Structure–activity relationship of natural and synthetic coumarins inhibiting the multidrug transporter P-glycoprotein

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 μM. Four natural compounds, previously isolated from Calophyllum dispar (Clusiaceae) and substituted by a common α-(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 α-(hydroxyisopropyl)dihydrofuran moiety, beside C5–C6 or C7–C8 positions. In addition, the analysis revealed an important hydrophobic, neutral charge group, like phenyl, in position C4 on the coumarinic ring.

The substitution of the basic structure of coumarin, by phenyl group on position C4 and α-(hydroxyisopropyl)dihydrofuran moiety on position C5–C6 or C7–C8, reduces the P-gp-mediated drug efflux of daunorubicin out of human leukemic cells (K562/R7).Figure optionsDownload as PowerPoint slide