Potent Antitubulin Tumor Cell Cytotoxins Based on 3-Aroyl Indazoles
A series of 3-aroyl indazoles was synthesized. Modification of the C-7 position resulted in a significant structure−activity relationship (SAR) with acetylene modifications conferring unusual potency in a tumor cell cytotoxicity assay. The most potent compounds exceeded the activity of combretastati...
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| Veröffentlicht in: | Journal of medicinal chemistry 2007-03, Vol.50 (5), p.1001-1006 |
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| container_title | Journal of medicinal chemistry |
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| creator | Duan, Jian-Xin Cai, Xiaohong Meng, Fanying Lan, Leslie Hart, Charles Matteucci, Mark |
| description | A series of 3-aroyl indazoles was synthesized. Modification of the C-7 position resulted in a significant structure−activity relationship (SAR) with acetylene modifications conferring unusual potency in a tumor cell cytotoxicity assay. The most potent compounds exceeded the activity of combretastatin A4 (CA-4), showing single digit nM IC50 values against all cell lines tested including those with known efflux resistance pumps. The inhibition of in vitro tubulin polymerization was comparable to CA-4, consistent with tubulin being the target for these compounds. Competition binding experiments employing [3H]colchicine and purified tubulins demonstrated that the compound specifically binds to the colchicine site. |
| doi_str_mv | 10.1021/jm061348t |
| format | Article |
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Modification of the C-7 position resulted in a significant structure−activity relationship (SAR) with acetylene modifications conferring unusual potency in a tumor cell cytotoxicity assay. The most potent compounds exceeded the activity of combretastatin A4 (CA-4), showing single digit nM IC50 values against all cell lines tested including those with known efflux resistance pumps. The inhibition of in vitro tubulin polymerization was comparable to CA-4, consistent with tubulin being the target for these compounds. Competition binding experiments employing [3H]colchicine and purified tubulins demonstrated that the compound specifically binds to the colchicine site.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm061348t</identifier><identifier>PMID: 17286393</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Acetylene - chemistry ; Animals ; Antineoplastic agents ; Binding Sites ; Binding, Competitive ; Biological and medical sciences ; Cattle ; Cell Line, Tumor ; Colchicine - chemistry ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; General aspects ; Humans ; Indazoles - chemical synthesis ; Indazoles - chemistry ; Indazoles - pharmacology ; Medical sciences ; Pharmacology. Drug treatments ; Radioligand Assay ; Stilbenes - chemistry ; Stilbenes - pharmacology ; Structure-Activity Relationship ; Tubulin - chemistry ; Tubulin Modulators - chemical synthesis ; Tubulin Modulators - chemistry ; Tubulin Modulators - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2007-03, Vol.50 (5), p.1001-1006</ispartof><rights>Copyright © 2007 American Chemical Society</rights><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a478t-6121e68be8c62bd06d3885be6560363553c5aa313671f313fd26634eab7e49c73</citedby><cites>FETCH-LOGICAL-a478t-6121e68be8c62bd06d3885be6560363553c5aa313671f313fd26634eab7e49c73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm061348t$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm061348t$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18652250$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17286393$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Duan, Jian-Xin</creatorcontrib><creatorcontrib>Cai, Xiaohong</creatorcontrib><creatorcontrib>Meng, Fanying</creatorcontrib><creatorcontrib>Lan, Leslie</creatorcontrib><creatorcontrib>Hart, Charles</creatorcontrib><creatorcontrib>Matteucci, Mark</creatorcontrib><title>Potent Antitubulin Tumor Cell Cytotoxins Based on 3-Aroyl Indazoles</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of 3-aroyl indazoles was synthesized. Modification of the C-7 position resulted in a significant structure−activity relationship (SAR) with acetylene modifications conferring unusual potency in a tumor cell cytotoxicity assay. The most potent compounds exceeded the activity of combretastatin A4 (CA-4), showing single digit nM IC50 values against all cell lines tested including those with known efflux resistance pumps. The inhibition of in vitro tubulin polymerization was comparable to CA-4, consistent with tubulin being the target for these compounds. Competition binding experiments employing [3H]colchicine and purified tubulins demonstrated that the compound specifically binds to the colchicine site.</description><subject>Acetylene - chemistry</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Binding Sites</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Cattle</subject><subject>Cell Line, Tumor</subject><subject>Colchicine - chemistry</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug Screening Assays, Antitumor</subject><subject>General aspects</subject><subject>Humans</subject><subject>Indazoles - chemical synthesis</subject><subject>Indazoles - chemistry</subject><subject>Indazoles - pharmacology</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Radioligand Assay</subject><subject>Stilbenes - chemistry</subject><subject>Stilbenes - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Tubulin - chemistry</subject><subject>Tubulin Modulators - chemical synthesis</subject><subject>Tubulin Modulators - chemistry</subject><subject>Tubulin Modulators - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMFu1DAURS1ERYe2C34AZQNSFwHbL372LKcRhYqiVjBlazmJI2VI7NZ2pE6_Hlcz6myQWN3FOzq67xLyjtFPjHL2eTNRZFCp9IosmOC0rBStXpMFpZyXHDkck7cxbiilwDi8IcdMcoWwhAWpb32yLhUrl4Y0N_M4uGI9Tz4UtR3Hot4mn_zj4GJxYaLtCu8KKFfBb8fiynXmyY82npKj3ozRnu3zhNxdflnX38rrm69X9eq6NJVUqUTGmUXVWNUibzqKHSglGosCKSAIAa0wBhigZH2OvuOIUFnTSFstWwkn5OPOex_8w2xj0tMQ21zTOOvnqGV-N7vwvyBbygro8tl4vgPb4GMMttf3YZhM2GpG9fO0-mXazL7fS-dmst2B3G-ZgQ97wMTWjH0wrh3igVMocj-auXLHDTHZx5e7CX80SpBCr29_6Z-_Uf24-C40P3hNG_XGz8Hlkf9R8C_A75mU</recordid><startdate>20070308</startdate><enddate>20070308</enddate><creator>Duan, Jian-Xin</creator><creator>Cai, Xiaohong</creator><creator>Meng, Fanying</creator><creator>Lan, Leslie</creator><creator>Hart, Charles</creator><creator>Matteucci, Mark</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20070308</creationdate><title>Potent Antitubulin Tumor Cell Cytotoxins Based on 3-Aroyl Indazoles</title><author>Duan, Jian-Xin ; Cai, Xiaohong ; Meng, Fanying ; Lan, Leslie ; Hart, Charles ; Matteucci, Mark</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a478t-6121e68be8c62bd06d3885be6560363553c5aa313671f313fd26634eab7e49c73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Acetylene - chemistry</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Binding Sites</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Cattle</topic><topic>Cell Line, Tumor</topic><topic>Colchicine - chemistry</topic><topic>Drug Resistance, Neoplasm</topic><topic>Drug Screening Assays, Antitumor</topic><topic>General aspects</topic><topic>Humans</topic><topic>Indazoles - chemical synthesis</topic><topic>Indazoles - chemistry</topic><topic>Indazoles - pharmacology</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Radioligand Assay</topic><topic>Stilbenes - chemistry</topic><topic>Stilbenes - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Tubulin - chemistry</topic><topic>Tubulin Modulators - chemical synthesis</topic><topic>Tubulin Modulators - chemistry</topic><topic>Tubulin Modulators - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Duan, Jian-Xin</creatorcontrib><creatorcontrib>Cai, Xiaohong</creatorcontrib><creatorcontrib>Meng, Fanying</creatorcontrib><creatorcontrib>Lan, Leslie</creatorcontrib><creatorcontrib>Hart, Charles</creatorcontrib><creatorcontrib>Matteucci, Mark</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Duan, Jian-Xin</au><au>Cai, Xiaohong</au><au>Meng, Fanying</au><au>Lan, Leslie</au><au>Hart, Charles</au><au>Matteucci, Mark</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Potent Antitubulin Tumor Cell Cytotoxins Based on 3-Aroyl Indazoles</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2007-03-08</date><risdate>2007</risdate><volume>50</volume><issue>5</issue><spage>1001</spage><epage>1006</epage><pages>1001-1006</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of 3-aroyl indazoles was synthesized. Modification of the C-7 position resulted in a significant structure−activity relationship (SAR) with acetylene modifications conferring unusual potency in a tumor cell cytotoxicity assay. The most potent compounds exceeded the activity of combretastatin A4 (CA-4), showing single digit nM IC50 values against all cell lines tested including those with known efflux resistance pumps. The inhibition of in vitro tubulin polymerization was comparable to CA-4, consistent with tubulin being the target for these compounds. Competition binding experiments employing [3H]colchicine and purified tubulins demonstrated that the compound specifically binds to the colchicine site.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>17286393</pmid><doi>10.1021/jm061348t</doi><tpages>6</tpages></addata></record> |
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| subjects | Acetylene - chemistry Animals Antineoplastic agents Binding Sites Binding, Competitive Biological and medical sciences Cattle Cell Line, Tumor Colchicine - chemistry Drug Resistance, Neoplasm Drug Screening Assays, Antitumor General aspects Humans Indazoles - chemical synthesis Indazoles - chemistry Indazoles - pharmacology Medical sciences Pharmacology. Drug treatments Radioligand Assay Stilbenes - chemistry Stilbenes - pharmacology Structure-Activity Relationship Tubulin - chemistry Tubulin Modulators - chemical synthesis Tubulin Modulators - chemistry Tubulin Modulators - pharmacology |
| title | Potent Antitubulin Tumor Cell Cytotoxins Based on 3-Aroyl Indazoles |
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