期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 -, 页码 28-39出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.12.042
关键词
Benzoxepin; Combretastatin; isoCA-4; Tubulin; Cytotoxicity; Apoptosis; Cancer
资金
- CNRS (Centre National de la Recherche Scientifique)
- MRES (Ministere de la Recherche et de l'Enseignement Superieur)
- ANR (Agence Nationale de la Recherche) [ANR-10-LABX-33]
- ANR [ANR-09-BLAN-0071]
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 G(2)/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 beta-tubulin. (C) 2013 Elsevier Masson SAS. All rights reserved.
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