Bioorganic & Medicinal Chemistry 2011-04-15

Inhibitors and promoters of tubulin polymerization: synthesis and biological evaluation of chalcones and related dienones as potential anticancer agents.

Christine Dyrager, Malin Wickström, Maria Fridén-Saxin, Annika Friberg, Kristian Dahlén, Erik A A Wallén, Joachim Gullbo, Morten Grøtli, Kristina Luthman

Index: Bioorg. Med. Chem. 19(8) , 2659-65, (2011)

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Abstract

A series of dihalogenated chalcones and structurally related dienones were synthesized and evaluated for their antiproliferative activity in 10 different cancer cell lines and for their effect on microtubule assembly. All compounds showed cytotoxic activity, with IC(50) values in the 5-280 μM range depending on the chalcone structure and the cell line. Five of the compounds were found to be tubulin polymerization inhibitors. In contrast, one of the compounds was found to stabilize tubulin to the same extent as the anticancer drug docetaxel. Molecular modeling suggested that the tubulin inhibitors bind to the colchicine binding site of β-tubulin while the novel tubulin stabilization agent seems to interact with the paclitaxel binding site.Copyright © 2011 Elsevier Ltd. All rights reserved.