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

Glucokinase (GK) and PPARγ are important targets for antidiabetic use. Silybin is one of the major active ingredients of . 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 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.