Constructing novel dihydrofuran and dihydroisoxazole analogues of isocombretastatin-4 as tubulin polymerization inhibitors through [3+2] reactions

Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Ming-Yu Song, Chen-Yu Cao, Qiu-Rui He, Qing-Miao Dong, Ding Li, Jiang-Jiang Tang, Jin-Ming Gao
[3+2] reactions play a key role in constructing various pharmaceutical moleculars. In this study, using Mn(OAc)3 mediated and 1,3-dipolar [3+2] cyclization reactions, 38 novel dihydrofuran and dihydroisoxazole analogues of isoCA-4 were synthesized as inhibitors of tubulin polymerization. Among them, compound 6g was found to be the most potent cytotoxic agents against PC-3 cells with IC50 value of 0.47μM, and compound 5p exhibted highest activity on HeLa cells with IC50 vaule of 2.32µM. Tubulin polymerization assay revealed that 6g was a dose-dependent and effective inhibitor of tubulin assembly. Immunohistochemistry studies and cell cycle distribution analysis indicated that 6g severely disrupted microtubule network and significantly arrested most cells in the G2/M phase of the cell cycle in PC-3 cells. In addition, molecular docking studies showed that two chiral isomers of 6g can bind efficiently and similarly at colchicine binding site of tubulin.

Graphical abstract

http://ift.tt/2yzMXhf