Synthesis and anti-obesity effects in vivo of Crotadihydrofuran C as a novel PPARγ antagonist from Crotalaria albida

Crotadihydrofuran C (CC) from the herbs of Crotalaria albida is able to inhibit adipocyte differentiation and lipid accumulation. However, the effects of CC on obesity and metabolic disorders have not yet been elucidated. In our study, the first enantioselective synthesis of the 2-isopropenyl dihydrofuran isoflavone skeleton (CC) is described. The convenient and efficient synthetic protocols developed skilfully solve the problems of the ortho-para directing group and Suzuki coupling reaction using a boronic acid pinacol ester that was more stable and easy to obtain. Furthermore, CC treatment of high-fat diet (HFD)-fed obese mice remarkably reduced their body weight, fat mass, and lipid level as well as improved insulin resistance and non-alcoholic fatty liver disease (NAFLD). A TR-FRET assay showed that CC was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study. These results suggest that CC could be a useful and potential natural product for treating metabolic diseases, including obesity, hyperlipidemia insulin resistance and NAFLD, without toxic side-effects.