3-Substituted 2-Phenylimidazo[2,1-b]benzothiazoles: Synthesis, Anticancer Activity, and Inhibition of Tubulin Polymerization

A new series of 3-substituted 2-phenylimidazo[2,1-b]benzothiazoles (3?ah) were synthesized by C-arylation of 2-arylimidazo[2,1-b]benzothiazoles using palladium acetate as catalyst, and the resulting compounds were evaluated for their anticancer activity. Compounds 3?a, 3?e, and 3?h exhibited good antiproliferative activity, with GI50 values in the range of 0.1983.1 mu M. Compound 3?h showed potent anticancer efficacy against 60 human cancer cell lines, with a mean GI50 value of 0.88 mu M. This compound also induced cell-cycle arrest in the G2/M phase and inhibited tubulin polymerization followed by activation of caspase-3 and apoptosis. A high-throughput tubulin polymerization assay showed that the level of inhibition for compound 3?h is similar to that of combretastatin A-4. Molecular modeling studies provided a molecular basis for the favorable binding of compounds 3?a, 3?e, and 3?h to the colchicine binding pocket of tubulin.