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

Combes, Sebastien, Barbier, Pascale, Douillard, Soazig, McLeer-Florin, Anne, Bourgarel-Rey, Veronique, Pierson, Jean-Thomas, Fedorov, Alexey Yu, Finet, Jean-Pierre, Boutonnat, Jean and Peyrot, Vincent (2011) Synthesis and biological evaluation of 4-arylcoumarin analogues of combretastatins. Part 2. Journal of Medicinal Chemistry, 54 9: 3153-3162. doi:10.1021/jm901826e

Author Combes, Sebastien
Barbier, Pascale
Douillard, Soazig
McLeer-Florin, Anne
Bourgarel-Rey, Veronique
Pierson, Jean-Thomas
Fedorov, Alexey Yu
Finet, Jean-Pierre
Boutonnat, Jean
Peyrot, Vincent
Title Synthesis and biological evaluation of 4-arylcoumarin analogues of combretastatins. Part 2
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2011-05-12
Sub-type Article (original research)
DOI 10.1021/jm901826e
Open Access Status
Volume 54
Issue 9
Start page 3153
End page 3162
Total pages 10
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Pharmacy Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 55 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 54 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 26 Jul 2011, 19:40:22 EST by Dr Jean-thomas Pierson on behalf of School of Pharmacy