Synthesis and biological evaluation of B-ring modified colchicine and isocolchicine analogs

A series of modified colchicine and isocolchicine analogs (C-7 substituent) were synthesized and evaluated in vitro against a PC3 cancer cell line and for inhibition of microtubule polymerization. The colchicine analogs all displayed strong inhibition of tubulin polymerization, while compounds 6 and 20 also possessed an increased cytotoxic activity as compared to colchicine. More importantly, isocolchicine analogs 7, 15, and 17 showed inhibition of microtubule polymerization with IC50 values ranging from 58 to 68 μM. In addition, 7 displayed strong cytotoxic activity with an IC50 = 93 nM which was more potent than colchicine analog 12.

Graphical abstractA series of colchicine (1) and isocolchicine (2) derivatives modified at the B-ring substituent (R1) were prepared and evaluated in vitro against both microtubule polymerization and PC3 cancer cell lines. The modified colchicine analogs all displayed strong inhibitory activities. More importantly, however, select isocolchicine analogs (7, 15, and 17) also showed inhibition of microtubule polymerization and 7 exhibited strong cytotoxic activity.Figure optionsDownload full-size imageDownload as PowerPoint slide