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

Abstract

We found compound 12 N - 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/calmodulin-dependent protein kinase (CaMKK), which synergistically activates AMPK α and 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. Tricyclic matrinic derivative 9a exerts good anti-diabetic effects, and alleviates diabetic nephropathy and islet damage in vivo by activating AMPK α and stimulating GLUT4 membrane translocation and 2-DG uptake.