化学
P-糖蛋白
立体化学
部分
结构-活动关系
数量结构-活动关系
生物活性
柔红霉素
夜蛾科
多重耐药
生物化学
体外
传统医学
内科学
抗生素
白血病
医学
作者
Imad Raad,Raphaël Terreux,Pascal Richomme,Eva–Laure Matera,Charles Dumontet,Jean Raynaud,David Guilet
标识
DOI:10.1016/j.bmc.2006.06.026
摘要
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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