title: Antitumor agents 210. Synthesis and evaluation of taxoid-epipodophyllotoxin conjugates as novel cytotoxic agents.
abstract: Five compounds composed of a taxoid (paclitaxel or cephalomannine) and a 4'-O-demethyl epipodophyllotoxin derivative joined by an imine linkage were prepared and evaluated as cytotoxic agents and inhibitors of mammalian DNA topoisomerase II. Compounds 12 and 14-16 exhibited comparable or better activity than the unconjugated epipodophyllotoxin derivatives in most tumor cell lines, and 12, 15, and 16 also showed enhanced activity against paclitaxel-resistant cells. Compound 13, which contains an epipodophyllotoxin moiety at both the taxoid 2' and 7 positions, did not stimulate protein-DNA breaks, but was 2-fold more potent than 12 and 15 and comparable to GL-331 in the topo II inhibitory assay.
authors.affiliation: Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Shi
authors.forename: H K
authors.initials: HK
authors.lastname: Wang
authors.forename: K F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Y
authors.initials: Y
authors.lastname: Tachibana
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.forename: F Y
authors.initials: FY
authors.lastname: Lee
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003432:Cross-Linking Reagents; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology; D011034:Podophyllotoxin / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D059005:Topoisomerase II Inhibitors; D011034:Podophyllotoxin; D017239:Paclitaxel