New Antimitotic Agents with Activity in Multi-Drug-Resistant Cell Lines and in Vivo Efficacy in Murine Tumor Models
During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but...
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| Veröffentlicht in: | Journal of medicinal chemistry 2001-12, Vol.44 (25), p.4416-4430 |
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| creator | Szczepankiewicz, Bruce G Liu, Gang Jae, Hwan-Soo Tasker, Andrew S Gunawardana, Indrani W von Geldern, Thomas W Gwaltney, Stephen L Wu-Wong, J. Ruth Gehrke, Laura Chiou, William J Credo, R. Bruce Alder, Jeffery D Nukkala, Michael A Zielinski, Nicolette A Jarvis, Ken Mollison, Karl W Frost, David J Bauch, Joy L Hui, Yu Hua Claiborne, Akiyo K Li, Qun Rosenberg, Saul H |
| description | During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers. |
| doi_str_mv | 10.1021/jm010231w |
| format | Article |
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Ruth ; Gehrke, Laura ; Chiou, William J ; Credo, R. Bruce ; Alder, Jeffery D ; Nukkala, Michael A ; Zielinski, Nicolette A ; Jarvis, Ken ; Mollison, Karl W ; Frost, David J ; Bauch, Joy L ; Hui, Yu Hua ; Claiborne, Akiyo K ; Li, Qun ; Rosenberg, Saul H</creator><creatorcontrib>Szczepankiewicz, Bruce G ; Liu, Gang ; Jae, Hwan-Soo ; Tasker, Andrew S ; Gunawardana, Indrani W ; von Geldern, Thomas W ; Gwaltney, Stephen L ; Wu-Wong, J. Ruth ; Gehrke, Laura ; Chiou, William J ; Credo, R. Bruce ; Alder, Jeffery D ; Nukkala, Michael A ; Zielinski, Nicolette A ; Jarvis, Ken ; Mollison, Karl W ; Frost, David J ; Bauch, Joy L ; Hui, Yu Hua ; Claiborne, Akiyo K ; Li, Qun ; Rosenberg, Saul H</creatorcontrib><description>During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm010231w</identifier><identifier>PMID: 11728187</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Chemotherapy ; Chromatography, High Pressure Liquid ; Colchicine - chemistry ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Female ; Magnetic Resonance Spectroscopy ; Male ; Mass Spectrometry ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Oxazoles - chemical synthesis ; Oxazoles - chemistry ; Oxazoles - pharmacology ; Pharmacology. Drug treatments ; Structure-Activity Relationship ; Transplantation, Heterologous ; Tumor Cells, Cultured</subject><ispartof>Journal of medicinal chemistry, 2001-12, Vol.44 (25), p.4416-4430</ispartof><rights>Copyright © 2001 American Chemical Society</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a379t-e9edda1cc0a4e4aa3f03483d9e451d62dbcc3defe4ce2e21e0d530d8c4ec57113</citedby><cites>FETCH-LOGICAL-a379t-e9edda1cc0a4e4aa3f03483d9e451d62dbcc3defe4ce2e21e0d530d8c4ec57113</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/jm010231w$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm010231w$$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=14130903$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11728187$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Szczepankiewicz, Bruce G</creatorcontrib><creatorcontrib>Liu, Gang</creatorcontrib><creatorcontrib>Jae, Hwan-Soo</creatorcontrib><creatorcontrib>Tasker, Andrew S</creatorcontrib><creatorcontrib>Gunawardana, Indrani W</creatorcontrib><creatorcontrib>von Geldern, Thomas W</creatorcontrib><creatorcontrib>Gwaltney, Stephen L</creatorcontrib><creatorcontrib>Wu-Wong, J. Ruth</creatorcontrib><creatorcontrib>Gehrke, Laura</creatorcontrib><creatorcontrib>Chiou, William J</creatorcontrib><creatorcontrib>Credo, R. Bruce</creatorcontrib><creatorcontrib>Alder, Jeffery D</creatorcontrib><creatorcontrib>Nukkala, Michael A</creatorcontrib><creatorcontrib>Zielinski, Nicolette A</creatorcontrib><creatorcontrib>Jarvis, Ken</creatorcontrib><creatorcontrib>Mollison, Karl W</creatorcontrib><creatorcontrib>Frost, David J</creatorcontrib><creatorcontrib>Bauch, Joy L</creatorcontrib><creatorcontrib>Hui, Yu Hua</creatorcontrib><creatorcontrib>Claiborne, Akiyo K</creatorcontrib><creatorcontrib>Li, Qun</creatorcontrib><creatorcontrib>Rosenberg, Saul H</creatorcontrib><title>New Antimitotic Agents with Activity in Multi-Drug-Resistant Cell Lines and in Vivo Efficacy in Murine Tumor Models</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Chemotherapy</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Colchicine - chemistry</subject><subject>Drug Resistance, Multiple</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Female</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Mass Spectrometry</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred DBA</subject><subject>Oxazoles - chemical synthesis</subject><subject>Oxazoles - chemistry</subject><subject>Oxazoles - pharmacology</subject><subject>Pharmacology. 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Bruce</creator><creator>Alder, Jeffery D</creator><creator>Nukkala, Michael A</creator><creator>Zielinski, Nicolette A</creator><creator>Jarvis, Ken</creator><creator>Mollison, Karl W</creator><creator>Frost, David J</creator><creator>Bauch, Joy L</creator><creator>Hui, Yu Hua</creator><creator>Claiborne, Akiyo K</creator><creator>Li, Qun</creator><creator>Rosenberg, Saul H</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>7X8</scope></search><sort><creationdate>20011206</creationdate><title>New Antimitotic Agents with Activity in Multi-Drug-Resistant Cell Lines and in Vivo Efficacy in Murine Tumor Models</title><author>Szczepankiewicz, Bruce G ; Liu, Gang ; Jae, Hwan-Soo ; Tasker, Andrew S ; Gunawardana, Indrani W ; von Geldern, Thomas W ; Gwaltney, Stephen L ; Wu-Wong, J. Ruth ; Gehrke, Laura ; Chiou, William J ; Credo, R. Bruce ; Alder, Jeffery D ; Nukkala, Michael A ; Zielinski, Nicolette A ; Jarvis, Ken ; Mollison, Karl W ; Frost, David J ; Bauch, Joy L ; Hui, Yu Hua ; Claiborne, Akiyo K ; Li, Qun ; Rosenberg, Saul H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a379t-e9edda1cc0a4e4aa3f03483d9e451d62dbcc3defe4ce2e21e0d530d8c4ec57113</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Chemotherapy</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Colchicine - chemistry</topic><topic>Drug Resistance, Multiple</topic><topic>Drug Resistance, Neoplasm</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Female</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Male</topic><topic>Mass Spectrometry</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred DBA</topic><topic>Oxazoles - chemical synthesis</topic><topic>Oxazoles - chemistry</topic><topic>Oxazoles - pharmacology</topic><topic>Pharmacology. 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Ruth</au><au>Gehrke, Laura</au><au>Chiou, William J</au><au>Credo, R. Bruce</au><au>Alder, Jeffery D</au><au>Nukkala, Michael A</au><au>Zielinski, Nicolette A</au><au>Jarvis, Ken</au><au>Mollison, Karl W</au><au>Frost, David J</au><au>Bauch, Joy L</au><au>Hui, Yu Hua</au><au>Claiborne, Akiyo K</au><au>Li, Qun</au><au>Rosenberg, Saul H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New Antimitotic Agents with Activity in Multi-Drug-Resistant Cell Lines and in Vivo Efficacy in Murine Tumor Models</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2001-12-06</date><risdate>2001</risdate><volume>44</volume><issue>25</issue><spage>4416</spage><epage>4430</epage><pages>4416-4430</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>11728187</pmid><doi>10.1021/jm010231w</doi><tpages>15</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2001-12, Vol.44 (25), p.4416-4430 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biological and medical sciences Chemotherapy Chromatography, High Pressure Liquid Colchicine - chemistry Drug Resistance, Multiple Drug Resistance, Neoplasm Drug Screening Assays, Antitumor Female Magnetic Resonance Spectroscopy Male Mass Spectrometry Medical sciences Mice Mice, Inbred C57BL Mice, Inbred DBA Oxazoles - chemical synthesis Oxazoles - chemistry Oxazoles - pharmacology Pharmacology. Drug treatments Structure-Activity Relationship Transplantation, Heterologous Tumor Cells, Cultured |
| title | New Antimitotic Agents with Activity in Multi-Drug-Resistant Cell Lines and in Vivo Efficacy in Murine Tumor Models |
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