Article ID Journal Published Year Pages File Type
1394280 European Journal of Medicinal Chemistry 2013 12 Pages PDF
Abstract

A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogs according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on β-tubulin.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Benzoxepins 6 as restricted-analogs of isoCA-4 have been synthesized. ► Highly cytotoxic benzoxepin 6b inhibited tubulin assembly at a micromolar level. ► Compound 6b arrested the cellular cycle in the G2/M phase and induced apoptosis. ► Presumptive binding mode of 6b and isoCA-4 are similar on β-tubulin.

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Physical Sciences and Engineering Chemistry Organic Chemistry
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