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J Med Chem. 2011 May 12;54(9):3153-62. doi: 10.1021/jm901826e. Epub 2011 Apr 13.

Synthesis and biological evaluation of 4-arylcoumarin analogues of combretastatins. Part 2.

Author information

1
Laboratoire Chimie Provence, UMR-CNRS 6264, Université d'Aix-Marseille , Faculté des Sciences Saint-Jérôme, case 521, 13397 Marseille Cedex 20, France. sebastien.combes@univ-provence.fr

Abstract

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 × 10 (6) M(-1). 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.

PMID:
21488686
DOI:
10.1021/jm901826e
[Indexed for MEDLINE]

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