糖尿病是一种持续高血糖慢性代谢性疾病，发病率逐年增高，成为危害人类健康的重大疾病，现有糖尿病药物易产生低血糖和胃肠道反应等副作用，中药在治疗糖尿病具有重要作用。青钱柳是我国特有的单种属植物，因其叶具有降血糖，降血压作用而用于保健品。我们前期从青钱柳中分离得到17个化合物，其中7个化合物对α-葡萄糖苷酶有较好的抑制作用，其IC50值范围为0.53-1.87 mg/mL。通过对J306进行体内活性评价，发现其对Ⅱ型糖尿病模型BKS-db小鼠的餐后血糖具有明显的降糖作用，对正常小鼠的餐后血糖也有调节作用。本研究拟在此基础上，对J306进行结构修饰合成80-100个衍生物并研究其构效关系，对高活性化合物进行BKS-db小鼠和正常小鼠模型体内药效评价，药代动力学研究和初步安全性评价，并利用Western blot分析和Q-PCR技术研究其作用机制，为发现治疗2型糖尿病的候选化合物提供化学和药学依据。

Diabetes mellitus was a chronic metabolic disease characterized by hyperglycemia. The incidence of diabetes increased year by year, becoming one of the major risks to human health. Traditional anti-diabetics frequently led to various side effects, such as hypoglycemia, gastrointestinal tract reaction. Traditional Chinese medicines play an important role in the treatment of type 2 diabetes. Cyclocarya paliurus is an endemic species growing in China. Due to its function on the treatment of anti-diabetes and anti-hypertention, C. paliurus leaves have been used to make health products for a long time. In our previous study, bioactivity-guided fractionation on the active part of C. paliurus led to the isolation and identification of seventeen compounds. Seven compounds noticeably inhibited the activity of α-glucosidase with IC50 values ranged from 0.53-1.87 mg/mL. Particularly, oral administration of J306 to C57BL/6 and BKS-DB mice to significantly decreased the serum glucose level. In this project, J306 derivatives were designed and synthesized to obtain 80-100 compounds with strong activity against the α-glucosidase and to study structure-activity relationship. Then, to further evaluated the most potent compounds in diabetic BKS-DB mice and identify their major metabolites in liver microsomes and in rats by LC/MS-IT-TOF. Western blot analyses and Q-PCR technique will be used to study their potential mechanism. At the end, we hope to discover 1-2 compounds promising to be developed into a drug candidate in the treatment of type 2 diabetes.