Novel Seco Cyclopropa[c]pyrrolo[3,2-e]indole Bisalkylators Bearing a 3,3‘-Arylenebisacryloyl Group as a Linker
We synthesized the novel seco cyclopropa[c]pyrrolo[3,2-e]indole (CPI) bisalkylators and evaluated their antitumor activity. Among these derivatives, 11a (AT-760), in which the two seco 3-methoxycarbonyl-2-trifluoromethyl CPI (MCTFCPI) moieties are connected with a 3,3‘-(1,4-phenylene)bisacryloyl gro...
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| Veröffentlicht in: | Journal of medicinal chemistry 2001-04, Vol.44 (9), p.1396-1406 |
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| container_end_page | 1406 |
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| container_issue | 9 |
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| container_title | Journal of medicinal chemistry |
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| creator | Fukuda, Yasumichi Seto, Shigeki Furuta, Hirosuke Ebisu, Hiroyuki Oomori, Yasuo Terashima, Shiro |
| description | We synthesized the novel seco cyclopropa[c]pyrrolo[3,2-e]indole (CPI) bisalkylators and evaluated their antitumor activity. Among these derivatives, 11a (AT-760), in which the two seco 3-methoxycarbonyl-2-trifluoromethyl CPI (MCTFCPI) moieties are connected with a 3,3‘-(1,4-phenylene)bisacryloyl group, was found to exhibit more potent cytotoxicity and antitumor activity against HeLaS3 human uterine cervix carcinoma cells and Colon 26 adenocarcinoma cells, respectively, than 8 (bizelesin, U-77,779). It also appeared that compound 11a exhibits improved in vivo efficacy in the human colon CX-1 model when compared to either compound 8 or mitomycin C (MMC). Efficacious doses for 11a were found to be 2-fold lower than those for 8. |
| doi_str_mv | 10.1021/jm000107x |
| format | Article |
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Among these derivatives, 11a (AT-760), in which the two seco 3-methoxycarbonyl-2-trifluoromethyl CPI (MCTFCPI) moieties are connected with a 3,3‘-(1,4-phenylene)bisacryloyl group, was found to exhibit more potent cytotoxicity and antitumor activity against HeLaS3 human uterine cervix carcinoma cells and Colon 26 adenocarcinoma cells, respectively, than 8 (bizelesin, U-77,779). It also appeared that compound 11a exhibits improved in vivo efficacy in the human colon CX-1 model when compared to either compound 8 or mitomycin C (MMC). Efficacious doses for 11a were found to be 2-fold lower than those for 8.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm000107x</identifier><identifier>PMID: 11311062</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents, Alkylating - chemical synthesis ; Antineoplastic Agents, Alkylating - chemistry ; Antineoplastic Agents, Alkylating - pharmacology ; Benzylidene Compounds - chemical synthesis ; Benzylidene Compounds - chemistry ; Benzylidene Compounds - pharmacology ; Biological and medical sciences ; Drug Screening Assays, Antitumor ; General aspects ; Humans ; Indoles - pharmacology ; Inhibitory Concentration 50 ; Medical sciences ; Mice ; Mice, Nude ; Pharmacology. Drug treatments ; Pyrroles - chemical synthesis ; Pyrroles - chemistry ; Pyrroles - pharmacology ; Structure-Activity Relationship ; Transplantation, Heterologous ; Tumor Cells, Cultured ; Urea - analogs & derivatives ; Urea - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2001-04, Vol.44 (9), p.1396-1406</ispartof><rights>Copyright © 2001 American Chemical Society</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm000107x$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm000107x$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=959528$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11311062$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fukuda, Yasumichi</creatorcontrib><creatorcontrib>Seto, Shigeki</creatorcontrib><creatorcontrib>Furuta, Hirosuke</creatorcontrib><creatorcontrib>Ebisu, Hiroyuki</creatorcontrib><creatorcontrib>Oomori, Yasuo</creatorcontrib><creatorcontrib>Terashima, Shiro</creatorcontrib><title>Novel Seco Cyclopropa[c]pyrrolo[3,2-e]indole Bisalkylators Bearing a 3,3‘-Arylenebisacryloyl Group as a Linker</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>We synthesized the novel seco cyclopropa[c]pyrrolo[3,2-e]indole (CPI) bisalkylators and evaluated their antitumor activity. Among these derivatives, 11a (AT-760), in which the two seco 3-methoxycarbonyl-2-trifluoromethyl CPI (MCTFCPI) moieties are connected with a 3,3‘-(1,4-phenylene)bisacryloyl group, was found to exhibit more potent cytotoxicity and antitumor activity against HeLaS3 human uterine cervix carcinoma cells and Colon 26 adenocarcinoma cells, respectively, than 8 (bizelesin, U-77,779). It also appeared that compound 11a exhibits improved in vivo efficacy in the human colon CX-1 model when compared to either compound 8 or mitomycin C (MMC). Efficacious doses for 11a were found to be 2-fold lower than those for 8.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Alkylating - chemical synthesis</subject><subject>Antineoplastic Agents, Alkylating - chemistry</subject><subject>Antineoplastic Agents, Alkylating - pharmacology</subject><subject>Benzylidene Compounds - chemical synthesis</subject><subject>Benzylidene Compounds - chemistry</subject><subject>Benzylidene Compounds - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Drug Screening Assays, Antitumor</subject><subject>General aspects</subject><subject>Humans</subject><subject>Indoles - pharmacology</subject><subject>Inhibitory Concentration 50</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrroles - chemical synthesis</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Transplantation, Heterologous</subject><subject>Tumor Cells, Cultured</subject><subject>Urea - analogs & derivatives</subject><subject>Urea - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo90dtq20AQBuCltNSum4u-QBGU3EXN7o6Ol7apnYLJAbsQCGEZrUZB9lordu1i3fUx8nx5kio48dUMzMcPw8_YN8F_Ci7F5XrLORc8PXxgQxFLHkYZjz6yIedShjKRMGBfvF_3CISEz2wgBAjBEzlk7bX9SyZYkrbBtNPGts62-KAf2845a-wDXMiQHuumtIaCSe3RbDqDO-t8MCF0dfMUYAAX8PLvORy7zlBDRa90v9rOBHNn922AvkeLutmQ-8o-VWg8nb3NEfsz-7WaXoWLm_nv6XgRInDYhQAJIEU6IsoozVNZRrKI81zEGUUZVHmRZIUo4iLXmRRQFWWpY6l1RZgCooYR-37MbffFlkrVunqLrlPvr_fgxxtAr9FUDhtd-5PL4zyWWa_Co6r9jg6nK7qNSlJIY7W6XarZfMrT-7uVek09P3rUXq3t3jX9k0pw9VqUOhUF_wHIvYOi</recordid><startdate>20010426</startdate><enddate>20010426</enddate><creator>Fukuda, Yasumichi</creator><creator>Seto, Shigeki</creator><creator>Furuta, Hirosuke</creator><creator>Ebisu, Hiroyuki</creator><creator>Oomori, Yasuo</creator><creator>Terashima, Shiro</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></search><sort><creationdate>20010426</creationdate><title>Novel Seco Cyclopropa[c]pyrrolo[3,2-e]indole Bisalkylators Bearing a 3,3‘-Arylenebisacryloyl Group as a Linker</title><author>Fukuda, Yasumichi ; Seto, Shigeki ; Furuta, Hirosuke ; Ebisu, Hiroyuki ; Oomori, Yasuo ; Terashima, Shiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a303t-3363ae4c4ee8e7972d42b599158e483f9b68b1b5b9c8213fbddc52ccfea73aac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Alkylating - chemical synthesis</topic><topic>Antineoplastic Agents, Alkylating - chemistry</topic><topic>Antineoplastic Agents, Alkylating - pharmacology</topic><topic>Benzylidene Compounds - chemical synthesis</topic><topic>Benzylidene Compounds - chemistry</topic><topic>Benzylidene Compounds - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Drug Screening Assays, Antitumor</topic><topic>General aspects</topic><topic>Humans</topic><topic>Indoles - pharmacology</topic><topic>Inhibitory Concentration 50</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrroles - chemical synthesis</topic><topic>Pyrroles - chemistry</topic><topic>Pyrroles - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Transplantation, Heterologous</topic><topic>Tumor Cells, Cultured</topic><topic>Urea - analogs & derivatives</topic><topic>Urea - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fukuda, Yasumichi</creatorcontrib><creatorcontrib>Seto, Shigeki</creatorcontrib><creatorcontrib>Furuta, Hirosuke</creatorcontrib><creatorcontrib>Ebisu, Hiroyuki</creatorcontrib><creatorcontrib>Oomori, Yasuo</creatorcontrib><creatorcontrib>Terashima, Shiro</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fukuda, Yasumichi</au><au>Seto, Shigeki</au><au>Furuta, Hirosuke</au><au>Ebisu, Hiroyuki</au><au>Oomori, Yasuo</au><au>Terashima, Shiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Seco Cyclopropa[c]pyrrolo[3,2-e]indole Bisalkylators Bearing a 3,3‘-Arylenebisacryloyl Group as a Linker</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2001-04-26</date><risdate>2001</risdate><volume>44</volume><issue>9</issue><spage>1396</spage><epage>1406</epage><pages>1396-1406</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>We synthesized the novel seco cyclopropa[c]pyrrolo[3,2-e]indole (CPI) bisalkylators and evaluated their antitumor activity. Among these derivatives, 11a (AT-760), in which the two seco 3-methoxycarbonyl-2-trifluoromethyl CPI (MCTFCPI) moieties are connected with a 3,3‘-(1,4-phenylene)bisacryloyl group, was found to exhibit more potent cytotoxicity and antitumor activity against HeLaS3 human uterine cervix carcinoma cells and Colon 26 adenocarcinoma cells, respectively, than 8 (bizelesin, U-77,779). It also appeared that compound 11a exhibits improved in vivo efficacy in the human colon CX-1 model when compared to either compound 8 or mitomycin C (MMC). Efficacious doses for 11a were found to be 2-fold lower than those for 8.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>11311062</pmid><doi>10.1021/jm000107x</doi><tpages>11</tpages></addata></record> |
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| subjects | Animals Antineoplastic agents Antineoplastic Agents, Alkylating - chemical synthesis Antineoplastic Agents, Alkylating - chemistry Antineoplastic Agents, Alkylating - pharmacology Benzylidene Compounds - chemical synthesis Benzylidene Compounds - chemistry Benzylidene Compounds - pharmacology Biological and medical sciences Drug Screening Assays, Antitumor General aspects Humans Indoles - pharmacology Inhibitory Concentration 50 Medical sciences Mice Mice, Nude Pharmacology. Drug treatments Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Structure-Activity Relationship Transplantation, Heterologous Tumor Cells, Cultured Urea - analogs & derivatives Urea - pharmacology |
| title | Novel Seco Cyclopropa[c]pyrrolo[3,2-e]indole Bisalkylators Bearing a 3,3‘-Arylenebisacryloyl Group as a Linker |
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