Synthesis and Biological Evaluation of Gem-Difluoromethylenated Statin Derivatives as Highly Potent HMG-CoA Reductase Inhibitors

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• 作者：Zhao Zhao ; Jiaxin Cui ; Yan Yin ; Heng Zhang ; Yecheng Liu ; Rui Zeng ; Chao Fang ; Zhenpeng Kai ; Zhonghua Wang and Fanhong Wu
• 刊名：Chinese Journal of Chemistry
• 出版年：2016
• 出版时间：August, 2016
• 年：2016
• 卷：34
• 期：8
• 页码：801-808
• 全文大小：473K
• ISSN：1614-7065

文摘

HMG-CoA reductase inhibitors were widely used as lipid-lowing agents through effectively blocking the rate-limiting step of cholesterol biosynthesis. 8 analogs of Rosuvastatin were firstly prepared with different distance and functional group between the O5-hydroxyl group and terminal COOH group in the hydrophilic side-chain. In primary and secondary screening of the inhibitory activities against human HMG-CoA reductase, gem-difluoromethylenated derivatives exhibited more than 50% inhibition rate. Then 4 compounds with gem-difluoro group were further synthesized and evaluated in vitro, three compounds among them exhibited low single digital nmol/L IC₅₀ values against HMG-CoA reductase. Molecular docking also well explained the observed special contribution of the gem-difluoro group.