Synthesis and Biological Evaluation of Gem‐Difluoromethylenated Statin Derivatives as Highly Potent HMG‐CoA Reductase Inhibitors |
| |
| Authors: | Zhao Zhao Jiaxin Cui Yan Yin Heng Zhang Yecheng Liu Rui Zeng Chao Fang Zhenpeng Kai Zhonghua Wang Fanhong Wu |
| |
| Affiliation: | 1. School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China;2. Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China |
| |
| Abstract: | 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. |
| |
| Keywords: | HMG‐CoA reductase inhibitors gem‐difluoromethylenated compounds statin derivatives hypercholesterolemia molecular docking |
|
