Colchicine-like β-acetamidoketones as inhibitors of microtubule polymerization: Design, synthesis and biological evaluation of anticancer activity.

OBJECTIVES

In this study a series of novel colchicine-like β-acetamidoketones was designed and synthesized as potential tubulin inhibitors.

MATERIALS AND METHODS

The cytotoxicity of the novel synthesized β-acetamidoketones was assessed against two cancerous cell lines including MCF-7 (human breast cancer cells) and A549 (adenocarcinomic human alveolar basal epithelial cells) employing the MTT test. Tubulin polymerization test was done by using a commercial kit (tubulin polymerization assay kit).

RESULTS

In general, the cytotoxicity activities were highly dependent on the aromatic substitution pattern of phenyl ring at β position of β-acetamidoketones. Based upon, compound possessing the same structural elements of colchicine and chalcone 1, revealed the most cytotoxicity more than the other β-acetamidoketone against the cancerous cell lines and showed moderate antitubulin effect. The tubulin inhibitory effect of , colchicine and chalcone 1 were consistent with their antiproliferative activities. Molecular docking studies of , into the colchicine-binding site of tubulin exhibited possible mode of interaction between this compound and tubulin.

CONCLUSION

The structure activity relationship (SAR) data attained showed that the presence of trimethoxy phenyl attached to carbonyl group of β-acetamidoketones and a methoxy group at position of the other ring are essential for cytotoxic activity. In general, the cytotoxicity activities were highly dependent on the aromatic substitution pattern of phenyl ring at β position of β-acetamidoketones.