Combretastatin-Inspired Heterocycles as Antitubulin Anticancer Agents

[Image: see text] Combretastatin (CA-4) and its analogues are undergoing several clinical trials for treating different types of tumors. In this work, the antiproliferative activity of a series of 2-aminoimidazole-carbonyl analogs of clinically relevant combretastatins A-4 (CA-4) and A-1 was evaluated using a cell-based assay. Among the compounds tested, C-13 and C-21 displayed strong antiproliferative activities against HeLa cells. C-13 inhibited the proliferation of lung carcinoma (A549) cells more potently than combretastatin A-4. C-13 also retarded the migration of A549 cells. Interestingly, C-13 displayed much stronger antiproliferative effects against breast carcinoma and skin melanoma cells compared to noncancerous breast epithelial and skin fibroblast cells. C-13 strongly disassembled cellular microtubules, perturbed the localization of EB1 protein, inhibited mitosis in cultured cells, and bound to tubulin at the colchicine site and inhibited the polymerization of reconstituted microtubules in vitro. C-13 treatment increased the level of reactive oxygen species and induced apoptosis via poly(ADP-ribose) polymerase-cleavage in HeLa cells. The results revealed the importance of the 2-aminoimidazole-carbonyl motif as a double bond replacement in combretastatin and indicated a pharmacodynamically interesting pattern of H-bond acceptors/donors and requisite syn-templated aryls.