Phthalascidin, a Synthetic Antitumor Agent with Potency and Mode of Action Comparable to Ecteinascidin 743
A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action ac...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1999-03, Vol.96 (7), p.3496-3501 |
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| creator | Martinez, Eduardo J. Owa, Takashi Schreiber, Stuart L. Corey, E. J. |
| description | A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action across a variety of cell types. The antiproliferative activity of phthalascidin (IC50= 0.1-1 nM) is greater than that of the agents Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude, and the mechanism of action is clearly different from these currently used drugs. Phthalascidin and Et 743 induce DNA-protein cross-linking and, although they seem to interact with topoisomerase (topo) I (but not topo II), topo I may not be the primary protein target of these agents. Phthalascidin and Et 743 show undiminished potency in camptothecin- and etoposide-resistant cells. Phthalascidin is more readily synthesized and more stable than Et 743, which is currently undergoing clinical trials. The relationship of chemical structure and antitumor activity for this class of molecules has been clarified by this study. |
| doi_str_mv | 10.1073/pnas.96.7.3496 |
| format | Article |
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J.</creator><creatorcontrib>Martinez, Eduardo J. ; Owa, Takashi ; Schreiber, Stuart L. ; Corey, E. J.</creatorcontrib><description>A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action across a variety of cell types. The antiproliferative activity of phthalascidin (IC50= 0.1-1 nM) is greater than that of the agents Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude, and the mechanism of action is clearly different from these currently used drugs. Phthalascidin and Et 743 induce DNA-protein cross-linking and, although they seem to interact with topoisomerase (topo) I (but not topo II), topo I may not be the primary protein target of these agents. Phthalascidin and Et 743 show undiminished potency in camptothecin- and etoposide-resistant cells. Phthalascidin is more readily synthesized and more stable than Et 743, which is currently undergoing clinical trials. The relationship of chemical structure and antitumor activity for this class of molecules has been clarified by this study.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.96.7.3496</identifier><identifier>PMID: 10097064</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Alkylation ; Antineoplastic Agents, Alkylating - chemistry ; Antineoplastic Agents, Alkylating - toxicity ; Antineoplastics ; Bleomycin - toxicity ; Camptothecin - toxicity ; Cell Division - drug effects ; Cell growth ; Cell lines ; Cisplatin - toxicity ; Cross-Linking Reagents - chemistry ; Cross-Linking Reagents - toxicity ; Cultured cells ; Dioxoles - chemistry ; Dioxoles - toxicity ; DNA ; DNA Topoisomerases, Type I - metabolism ; DNA, Neoplasm - metabolism ; Doxorubicin - toxicity ; Drug therapy ; Etoposide - toxicity ; Female ; HCT116 cells ; Humans ; Inhibitory concentration 50 ; Isoquinolines - chemistry ; Isoquinolines - toxicity ; Lungs ; Male ; Mitomycin - toxicity ; Models, Molecular ; Molecular Structure ; Molecules ; Neoplasm Proteins - metabolism ; Paclitaxel - toxicity ; Phthalimides - chemistry ; Phthalimides - toxicity ; Physical Sciences ; Radioactive decay ; Structure-Activity Relationship ; Synthetic products ; Tetrahydroisoquinolines ; Trabectedin ; Tumor Cells, Cultured ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1999-03, Vol.96 (7), p.3496-3501</ispartof><rights>Copyright 1993-1999 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Mar 30, 1999</rights><rights>Copyright © 1999, The National Academy of Sciences 1999</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c514t-d7646e53f379302bbe222876821f9c8164c319127e74e59008198456d7b9d8c53</citedby><cites>FETCH-LOGICAL-c514t-d7646e53f379302bbe222876821f9c8164c319127e74e59008198456d7b9d8c53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/96/7.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/47665$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/47665$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27922,27923,53789,53791,58015,58248</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10097064$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martinez, Eduardo J.</creatorcontrib><creatorcontrib>Owa, Takashi</creatorcontrib><creatorcontrib>Schreiber, Stuart L.</creatorcontrib><creatorcontrib>Corey, E. J.</creatorcontrib><title>Phthalascidin, a Synthetic Antitumor Agent with Potency and Mode of Action Comparable to Ecteinascidin 743</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action across a variety of cell types. The antiproliferative activity of phthalascidin (IC50= 0.1-1 nM) is greater than that of the agents Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude, and the mechanism of action is clearly different from these currently used drugs. Phthalascidin and Et 743 induce DNA-protein cross-linking and, although they seem to interact with topoisomerase (topo) I (but not topo II), topo I may not be the primary protein target of these agents. Phthalascidin and Et 743 show undiminished potency in camptothecin- and etoposide-resistant cells. Phthalascidin is more readily synthesized and more stable than Et 743, which is currently undergoing clinical trials. The relationship of chemical structure and antitumor activity for this class of molecules has been clarified by this study.</description><subject>Alkylation</subject><subject>Antineoplastic Agents, Alkylating - chemistry</subject><subject>Antineoplastic Agents, Alkylating - toxicity</subject><subject>Antineoplastics</subject><subject>Bleomycin - toxicity</subject><subject>Camptothecin - toxicity</subject><subject>Cell Division - drug effects</subject><subject>Cell growth</subject><subject>Cell lines</subject><subject>Cisplatin - toxicity</subject><subject>Cross-Linking Reagents - chemistry</subject><subject>Cross-Linking Reagents - toxicity</subject><subject>Cultured cells</subject><subject>Dioxoles - chemistry</subject><subject>Dioxoles - toxicity</subject><subject>DNA</subject><subject>DNA Topoisomerases, Type I - metabolism</subject><subject>DNA, Neoplasm - metabolism</subject><subject>Doxorubicin - toxicity</subject><subject>Drug therapy</subject><subject>Etoposide - toxicity</subject><subject>Female</subject><subject>HCT116 cells</subject><subject>Humans</subject><subject>Inhibitory concentration 50</subject><subject>Isoquinolines - chemistry</subject><subject>Isoquinolines - toxicity</subject><subject>Lungs</subject><subject>Male</subject><subject>Mitomycin - toxicity</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Molecules</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Paclitaxel - toxicity</subject><subject>Phthalimides - chemistry</subject><subject>Phthalimides - toxicity</subject><subject>Physical Sciences</subject><subject>Radioactive decay</subject><subject>Structure-Activity Relationship</subject><subject>Synthetic products</subject><subject>Tetrahydroisoquinolines</subject><subject>Trabectedin</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9rFDEcxYNY7Fq9ehCU0IMnZ8yvSSbgZVmqFioW1HPIZDKdLDPJmmS0-987y67L2kNPCbzPe7wvD4BXGJUYCfph43UqJS9FSZnkT8ACI4kLziR6ChYIEVHUjLBz8DylNUJIVjV6Bs7x_BOIswVY3_a514NOxrXOv4caft_63NvsDFz67PI0hgiXd9Zn-MflHt6GbL3ZQu1b-DW0FoYOLk12wcNVGDc66mawMAd4ZbJ1_hAMBaMvwFmnh2RfHt4L8PPT1Y_Vl-Lm2-fr1fKmMBVmuWgFZ9xWtKNCUkSaxhJCasFrgjtpasyZoVhiIqxgtpII1VjWrOKtaGRbm4pegI_73M3UjLY1c_WoB7WJbtRxq4J26n_Fu17dhd-KEErwbH93sMfwa7Ipq9ElY4dBexumpLAgSFQVmsHLB-A6TNHPpymCMGWCsXqGyj1kYkgp2u7YAyO1W1DtFlSSK6F2C86Gt6ftT_D9ZCf9dsZ_8jFAddMwZHufZ_DNY-Csv97r65RDPAJMcF7Rv0t-tww</recordid><startdate>19990330</startdate><enddate>19990330</enddate><creator>Martinez, Eduardo J.</creator><creator>Owa, Takashi</creator><creator>Schreiber, Stuart L.</creator><creator>Corey, E. 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J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c514t-d7646e53f379302bbe222876821f9c8164c319127e74e59008198456d7b9d8c53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Alkylation</topic><topic>Antineoplastic Agents, Alkylating - chemistry</topic><topic>Antineoplastic Agents, Alkylating - toxicity</topic><topic>Antineoplastics</topic><topic>Bleomycin - toxicity</topic><topic>Camptothecin - toxicity</topic><topic>Cell Division - drug effects</topic><topic>Cell growth</topic><topic>Cell lines</topic><topic>Cisplatin - toxicity</topic><topic>Cross-Linking Reagents - chemistry</topic><topic>Cross-Linking Reagents - toxicity</topic><topic>Cultured cells</topic><topic>Dioxoles - chemistry</topic><topic>Dioxoles - toxicity</topic><topic>DNA</topic><topic>DNA Topoisomerases, Type I - metabolism</topic><topic>DNA, Neoplasm - metabolism</topic><topic>Doxorubicin - toxicity</topic><topic>Drug therapy</topic><topic>Etoposide - toxicity</topic><topic>Female</topic><topic>HCT116 cells</topic><topic>Humans</topic><topic>Inhibitory concentration 50</topic><topic>Isoquinolines - chemistry</topic><topic>Isoquinolines - toxicity</topic><topic>Lungs</topic><topic>Male</topic><topic>Mitomycin - toxicity</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Molecules</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Paclitaxel - toxicity</topic><topic>Phthalimides - chemistry</topic><topic>Phthalimides - toxicity</topic><topic>Physical Sciences</topic><topic>Radioactive decay</topic><topic>Structure-Activity Relationship</topic><topic>Synthetic products</topic><topic>Tetrahydroisoquinolines</topic><topic>Trabectedin</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martinez, Eduardo J.</creatorcontrib><creatorcontrib>Owa, Takashi</creatorcontrib><creatorcontrib>Schreiber, Stuart L.</creatorcontrib><creatorcontrib>Corey, E. 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J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phthalascidin, a Synthetic Antitumor Agent with Potency and Mode of Action Comparable to Ecteinascidin 743</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1999-03-30</date><risdate>1999</risdate><volume>96</volume><issue>7</issue><spage>3496</spage><epage>3501</epage><pages>3496-3501</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action across a variety of cell types. The antiproliferative activity of phthalascidin (IC50= 0.1-1 nM) is greater than that of the agents Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude, and the mechanism of action is clearly different from these currently used drugs. Phthalascidin and Et 743 induce DNA-protein cross-linking and, although they seem to interact with topoisomerase (topo) I (but not topo II), topo I may not be the primary protein target of these agents. Phthalascidin and Et 743 show undiminished potency in camptothecin- and etoposide-resistant cells. Phthalascidin is more readily synthesized and more stable than Et 743, which is currently undergoing clinical trials. The relationship of chemical structure and antitumor activity for this class of molecules has been clarified by this study.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>10097064</pmid><doi>10.1073/pnas.96.7.3496</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1999-03, Vol.96 (7), p.3496-3501 |
| issn | 0027-8424 1091-6490 |
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| source | MEDLINE; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Alkylation Antineoplastic Agents, Alkylating - chemistry Antineoplastic Agents, Alkylating - toxicity Antineoplastics Bleomycin - toxicity Camptothecin - toxicity Cell Division - drug effects Cell growth Cell lines Cisplatin - toxicity Cross-Linking Reagents - chemistry Cross-Linking Reagents - toxicity Cultured cells Dioxoles - chemistry Dioxoles - toxicity DNA DNA Topoisomerases, Type I - metabolism DNA, Neoplasm - metabolism Doxorubicin - toxicity Drug therapy Etoposide - toxicity Female HCT116 cells Humans Inhibitory concentration 50 Isoquinolines - chemistry Isoquinolines - toxicity Lungs Male Mitomycin - toxicity Models, Molecular Molecular Structure Molecules Neoplasm Proteins - metabolism Paclitaxel - toxicity Phthalimides - chemistry Phthalimides - toxicity Physical Sciences Radioactive decay Structure-Activity Relationship Synthetic products Tetrahydroisoquinolines Trabectedin Tumor Cells, Cultured Tumors |
| title | Phthalascidin, a Synthetic Antitumor Agent with Potency and Mode of Action Comparable to Ecteinascidin 743 |
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