Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted isocombretastatin A-4 analogs

被引：48

作者：

Rasolofonjatovo, Evelia ^{[1
]}

Provot, Olivier ^{[1
]}

Hamze, Abdallah ^{[1
]}

Rodrigo, Jordi ^{[1
]}

Bignon, Jerome ^{[2
]}

Wdzieczak-Bakala, Joanna ^{[2
]}

Lenoir, Christine ^{[2
]}

Desravines, Deborah ^{[2
]}

Dubois, Joelle ^{[2
]}

Brion, Jean-Daniel ^{[1
]}

Alami, Mouad ^{[1
]}

机构：

[1] Univ Paris Sud, Fac Pharm, CNRS, Chim Therapeut Lab,LabEx LERMIT,BioCIS UMR 8076, F-92296 Chatenay Malabry, France

[2] CNRS, Inst Chim Subst Nat, UPR 2301, F-91198 Gif Sur Yvette, France

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 62卷

关键词：

Benzoxepin; Combretastatin; isoCA-4; Tubulin; Cytotoxicity; Apoptosis; Cancer; COMBRETASTATIN A4 PHOSPHATE; ARYL HALIDES SYNTHESIS; ANTINEOPLASTIC AGENTS; BIOLOGICAL EVALUATION; TUBULIN POLYMERIZATION; REGIOSELECTIVE ACCESS; CATALYZED REACTION; ANTITUMOR-ACTIVITY; N-TOSYLHYDRAZONES; ARYLALKYNES;

D O I：

10.1016/j.ejmech.2012.12.042

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：28 / 39

页数：12

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