Discovery and development of tricyclic matrinic derivatives as anti-diabetic candidates by AMPKαactivation

We found compound 12N-p-trifluoromethylbenzenesulfonyl matrinane(1)was a potent anti-diabetic agent.Thirty-five tricyclic matrinic derivatives were synthesized and determined for their stimulatory effects on glucose consumption in L6 myotubes,taking 1 as the lead.In high-fat diet(HFD)and STZ induced diabetic mice,9a significantly lowers blood glucose,improves glucose tolerance,and especially alleviates diabetic nephropathy and islet damage.Mechanism study indicates that 9a simultaneously targets mitochondrial complex I to increase AMP/ATP ratio,as well as liver kinase B1(LKB1)and calcium/calmodulindependent protein kinase(Ca MKK),which synergistically activates AMPKαand then stimulates glucose transporter 4(GLUT4)membrane translocation and 2-deoxyglucose(2-DG)uptake to exert anti-diabetic efficacy.Therefore,compound 9a with a novel structure is a promising anti-diabetic candidate with the advantage of multiple-target mechanism,worthy of further investigation.

Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells

Matrine （MT）, the effective component of Sophora fla- vescens Air, has been shown to have anti-inflammation, immune-suppressive, anti-tumor, and anti-hepatic fibrosis activities. However, the pharmacological effects of MT still need to be strengthened due to its relatively low efficacy and short half-life. In the present study, we report a more effective thio derivative of MT, MD-1, and its inhibitory effects on the activation of hepatic stellate cells （HSCs） in both cell culture and animal models. Cytological experiments showed that MD-1 can inhibit the proliferation of HSC-T6 cells with a half-maximal inhibitory concentration （ICs0） of 62 pmollL. In addition, MD-1 more strongly inhibits the migration of HSC-T6 cells compared to MT and can more effectively induce G0/G1 arrest and apoptosis. Investigating the biological mechanisms underlying anti-hepatic fibrosis in the presence of MD-I, we found that MD-I can bind the epidermal growth factor receptor （EGFR） on the surface of HSC-T6 cells, which can further inhibit the phospho- rylaUon of EGFR and its downstream protein kinase B （Akt）, resulting in decreased expression of cyclin D1 and eventual inhibition of the activation of HSC-T6 cells. Furthermore, in rats with dimethylnitrosamine （DMN）- induced hepatic fibrosis, MD-1 slowed the development and progression of hepatic fibrosis, protecting hepatic parenchymal cells and improving hepatic functions. Therefore, MD-1 is a potential drug for anti-hepatic fibrosis.