title: Structure-activity relationship of natural and synthetic coumarins inhibiting the multidrug transporter P-glycoprotein.
abstract: A set of 32 natural and synthetic coumarins were tested in order to evaluate their activity on human leukemic cells (K562/R7) overexpressing P-glycoprotein (P-gp). Their ability to reduce the P-gp-mediated drug efflux of daunorubicin out of cells was evaluated at 10 microM. Four natural compounds, previously isolated from Calophyllum dispar (Clusiaceae) and substituted by a common alpha-(hydroxyisopropyl)dihydrofuran moiety, exhibited a significant inhibitory effect on P-gp when compared to the positive control cyclosporin A. A 3D-quantitative structure-activity relationship (3D-QSAR) analysis of the coumarins was performed using the biological results obtained by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of P-gp. Results showed a favorable electrostatic and steric volume, like the alpha-(hydroxyisopropyl)dihydrofuran moiety, beside C(5)-C(6) or C(7)-C(8) positions. In addition, the analysis revealed an important hydrophobic, neutral charge group, like phenyl, in position C(4) on the coumarinic ring.
authors.affiliation: Université Claude Bernard Lyon-1, Laboratoire de Pharmacognosie, Faculté de Pharmacie, 69373 Lyon Cedex 8, France.
authors.forename: Imad
authors.initials: I
authors.lastname: Raad
authors.forename: Raphael
authors.initials: R
authors.lastname: Terreux
authors.forename: Pascal
authors.initials: P
authors.lastname: Richomme
authors.forename: Eva-Laure
authors.initials: EL
authors.lastname: Matera
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.forename: Jean
authors.initials: J
authors.lastname: Raynaud
authors.forename: David
authors.initials: D
authors.lastname: Guilet
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D029759:Calophyllum / Q000737:chemistry; D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D012015:Reference Standards; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003374:Coumarins