Antitumor agents 210. synthesis and evaluation of taxoid–epipodophyllotoxin conjugates as novel cytotoxic agents Original Research Article

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.