Biological Evaluation, Structure-Activity Relationships, and Three-Dimensional Quantitative Structure-Activity Relationship Studies of Dihydro--agarofuran Sesquiterpenes as Modulators of P-Glycoprotei

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• 作者：Carolina P. Reyes ; Francisco Muñ ; oz-Martí ; nez ; Ivan R. Torrecillas ; Cristina R. Mendoza ; Francisco Gamarro ; Isabel L. Bazzocchi ; Marvin J. Nú ; ñ ; ez ; Leonardo Pardo ; Santiago Cas
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 4, 2007
• 年：2007
• 卷：50
• 期：20
• 页码：4808 - 4817
• 全文大小：271K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

文摘

Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, andother important diseases. Here, we report the inhibitory activity of a series of 76 dihydro--agarofuransesquiterpenes, tested on NIH-3T3 cells expressing the human P-glycoprotein (Pgp) multidrug transporter,to establish quantitative comparisons of their respective abilities to block the drug transport activity. Thescreening was performed on the basis of the ability of sesquiterpenes to modulate the intracellular accumulationof the classical Pgp substrate daunorubicin. To understand the structural basis for inhibitory activity andguide the design of more potent Pgp inhibitors, we have performed a three-dimensional quantitative structure-activity relationship model using the comparative molecular similarity indices analysis (CoMSIA). The mostsalient features of these requirements are in the region of the substituents at the C-2, C-3, and C-8 positions,which seem to be critical for determining the overall effectiveness of sesquiterpenes as Pgp inhibitors.