Synthesis and Biological Evaluation of 4-Arylcoumarin Analogues of Combretastatins. Part 2
| Autor: | Alexey Yu. Fedorov, Véronique Bourgarel-Rey, Jean Boutonnat, Vincent Peyrot, Soazig Douillard, Pascale Barbier, Jean-Pierre Finet, Anne McLeer-Florin, Sebastien Combes, Jean-Thomas Pierson |
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| Rok vydání: | 2011 |
| Předmět: |
G2 Phase
Models Molecular Molecular model Stereochemistry Antineoplastic Agents Crystallography X-Ray Chemical synthesis Cell Line Structure-Activity Relationship chemistry.chemical_compound Coumarins Tubulin Cell Line Tumor Stilbenes Drug Discovery ATP Binding Cassette Transporter Subfamily G Member 2 Humans Moiety Structure–activity relationship ATP Binding Cassette Transporter Subfamily B Member 1 Mode of action Combretastatin Bicyclic molecule Chemistry Daunorubicin Coumarin Tubulin Modulators Neoplasm Proteins Drug Resistance Neoplasm Molecular Medicine ATP-Binding Cassette Transporters Drug Screening Assays Antitumor Mitoxantrone Cell Division |
| Zdroj: | Journal of Medicinal Chemistry. 54:3153-3162 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm901826e |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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