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

[Image: see text] 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.