Novel Puerarin Analogs with Anti-Diabetic Activity

DESCRIPTION (provided by applicant): In diabetics, hyperglycemia is most pronounced following a meal due to the absorption of glucose from the GI tract. Inhibiting glucose uptake in the intestines and/or promoting glucose disposal in the tissues may be beneficial for diabetic patients to control the blood glucose level in the postprandial state. We have recently demonstrated that puerarin, the major isoflavone C-glucoside found in kudzu dietary supplements significantly improved glucose tolerance in C57BL/6J-ob/ob mice, an animal model of type 2 diabetes, blunting the rise in blood glucose levels after i.p. or oral administration. Puerarin is rapidly absorbed from the intestine without metabolism and appears to exert its hypoglycemic activity by inhibiting glucose uptake from the intestine by interacting with the glucose transporters SGLT1 and GLUT2. These results warrant further investigation on mechanism of action and structure-activity relationship. The over-all objectives of this proposal are to synthesize novel puerarin analogs and to evaluate the potential of these compounds as hypoglycemic agents. To accomplish this goal, we will synthesize novel puerarin analogs and screen them for their ability to inhibit SGLT1 and/ or GLUT2 using isolated mouse intestinal brush border membrane vesicles (BBMVs) which express these transporters. This will enable us to examine the structure-activity relationship of puerarin derivatives with modifications on the different rings, leading ultimately to the synthesis of potent puerarin based SGLT1/GLUT2 inhibitor(s). We also plan to perform preliminary testing of the most potent lead compounds for their ability to improve glucose tolerance in obese mice. There are three specific aims in this phase 1 proposal: 1. To design and synthesize a series of novel puerarin derivatives. 2. To evaluate puerarin and its derivatives for their sodium ion glucose cotransporter (SGLT1) and facilitated glucose transporter (GLUT2) inhibitory activity and for compound uptake using mouse intestinal Brush Border Membrane Vesicles (BBMVS). 3. To determine the effects of the lead compounds on blood glucose and glucose tolerance in the ob/ob mouse model of type 2 diabetes. It is anticipated that these studies will lead to the development of a new class of novel antidiabetic and antiobesity agents based on the puerarin structure.