Combretatropone is a hybrid of combretastatin and colchicine in which the o-methoxyphenol of dihydrocombretastatin A-4 is replaced by an alpha-methoxytropone. Derivatives of combretatropone have been synthesized and evaluated for antimicrotubule activity. All combretatropones were less active than the corresponding colchicine derivatives, supporting the idea that loss of ligand conformational entropy upon tubulin binding results in decreased potency for colchicinoid ligands. The structure-activity relationship of the combretatropone series was different than that of the colchicine series. These data indicate that conformationally mobile and conformationally rigid colchicinoids do not interact with the receptor site in the same manner.