Antitumor Agents 238. Anti-tubulin and in vitro Cytotoxic Effects of N-Substituted Allocolchicinoids

Abstract

(-)-N-Substituted colchinol methyl ethers (6-10) and N-alkyl HCl salts (8a-10a) were synthesized from (-)-colchicine (1). The new compounds were evaluated for in vitro cytotoxic activity against five human tumor cell lines and for inhibition of tubulin polymerization. The new carbamate (6) and amide (7) showed 10-fold stronger activity against human tumor cell line replication than the amines (8-10). The corresponding HCl salts (8a-10a) generally showed decreased activity. Compounds (6) and (7) also exerted strong inhibitory effects on tubulin polymerization. All of the colchinol methyl ethers showed essentially equal cytotoxic effects against MDR-resistant (KB-V) and non-resistant (KB) cells, while the potency of colchicine was decreased 100-fold against KB-V cells.