1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation.

We report the synthesis, metabolism and biological evaluation of a series of 17 novel heterocyclic derivatives of isoCombretastatin-A4 and their structure-activity relationship. Among these derivatives, the most active compound 4f inhibited the growth of a panel of seven cancer cell lines with an IC50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon carcinoma cells and multidrug-resistant leukemia cells. It also induced G2/M cell cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-to-straight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood vessel-like assembly formed by human umbilical vein endothelial cells in vitro, suggesting its function as vascular disrupting agent. In vitro metabolism study of 4f showed its high human microsomal stability in comparison to isoCA-4. The physicochemical properties of 4f may be conducive to CNS permeability suggesting that this compound may be a possible candidate for the treatment of glioblastoma.