title: Antitumor agents 216. Synthesis and evaluation of paclitaxel-camptothecin conjugates as novel cytotoxic agents.
abstract: Five conjugates (16-20) composed of a paclitaxel and a camptothecin derivative joined by an imine linkage were synthesized and evaluated as cytotoxic agents and as inhibitors of DNA topoisomerase I. All of the conjugates were potent inhibitors of tumor cell replication with improved activity relative to camptothecin. Significantly, compounds 16-18 were more active than paclitaxel and camptothecin against HCT-8 (colon adenocarcinoma) cell replication, and the spectrum of activity was different from a simple mixture of paclitaxel and camptothecin. All of the conjugates were significantly less potent than camptothecin as inhibitors of human topoisomerase I in vitro with 16, 18, and 19 showing only marginal activity at 50 microM. Based on activity against drug-resistant cell line replication, one could conclude that the conjugates are simply acting as 'weak taxanes', but the spectrum of activity, particularly against MCF-7 and HCT-8, strongly suggests that a novel mechanism of action has been achieved through conjugation.
authors.affiliation: Natural Products Laboratory, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Hironori
authors.initials: H
authors.lastname: Ohtsu
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Lee
authors.forename: Kuo Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D017239:Paclitaxel; D002166:Camptothecin