Novel Puerarin Analogs with Anti-Diabetic Activity

描述（由申请人提供）：在糖尿病患者中，由于从胃肠道吸收葡萄糖，高血糖症在餐后最为明显。抑制肠道中的葡萄糖摄入和/或促进组织中的葡萄糖处置可能有利于糖尿病患者控制餐后状态的血糖水平。我们最近已经证明，葛根素，主要的β-葡糖苷在葛根素膳食补充剂中发现显着改善C57 BL/6 J-ob/ob小鼠的葡萄糖耐量，2型糖尿病的动物模型，钝化后的血糖水平的上升腹膜内或口服给药。葛根素从肠道快速吸收而无代谢，似乎通过与葡萄糖转运蛋白SGLT 1和GLUT 2相互作用抑制葡萄糖从肠道摄取来发挥其降血糖活性。这些结果值得进一步研究的作用机制和构效关系。本研究的主要目的是合成新型葛根素类似物，并评价其作为降血糖剂的潜力。为了实现这一目标，我们将合成新的葛根素类似物，并使用表达这些转运蛋白的分离的小鼠肠刷状缘膜囊泡（BBMV）筛选它们抑制SGLT 1和/或GLUT 2的能力。这将使我们能够检查在不同环上进行修饰的葛根素衍生物的结构-活性关系，最终合成基于葛根素的有效SGLT 1/GLUT 2抑制剂。我们还计划对最有效的先导化合物进行初步测试，以提高肥胖小鼠的葡萄糖耐量。第一阶段提案有三个具体目标：1.设计合成一系列新型葛根素衍生物。2.评价葛根素及其衍生物对钠离子葡萄糖协同转运蛋白（SGLT 1）和易化葡萄糖转运蛋白（GLUT 2）的抑制活性，并使用小鼠肠刷状缘膜囊泡（BBMVS）评价化合物摄取。3.确定先导化合物对2型糖尿病ob/ob小鼠模型血糖和糖耐量的影响。预计这些研究将导致一类新的基于葛根素结构的新型抗糖尿病和抗肥胖剂的开发。

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.