Optimization by Molecular Fine Tuning of Dihydro-β-agarofuran Sesquiterpenoids as Reversers of P-Glycoprotein-Mediated Multidrug Resistance
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- 作者：Oliver Callies ; María P. Sánchez-Cañete ; Francisco Gamarro ; Ignacio A. Jiménez ; Santiago Castanys ; Isabel L. Bazzocchi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：March 10, 2016
- 年：2016
- 卷：59
- 期：5
- 页码：1880-1890
- 全文大小：578K
- ISSN：1520-4804
文摘
P-glycoprotein (P-gp) plays a crucial role in the development of multidrug resistance (MDR), a major obstacle for successful chemotherapy in cancer. Herein, we report on the development of a natural-product-based library of 81 dihydro-β-agarofuran sesquiterpenes (2–82) by optimization of the lead compound 1. The compound library was evaluated for its ability to inhibit P-gp-mediated daunomycin efflux in MDR cells. Selected analogues were further analyzed for their P-gp inhibition constant, intrinsic toxicity, and potency to reverse daunomycin and vinblastine resistances. Analogues 6, 24, 28, 59, and 66 were identified as having higher potency than compound 1 and verapamil, a first-generation P-gp modulator. SAR analysis revealed the size of the aliphatic chains and presence of nitrogen atoms are important structural characteristics to modulate reversal activity. The present study highlights the potential of these analogues as modulators of P-gp mediated MDR in cancer cells.