Discovery of Potent Glucokinase and PPARγ Dual-Target Agonists through an Innovative Scheme for Regioselective Modification of Silybin

Zhipeng Zhang; Yanqiu Meng; Zhan Wang; Yu Mei; Shite Gao; Yuejiao Wu; Shuxian Du

doi:10.1021/acsomega.1c06778

Discovery of Potent Glucokinase and PPARγ Dual-Target Agonists through an Innovative Scheme for Regioselective Modification of Silybin

ACS Omega. 2022 Jan 20;7(4):3812-3822. doi: 10.1021/acsomega.1c06778. eCollection 2022 Feb 1.

Authors

Zhipeng Zhang¹, Yanqiu Meng¹, Zhan Wang², Yu Mei¹, Shite Gao¹, Yuejiao Wu¹, Shuxian Du¹

Affiliations

¹ Department of Pharmacy and Bioengineering, Shenyang University of Chemical Technology, Shenyang, Liaoning 100142, China.
² Analysis and Testing Center, Shenyang University of Chemical Technology, Shenyang, Liaoning 100142, China.

Abstract

Glucokinase (GK) and PPARγ are important targets for antidiabetic use. Silybin is one of the major active ingredients of Silybum marianum. The regioselective modification of the five hydroxyl groups in the silybin structure has always been a challenge. In this study, we found that silybin was an agonist of GK and PPARγ. A novel synthesis scheme of silybin derivatives was designed, and a series of novel silybin derivatives has been synthesized. The derivative 8d showed relatively strong activation activity for GK and PPARγ in enzyme activity and transactivation assays (GK activation fold: 1.86; PPARγ transactivation activation percentage: 90.32%). This research suggests that silybin and its derivatives could be used as novel GK and PPARγ dual-target agonists.