Synthesis and Biological Evaluation of 4-Arylcoumarin Analogues of Combretastatins. Part 2

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• 作者：Se虂bastien Combes ; Pascale Barbier ; Soazig Douillard ; Anne McLeer-Florin ; Ve虂ronique Bourgarel-Rey ; Jean-Thomas Pierson ; Alexey Yu. Fedorov ; Jean-Pierre Finet ; Jean Boutonnat ; Vincent Peyrot
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：May 12, 2011
• 年：2011
• 卷：54
• 期：9
• 页码：3153-3162
• 全文大小：954K
• 年卷期：v.54,no.9(May 12, 2011)
• ISSN：1520-4804

文摘

A series of A-ring variously methoxylated 4-(3-hydroxy-4-methoxyphenyl)coumarins related to combretastatin A-4 was prepared by cross-coupling reactions. Cytotoxicity studies indicated a potent activity against HBL100 cell line. Substitution patterns on A-ring had only a slight effect on antiproliferative activity. For most cytotoxic compounds, the activity as potential modulators of P-gp and BCRP efflux pumps was evaluated. The results show that compounds 2 and 7 were able to restore mitoxantrone accumulation (BCRP) at concentrations similar to that of cyclosporine A. Compound 7 was the most efficient to reverse P-gp activity. All compounds were found to potently inhibit in vitro microtubule formation via a substoichiometric mode of action for the most part. Compounds 1 and 2 were found to have an apparent affinity binding constant similar to that of combretastatin A-4, i.e., 1 脳 10 ⁶ M^鈥?. The molecular modeling of coumarin derivatives was performed on the basis of the molecular structure of 7, as determined by single-crystal X-ray crystallography. The calculations suggested that the presence of a methoxy group out of the plane of the chromenone moiety is an important steric hindrance factor embedding the accessibility of those molecules inside the binding pocket on tubulin.