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

Document Type : Original Article

Authors

1 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

Objective(s): 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 4f 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 4f, colchicine and chalcone 1 were consistent with their antiproliferative activities. Molecular docking studies of 4f, 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 para 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.

Keywords

Main Subjects

References

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Iranian Journal of Basic Medical Sciences
Volume 22, Issue 10
October 2019
Pages 1138-1146

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