Structure-activity relationship of natural and synthetic coumarins inhibiting the multidrug transporter P-glycoprotein |
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Authors: | Raad Imad Terreux Raphael Richomme Pascal Matera Eva-Laure Dumontet Charles Raynaud Jean Guilet David |
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Affiliation: | Université Claude Bernard Lyon-1, Laboratoire de Pharmacognosie, Faculté de Pharmacie, 69373 Lyon Cedex 8, France. |
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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. |
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