Synthesis, biological evaluation, and molecular docking studies of novel chalcone oxime derivatives as potential tubulin polymerization inhibitors

Abstract

Microtubule-targeted drugs are at present indispensable for various types of cancer therapy worldwide. A series of chalcone oxime derivatives were designed, synthesized and evaluated as potential tubulin polymerization inhibitors and for the cytotoxicity against anthropic cancer cell lines. These derivatives were completely demonstrated to have commendable inhibitory activity against tubulin polymerization by competing with the colchicine-binding site on tubulin, which was associated with G2/M phase cell cycle arrest as well as promising antiproliferative activity. Among the novel compounds, compound 13 was demonstrated to have the most potent inhibitory activity (tubulin IC₅₀ = 1.6 μM). Antiproliferative assay results displayed that compound 13 had potent antiproliferative activity against A549, Hela and MCF-7 with GI₅₀ values of 2.1, 3.5 and 3.6 μM, respectively, which were compared with the positive control colchicine and CA-4. Docking simulation showed that compound 13 could bind tightly to the colchicine domain of tubulin and act as a tubulin polymerization inhibitor. We also built a 3D-QSAR model to provide more information that could be applied to design new molecules with more potent tubulin inhibitory activity.