Antitumor agents 210. Synthesis and evaluation of taxoid-epipodophyllotoxin conjugates as novel cytotoxic agents.
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.
Shi
Q
Q
Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Wang
H K
HK
Bastow
K F
KF
Tachibana
Y
Y
Chen
K
K
Lee
F Y
FY
Lee
K H
KH
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
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D059005:Topoisomerase II Inhibitors; D011034:Podophyllotoxin; D017239:Paclitaxel