title: Synthesis and antitumor activity of ring A- and F-modified hexacyclic camptothecin analogues.
abstract: Nineteen ring A- and F-modified hexacyclic analogues of camptothecin were synthesized by Friedländer condensation of appropriately substituted bicyclic amino ketones with tricyclic ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory activity. Seventeen of the compounds showed cytotoxic effects comparable or superior to those of 7-ethyl-10-hydroxycamptothecin (SN-38) against mouse leukemia P388 and human tumor cell lines HOC-21 and QG-56. Introduction of a compact and inductively electron-withdrawing substituent such as a hydroxy, methoxy, chloro, or fluoro group into position 5 of ring A of the hexacyclic compound remarkably increased the antitumor activity. The potency of topoisomerase I inhibition of these compounds showed good correlation with their cytotoxicity. Among them, the 4-methyl-5-fluoro hexacyclic compound was the most potent of all and was 10 times as active as SN-38 in in vitro antitumor activity.
authors.affiliation: Tokyo R&D Center, Daiichi Pharmaceutical Company, Ltd., 16-13, Kitakasai 1-Chome, Edogawa-ku, Tokyo 134, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sugimori
authors.forename: A
authors.initials: A
authors.lastname: Ejima
authors.forename: S
authors.initials: S
authors.lastname: Ohsuki
authors.forename: K
authors.initials: K
authors.lastname: Uoto
authors.forename: I
authors.initials: I
authors.lastname: Mitsui
authors.forename: Y
authors.initials: Y
authors.lastname: Kawato
authors.forename: Y
authors.initials: Y
authors.lastname: Hirota
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: H
authors.initials: H
authors.lastname: Terasawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D007941:Leukemia P388 / Q000473:pathology; D051379:Mice; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: C112865:2,3-dihydro-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1H,12H-benzo(de)pyrano(3',4'-6,7)indolizino(1,2-b)quinoline-10,13(9H,15H)-dione; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin