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 p repared and evaluated as cytotoxic agents and inhibitors of mammalian DNA t opoisomerase II. Compounds 12 and 14-16 exhibited comparable or better acti vity than the unconjugated epipodophyllotoxin derivatives in most tumor cel l lines, and 12, 15, and 16 also showed enhanced activity against paclitaxe l-resistant cells. Compound 13, which contains an epipodophyllotoxin moiety at both the taxoid 2' and 7 positions, did not stimulate protein-DNA break s, but was 2-fold more potent than 12 and 15 and comparable to GL-331 in th e topo II inhibitory assay. (C) 2001 Elsevier Science Ltd. All rights reser ved.