title: Synthesis and biological evaluation of 4-arylcoumarin analogues of combretastatins. Part 2.
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.
authors.affiliation: 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
authors.forename: Sébastien
authors.initials: S
authors.lastname: Combes
authors.forename: Pascale
authors.initials: P
authors.lastname: Barbier
authors.forename: Soazig
authors.initials: S
authors.lastname: Douillard
authors.forename: Anne
authors.initials: A
authors.lastname: McLeer-Florin
authors.forename: Véronique
authors.initials: V
authors.lastname: Bourgarel-Rey
authors.forename: Jean-Thomas
authors.initials: JT
authors.lastname: Pierson
authors.forename: Alexey Yu
authors.initials: AY
authors.lastname: Fedorov
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Finet
authors.forename: Jean
authors.initials: J
authors.lastname: Boutonnat
authors.forename: Vincent
authors.initials: V
authors.lastname: Peyrot
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000096:biosynthesis; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D003374:Coumarins; D009363:Neoplasm Proteins; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; D008942:Mitoxantrone; C058728:fosbretabulin; D003630:Daunorubicin