Antitumor agents. Part 186: Synthesis and biological evaluation of demethylcolchiceinamide analogues as cytotoxic DNA topoisomerase II inhibitors

Demethylation of colchiceinamide (2) and its analogues (3-10) afforded a no vel class of mammalian DNA topoisomerase II inhibitors (2a-10a) without dis playing tubulin inhibitory activity. All target compounds inhibited the cat alytic activity of topoisomerase II at drug concentrations at 100 mu M. An in vitro cytotoxicity assay indicated that compounds 3a and 8a were strong and tissue-selective cytotoxic agents against the MCF-7 breast cancer cell line (IC50 = 0.36 and 0.48 mu g/mL, respectively) and the CAKI-1 renal canc er cell line (IC50 = 0.72 and 0.96 mu g/mL, respectively). (C) 1998 Elsevie r Science Ltd. All rights reserved.