Synthesis and Biological Evaluation of Gem-Difluoromethylenated Statin Derivatives as Highly Potent HMG-CoA Reductase Inhibitors
Zhao Zhao, Jiaxin Cui, Yan Yin, Heng Zhang, Yecheng Liu, Rui Zeng, Chao Fang, Zhenpeng Kai, Zhonghua Wang and Fanhong Wu
Version of Record online: 15 JUN 2016 | DOI: 10.1002/cjoc.201600180
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.