A new series of 3-substituted 2-phenylimidazo[2,1-b]benzothiazoles (3a-h) 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 3a, 3e, and 3h exhibited good antiproliferative activity, with GI50 values in the range of 0.19-83.1��M. Compound 3h showed potent anticancer efficacy against 60 human cancer cell lines, with a mean GI50 value of 0.88��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 3h is similar to that of combretastatin A-4. Molecular modeling studies provided a molecular basis for the favorable binding of compounds 3a, 3e, and 3h to the colchicine binding pocket of tubulin. �� 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.