oxidase-1. <span><span class="ref-journal">Molecular biology of the cell. </span>2008;<span class="ref-vol">19</span>:2984–2994.</span> [<a href="/pmc/articles/PMC2441655/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2441655</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18463161" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18463161</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>38.</dt><dd><div class="bk_ref" id="ml171.r38">Gimona M, Buccione R, Courtneidge SA, Linder S. Assembly and biological role of podosomes and invadopodia. <span><span class="ref-journal">Current opinion in cell biology. </span>2008;<span class="ref-vol">20</span>:235–241.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18337078" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18337078</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>39.</dt><dd><div class="bk_ref" id="ml171.r39">Lowe C, Yoneda T, Boyce BF, Chen H, Mundy GR, Soriano P. Osteopetrosis in Src-deficient mice is due to an autonomous defect of osteoclasts. <span><span class="ref-journal">Proceedings of the National Academy of Sciences of the United States of America. </span>1993;<span class="ref-vol">90</span>:4485–4489.</span> [<a href="/pmc/articles/PMC46536/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC46536</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7685105" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7685105</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>40.</dt><dd><div class="bk_ref" id="ml171.r40">Mitchell SC. Phenothiazine: the parent molecule. <span><span class="ref-journal">Current drug targets. </span>2006;<span class="ref-vol">7</span>:1181–1189.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17017893" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17017893</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>41.</dt><dd><div class="bk_ref" id="ml171.r41">Gianni D, Taulet N, Zhang H, Der Mardirossian C, Kister J, Martinez L, Roush WR, Brown SJ, Bokoch GM, Rosen H. A Novel and Specific NADPH Oxidase-1 (Nox1) Small-Molecule Inhibitor Blocks the Formation of Functional Invadopodia in Human Colon Cancer Cells. <span><span class="ref-journal">ACS Chem Biol. </span>2010;<span class="ref-vol">5</span>:981–993.</span> [<a href="/pmc/articles/PMC2955773/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2955773</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20715845" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20715845</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK98925_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">D Gianni</span>,<sup>1</sup> <span itemprop="author">N Nicolas</span>,<sup>1</sup> <span itemprop="author">H Zhang</span>,<sup>2</sup> <span itemprop="author">C Der Mardirossian</span>,<sup>1</sup> <span itemprop="author">J Kister</span>,<sup>3</sup> <span itemprop="author">L Martinez</span>,<sup>3</sup> <span itemprop="author">J Ferguson</span>,<sup>4</sup> <span itemprop="author">WR Roush</span>,<sup>3</sup> <span itemprop="author">SJ Brown</span>,<sup>4</sup> <span itemprop="author">GM Bokoch</span>,<sup>1</sup> <span itemprop="author">P Hodder</span>,<sup>3</sup> and <span itemprop="author">H Rosen</span><sup>4</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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Department of Immunology and Microbial Science and Department of Cell
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Biology, The Scripps Research Institute, La Jolla, CA 92037</div><div class="affiliation"><sup>2</sup>
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Department of Ophthalmology, University of California, San Francisco,
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San Francisco, CA 94122</div><div class="affiliation"><sup>3</sup>
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Department of Chemistry, The Scripps Research Institute, Jupiter,
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Florida 33458</div><div class="affiliation"><sup>4</sup>
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Department of Chemical Physiology, The Scripps Research Institute
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Molecular Screening Center, The Scripps Research Institute, La Jolla, CA 92037</div><div class="affiliation"><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>Corresponding author:
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.sppircs@nesorh" class="oemail">ude.sppircs@nesorh</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">October 13, 2010</span>; Last Update: <span itemprop="dateModified">December 12, 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>Gianni D, Nicolas N, Zhang H, et al. Optimization and Characterization of an Inhibitor for NADPH Oxidase 1 (NOX-1) 2010 Oct 13 [Updated 2011 Dec 12]. 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/ml172/?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/y2/?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="figobml171fu1"><div id="ml171.fu1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98925/bin/ml171fu1.jpg" alt="ML171." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a></span></h3></div></article><article data-type="table-wrap" id="figobml171tu1"><div id="ml171.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98925/table/ml171.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml171.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml171.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml171.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml171.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml171.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml171.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml171.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml171.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s) Name: IC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml171.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 81131/<a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a></td><td headers="hd_h_ml171.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NOX1</td><td headers="hd_h_ml171.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">129 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 57287864</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2808" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2808</a>]<br />156 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093115" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 92093115</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2538" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2538</a>]</td><td headers="hd_h_ml171.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NOX2, NOX3, NOX4, xanthine oxidase</td><td headers="hd_h_ml171.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>5 (NOX2), 3 (NOX3), 5 (NOX4)</b> [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 57287864</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435013" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435013</a>], <b>5.5 (xanthine oxidase)</b> [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 57287864</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435009" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435009</a>]</td><td headers="hd_h_ml171.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>NOX2, NOX4 & xanthine oxidase:</b> >30 fold; <b>NOX3</b>: 20 fold</td><td headers="hd_h_ml171.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>HEK293 INH:</b> 250 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 57287864</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435002</a>]<br /><b>Inhibition of invadopodia formation:</b> Active [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 57287864</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434993</a><br /><b>Inhibition of ECM degradation:</b> [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 57287864</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488778" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488778</a>]</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml171fu2"><div id="ml171.fu2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98925/bin/ml171fu2.jpg" alt="ML090 CID 616479 SID 23535836." /></div><h3><span class="title"><a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a><br />CID 616479<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/23535836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 23535836</a></span></h3></div></article><article data-type="table-wrap" id="figobml171t1"><div id="ml171.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Overview of PubChem assays for NOX1 inhibitor project</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98925/table/ml171.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml171.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AID</th><th id="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Name</th><th id="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Tested/Active</th><th id="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Non-ML Tested</th><th id="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Purch Tested/Active</th><th id="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Synth Tested/Active</th></tr></thead><tbody><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1792" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1792</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Luminescence-based primary cell-based high throughput screening assay to identify inhibitors of NADPH oxidase 1 (Nox1): Maybridge Library <i>Prior Probe Report (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>)</i></td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16000/130</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1796" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1796</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Summary of probe development efforts to identify inhibitors of NADPH oxidase 1 (Nox1) <i>Prior Probe Report (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>)</i></td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">N/A</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1823" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1823</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Luminescence-based counterscreen for inhibitors of NADPH oxidase 1 (Nox1): biochemical high throughput screening assay to identify inhibitors of luminol (Maybridge Library) <i>Prior Probe Report (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>)</i></td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16000/70</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2532" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2532</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of NOX1: HEK/293 IC<sub>50</sub>
|
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<i>Prior Probe Report (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>)</i></td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6/6</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6/6</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2538" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2538</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Luminescence-based cell-based dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1) <i>Prior Probe Report (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>)</i></td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22/16</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22/16</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2539" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2539</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of (NADPH oxidase 1) NOX1: Family selectivity <i>Prior Probe Report (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>)</i></td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7/5</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7/5</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2541" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2541</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Luminescence-based cell-based assay to identify inhibitors of NADPH oxidase 1 (NOX1) <i>Prior Probe Report (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>)</i></td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">96/68</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2545" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2545</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of (NADPH oxidase 1) NOX1: HEK/293 percent inhibition <i>Prior Probe Report (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>)</i></td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">42/11</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">42</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">42/11</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2556" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2556</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of (NADPH oxidase 1) NOX1: Xanthine Oxidase <i>Prior Probe Report (<a href="/pcsubstance/?term=ML090[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML090</a>)</i></td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6/2</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6/2</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1 hd_h_ml171.t1_1_1_1_2 hd_h_ml171.t1_1_1_1_3 hd_h_ml171.t1_1_1_1_4 hd_h_ml171.t1_1_1_1_5 hd_h_ml171.t1_1_1_1_6" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;"><b>The AIDs below are for the new current probe development effort (<a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a>)</b></td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2664" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2664</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage luminescence-based cell-based dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): Synthesized analogs</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14/7</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14/7</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2752" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2752</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage luminescence-based cell-based dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): Synthesized analogs 2</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12/7</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12/7</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2773" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2773</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage luminescence-based cell-based dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): Synthesized analogs 3</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5/2</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5/2</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2808" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2808</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage luminescence-based cell-based dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): Purchased analogs</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">105/23</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">105</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">105/23</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2819</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage luminescence-based cell-based dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): Purchased analogs 2</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20/6</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20/6</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434953" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434953</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage radioligand binding dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): PDSP screen Ki</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434974" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434974</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage radioligand binding assay to identify inhibitors of NADPH oxidase 1 (NOX1): PDSP screen</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434992" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434992</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage luminescence-based cell-based dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): Cytotoxicity assay</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434993" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434993</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage microscopic assay to identify inhibitors of NADPH oxidase 1 (NOX1): Inhibition of invadopodia formation</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/1</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/1</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434997" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434997</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Luminescence-based cell-based dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): Cherry picks 2</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5/5</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5/5</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435002" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435002</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of NOX1: HEK/293 IC<sub>50</sub> Set 2</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7/7</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7/7</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435009" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435009</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of (NADPH oxidase 1) NOX1: Xanthine Oxidase Set 2</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8/10</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8/10</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/435013" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 435013</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the probe development effort to identify inhibitors of (NADPH oxidase 1) NOX1: Family selectivity: Set 2</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4/3</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4/3</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/463255" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 463255</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage luminescence-based cell-based dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): Cytotoxicity assay 2</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488778" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488778</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage inhibition of ECM degradation</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/1</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/1</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504381" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504381</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage radioligand binding assay to identify inhibitors of NADPH oxidase 1 (NOX1): PDSP screen Set 2</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr><tr><td headers="hd_h_ml171.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504410" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504410</a></td><td headers="hd_h_ml171.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late-stage radioligand binding dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): PDSP screen Ki Set 2</td><td headers="hd_h_ml171.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml171.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1/0</td><td headers="hd_h_ml171.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml171fu3"><div id="ml171.fu3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98925/bin/ml171fu3.jpg" alt="CID 81131 SID57287864 ML171." /></div><h3><span class="title">CID 81131<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID57287864</a><br /><a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a></span></h3></div></article><article data-type="fig" id="figobml171f1"><div id="ml171.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98925/bin/ml171f1.jpg" alt="Figure 1. LC-MS of probe ML178." /></div><h3><span class="label">Figure 1</span><span class="title">LC-MS of probe <a href="/pcsubstance/?term=ML178[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML178</a></span></h3></div></article><article data-type="fig" id="figobml171f2"><div id="ml171.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98925/bin/ml171f2.jpg" alt="Figure 2. LRMS of probe ML178." /></div><h3><span class="label">Figure 2</span><span class="title">LRMS of probe <a href="/pcsubstance/?term=ML178[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML178</a></span></h3></div></article><article data-type="fig" id="figobml171f3"><div id="ml171.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98925/bin/ml171f3.jpg" alt="Figure 3. Stability of Probe ML171 in PBS." /></div><h3><span class="label">Figure 3</span><span class="title">Stability of Probe <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a> in PBS</span></h3></div></article><article data-type="table-wrap" id="figobml171t2"><div id="ml171.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Compounds Submitted to the MLSMR</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98925/table/ml171.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml171.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml171.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Designation</th><th id="hd_h_ml171.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound Number</th><th id="hd_h_ml171.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th id="hd_h_ml171.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th id="hd_h_ml171.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SRID</th><th id="hd_h_ml171.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS</th></tr></thead><tbody><tr><td headers="hd_h_ml171.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 1</b></td><td headers="hd_h_ml171.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>2</b></td><td headers="hd_h_ml171.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">717880</td><td headers="hd_h_ml171.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093123" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093123</a></td><td headers="hd_h_ml171.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-01000783716</td><td headers="hd_h_ml171.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003166899</td></tr><tr><td headers="hd_h_ml171.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Probe</b></td><td headers="hd_h_ml171.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>1</b></td><td headers="hd_h_ml171.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">81131</td><td headers="hd_h_ml171.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287864</a></td><td headers="hd_h_ml171.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-01000597201</td><td headers="hd_h_ml171.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003166900</td></tr><tr><td headers="hd_h_ml171.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 2</b></td><td headers="hd_h_ml171.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>3</b></td><td headers="hd_h_ml171.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7082</td><td headers="hd_h_ml171.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/26540425" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">26540425</a></td><td headers="hd_h_ml171.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-01000441858</td><td headers="hd_h_ml171.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003166902</td></tr><tr><td headers="hd_h_ml171.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 3</b></td><td headers="hd_h_ml171.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>--</b></td><td headers="hd_h_ml171.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">350929</td><td headers="hd_h_ml171.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287906" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287906</a></td><td headers="hd_h_ml171.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-03000000698</td><td headers="hd_h_ml171.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003166903</td></tr><tr><td headers="hd_h_ml171.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Analog 4</b></td><td headers="hd_h_ml171.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>4</b></td><td headers="hd_h_ml171.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7108</td><td headers="hd_h_ml171.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093121" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093121</a></td><td headers="hd_h_ml171.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-01000721844</td><td headers="hd_h_ml171.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003166904</td></tr><tr><td headers="hd_h_ml171.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Clorpromazine</b></td><td headers="hd_h_ml171.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>5</b></td><td headers="hd_h_ml171.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2762</td><td headers="hd_h_ml171.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287810" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287810</a></td><td headers="hd_h_ml171.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SR-01000000012</td><td headers="hd_h_ml171.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003166901</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml171f4"><div id="ml171.f4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20Synthetic%20schemes%20for%20probe%20compound%201.&p=BOOKS&id=98925_ml171f4.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/NBK98925/bin/ml171f4.jpg" alt="Figure 4. Synthetic schemes for probe compound 1." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">Synthetic schemes for probe compound 1</span></h3></div></article><article data-type="fig" id="figobml171f5"><div id="ml171.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98925/bin/ml171f5.jpg" alt="Figure 5. Flow chart of HTS screening for NOX1 inhibitors." /></div><h3><span class="label">Figure 5</span><span class="title">Flow chart of HTS screening for NOX1 inhibitors</span></h3></div></article><article data-type="fig" id="figobml171f6"><div id="ml171.f6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98925/bin/ml171f6.jpg" alt="Figure 6. Compound 1 (ML171) treatment significantly blocks invadopodia formation in DLD1 cells." /></div><h3><span class="label">Figure 6</span><span class="title">Compound 1 (<a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a>) treatment significantly blocks invadopodia formation in DLD1 cells</span></h3><div class="caption"><p>(a) Cells were stained with Alexa-Fluor-568 phalloidin (left column) or cortactin (right column) antibody, followed by Alexa-Fluor 568-conjugated secondary antibody and visualized by confocal miscroscopy (100X). White arrows indicate phalloidin-positive (right column) or cortactin-positive (left column) invadopodia. Scale bars, 5 μm. One representative picture from three separate experiments is shown. (b) Quantification from three independent biological experiments shown in (a) is given: the number of phalloidin positive-invadopodia (left panel) or cortactin positive-invadopodia (right panel) was counted and averaged from 50 cells/condition for each experiment. Error bars represent SEM: *p<0.001. Figure reproduced with permission from the American Chemical Society.</p></div></div></article><article data-type="fig" id="figobml171f7"><div id="ml171.f7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98925/bin/ml171f7.jpg" alt="Figure 7. Treatment with compound 1 (ML171) significantly blocks ECM degradation in DLD1 cells." /></div><h3><span class="label">Figure 7</span><span class="title">Treatment with compound 1 (<a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a>) significantly blocks ECM degradation in DLD1 cells</span></h3><div class="caption"><p>(a) DLD1 cells were transfected as indicated with SrcYF, empty vector (mock) or NOX1 expression plasmid. 24 hours later, cells were trypsinized and plated on FITC-labeled gelatin-coated coverslips. After 2 hours, cells were treated as indicated with 10 μM compound <b>1</b> (<a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a>), DPI (positive control), or DMSO (negative control). 24 hours later, cells were stained with Alexa-Fluor-568 phalloidin and visualized by epifluorescence microscopy (60X). The white arrows indicate areas in which cells (in red) degrade the ECM (in green). The merge is shown in the right column. Scale bar, 10 μm. One representative image from three separate experiments is shown. (b) Quantification from three independent biological experiments shown in (a) is given. Error bars represent SEM: *p <0.01 ** p<0.05 (Mann-Whitney U test). Figure reproduced with permission from the American Chemical Society.</p></div></div></article><article data-type="fig" id="figobml171f8"><div id="ml171.f8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK98925/bin/ml171f8.jpg" alt="Figure 8. Dose response curve for probe ML171." /></div><h3><span class="label">Figure 8</span><span class="title">Dose response curve for probe <a href="/pcsubstance/?term=ML171[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML171</a></span></h3></div></article><article data-type="table-wrap" id="figobml171t3"><div id="ml171.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Selectivity of parent hit and probe compounds compared to that of chlorpromazine</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98925/table/ml171.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml171.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml171.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound</th><th id="hd_h_ml171.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure</th><th id="hd_h_ml171.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50 (μM)<br />HT29 (NOX1)</th><th id="hd_h_ml171.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50 (μM)<br />HEK293-NOX1</th><th id="hd_h_ml171.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50 (μM)<br />HEK293-NOX2</th><th id="hd_h_ml171.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50 (μM)<br />HEK293-NOX3</th><th id="hd_h_ml171.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50 (μM)<br />HEK293-NOX4</th><th id="hd_h_ml171.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50 (μM)<br />Xanthine oxidase</th></tr></thead><tbody><tr><td headers="hd_h_ml171.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">2-(trifluoromethyl)-phenothiazine (parent hit; compound <b>3</b>)</td><td headers="hd_h_ml171.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu4.jpg" alt="Image ml171fu4.jpg" /></div></td><td headers="hd_h_ml171.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.32</td><td headers="hd_h_ml171.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.00</td><td headers="hd_h_ml171.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.00</td><td headers="hd_h_ml171.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.50</td><td headers="hd_h_ml171.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.00</td><td headers="hd_h_ml171.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.00</td></tr><tr><td headers="hd_h_ml171.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">2-acetylphenothiazine (probe, compound <b>1</b>)</td><td headers="hd_h_ml171.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu5.jpg" alt="Image ml171fu5.jpg" /></div></td><td headers="hd_h_ml171.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.129</td><td headers="hd_h_ml171.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.25</td><td headers="hd_h_ml171.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.00</td><td headers="hd_h_ml171.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.00</td><td headers="hd_h_ml171.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.00</td><td headers="hd_h_ml171.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.50</td></tr><tr><td headers="hd_h_ml171.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Chlorpromazine (negative control)</td><td headers="hd_h_ml171.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu6.jpg" alt="Image ml171fu6.jpg" /></div></td><td headers="hd_h_ml171.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50</td><td headers="hd_h_ml171.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td><td headers="hd_h_ml171.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td><td headers="hd_h_ml171.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td><td headers="hd_h_ml171.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td><td headers="hd_h_ml171.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml171.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">DPI (positive control)</td><td headers="hd_h_ml171.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml171.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.2</td><td headers="hd_h_ml171.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.2</td><td headers="hd_h_ml171.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.5</td><td headers="hd_h_ml171.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.75</td><td headers="hd_h_ml171.t3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.1</td><td headers="hd_h_ml171.t3_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.005</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml171t4"><div id="ml171.t4" class="table"><h3><span class="label">Table 4</span><span class="title">SAR Table of Phenothiazines</span></h3><div class="caption"><p>Fragment point of attachment is indicated with an <sup>*</sup></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98925/table/ml171.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml171.t4_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml171.t4_1_1_1_1" colspan="5" rowspan="1" style="text-align:center;vertical-align:middle;">SAR Analysis for Target</th><th id="hd_h_ml171.t4_1_1_1_2" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu7.jpg" alt="Image ml171fu7.jpg" /></div></th><th id="hd_h_ml171.t4_1_1_1_3" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;">Potency (μM) mean ± S.E.M.</th><th id="hd_h_ml171.t4_1_1_1_4" rowspan="3" colspan="1" headers="hd_h_ml171.t4_1_1_1_4" style="text-align:center;vertical-align:middle;">Target to Antitarget Fold Selectivity</th></tr><tr><th headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" id="hd_h_ml171.t4_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">Entry</th><th headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" id="hd_h_ml171.t4_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">CID</th><th headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" id="hd_h_ml171.t4_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">SID</th><th headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" id="hd_h_ml171.t4_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">Center Int. #</th><th headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" id="hd_h_ml171.t4_1_1_2_5" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">P/S<sup>†</sup></th><th headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" id="hd_h_ml171.t4_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">R1</th><th headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" id="hd_h_ml171.t4_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">R2</th><th headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" id="hd_h_ml171.t4_1_1_2_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">R3</th><th headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" id="hd_h_ml171.t4_1_1_2_9" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">R4</th><th headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" id="hd_h_ml171.t4_1_1_2_10" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">N</th><th headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" id="hd_h_ml171.t4_1_1_2_11" rowspan="2" colspan="1" style="text-align:center;vertical-align:bottom;">S</th><th headers="hd_h_ml171.t4_1_1_1_3" id="hd_h_ml171.t4_1_1_2_12" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">Target</th><th headers="hd_h_ml171.t4_1_1_1_3" id="hd_h_ml171.t4_1_1_2_13" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">Antitarget (NOX2)</th></tr><tr><th headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12" id="hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>**</sup></th><th headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12" id="hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50</th><th headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13" id="hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">n<sup>**</sup></th><th headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13" id="hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50</th></tr></thead><tbody><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">81131</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/4242284" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">4242284</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000597201-2</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu8.jpg" alt="Image ml171fu8.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.156</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">5.00</td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">>30</td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287864</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000597201-3</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.25</td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.128</td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">717880</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093123" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093123</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 010007837 16-2</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">—NH<sub>2</sub></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.044</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7082</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/26540425" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">26540425</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 010004418 58-2</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu11.jpg" alt="Image ml171fu11.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.32</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9.00</td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">28</td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7108</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093121" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093121</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000721844-4</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.349</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2726</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287810" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287810</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000000012-5</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cl</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu14.jpg" alt="Image ml171fu14.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>17</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">16682671</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093122" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093122</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000759464-4</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-4-(2- ethylidene hydrazinyl) benzoic acid</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.053</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">652628</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093114" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093114</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000477673-4</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu17.jpg" alt="Image ml171fu17.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.054</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">91401</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093119" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093119</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000683544-4</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu8.jpg" alt="Image ml171fu8.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.0</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">71024</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093111" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093111</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000393539-5</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu21.jpg" alt="Image ml171fu21.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.603</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1547835</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093110" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093110</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000388343-5</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu22.jpg" alt="Image ml171fu22.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu21.jpg" alt="Image ml171fu21.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>20</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">11</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">345722</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093126" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093126</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000852765-2</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu24.jpg" alt="Image ml171fu24.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu21.jpg" alt="Image ml171fu21.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>20</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">12</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">74491</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093105" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093105</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000025134-4</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu22.jpg" alt="Image ml171fu22.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>20</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">13</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">74200</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093124" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093124</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000809845-2</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu24.jpg" alt="Image ml171fu24.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.57</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">14</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">71014</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92093125" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92093125</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000852665-2</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu30.jpg" alt="Image ml171fu30.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>20</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">15</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">350929</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287906" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287906</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000000698-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu22.jpg" alt="Image ml171fu22.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.18</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">16</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4748</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57287811" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57287811</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000000137-4</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cl</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu32.jpg" alt="Image ml171fu32.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>17</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">17</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">66069</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/57288079" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57288079</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 01000000224-4</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu11.jpg" alt="Image ml171fu11.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu14.jpg" alt="Image ml171fu14.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>17</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">18</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10915650</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89649760" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89649760</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001197-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Br</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Br</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>50</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">19</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">638529</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89649761" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89649761</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001198-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Br</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>50</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44825233</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89649762" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89649762</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001199-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu39.jpg" alt="Image ml171fu39.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu39.jpg" alt="Image ml171fu39.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.051</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">21</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44825236</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89649763" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89649763</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001200-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu39.jpg" alt="Image ml171fu39.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.73</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">22</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44825232</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89649764" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89649764</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001201-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu39.jpg" alt="Image ml171fu39.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">17.66</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44825222</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89649765" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89649765</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001202-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu46.jpg" alt="Image ml171fu46.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>50</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44825243</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89649766" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89649766</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001203-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu48.jpg" alt="Image ml171fu48.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.653</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">25</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44825228</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/89649767" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">89649767</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001204-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu50.jpg" alt="Image ml171fu50.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.379</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">26</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44968110</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944630" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944630</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001206-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu52.jpg" alt="Image ml171fu52.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>20</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">27</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44968115</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944631" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944631</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001207-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Br</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>20</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">28</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44968125</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944632" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944632</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001208-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu55.jpg" alt="Image ml171fu55.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>20</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44968146</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944633" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944633</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001209-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu55.jpg" alt="Image ml171fu55.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Br</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">13.7</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">30</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44968124</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/90944634" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">90944634</a></td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SR- 03000001210-1</td><td headers="hd_h_ml171.t4_1_1_1_1 hd_h_ml171.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu59.jpg" alt="Image ml171fu59.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">—NH<sub>2</sub></td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Me</td><td headers="hd_h_ml171.t4_1_1_1_2 hd_h_ml171.t4_1_1_2_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK98925/bin/ml171fu9.jpg" alt="Image ml171fu9.jpg" /></div></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_12 hd_h_ml171.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.201</td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_3 hd_h_ml171.t4_1_1_2_13 hd_h_ml171.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></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="ml171.tfn1"><p class="no_margin">P = Purchased; S = Synthesized</p></div></dd></dl><dl class="bkr_refwrap"><dt>**</dt><dd><div id="ml171.tfn2"><p class="no_margin">n = Number of Replicates</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml171t5"><div id="ml171.t5" class="table"><h3><span class="label">Table 5</span><span class="title">NIMH’s Psychoactive Drug Screening Program results for compound 1</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK98925/table/ml171.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml171.t5_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Receptor</th><th id="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">% INH (10 μM)</th><th id="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ki (nM)</th><th id="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Receptor</th><th id="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">% INH (10 μM)</th><th id="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ki (nM)</th></tr></thead><tbody><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht1a</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21.4</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine receptor D4</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.9</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht1b</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.8</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine receptor D5</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">38.7</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht1d</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15.3</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Biogenic amine transporter DAT</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">29.1</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht1e</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−36.5</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opioid receptor DOR</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.8</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht2a</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.5</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GABA receptor GabaA</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">28.7</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht2b</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">78.9</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">299.7</td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine receptor H1</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">35.7</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht2c</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">31.5</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine receptor H2</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9.9</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht3</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7.8</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine receptor H3</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht5a</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−7.7</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine receptor H4</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−16</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht6</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.5</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opioid receptor KOR</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">102.4</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>10,000</td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seretonin receptor 5ht7</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−19</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic receptor M1</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−14.2</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>10,000</td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic receptor Alpha1A</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−2.9</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic receptor M2</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−6.7</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>10,000</td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic receptor Alpha1B</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic receptor M3</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−0.4</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic receptor Alpha1D</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17.9</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic receptor M4</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−9.4</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic receptor Beta1</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.6</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic receptor M5</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10.5</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic receptor Beta2</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">11.4</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opioid receptor MOR</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">16.6</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic receptor Beta3</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−13.9</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Biogenic amine transporter NET</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">74.1</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BZP Rat Brain Site</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">11.4</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Biogenic amine transporter SERT</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8.8</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine receptor D1</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">13.9</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma receptor 1</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.3</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine receptor D2</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−1.5</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma receptor 2</td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−12.2</td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml171.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine receptor D3</td><td headers="hd_h_ml171.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">97.3</td><td headers="hd_h_ml171.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>10,000</td><td headers="hd_h_ml171.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml171.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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