多聚水杨酸铬(III)配合物的生物降糖效应及分子机理

Chromium(III) helps insulin metabolize fat, turn protein into muscle and convert sugar into energy.It plays a important role in II diabete. But the michinism is still unknown.We have done plenty of work on the synthesis and properties of salicylate-Cr compounds. we find that the salicylate can help the absorption of Cr, and the compounds effectively suppress the increases in body mass and adipose mass. On this basis we will select the polysalicalic acid(bi-and triplesalicylic acid) to compose 20 chromium complexes, which are expected to have little toxity and higher activities.Then it can be used to diebete mice model. Many works will be conducted such as highthroughput drug screening，Body hypoglycemic activity，Toxicology experiment and intestine microflora. On the other side, molecular biology experiment of chromium will be carried out, which include bioavailability, insulin activity, target molecules selection and the way of chromium to pump out the endosomes. Through the analysis of structure-activity relationship,we will screen 1-2 kinds of high efficiency, low toxicity and having a specific of crystalline polysalicylic acid chromium complexes. we try to estimate the polysalicylic-chromium complexes of biological hypoglycemic effect, reveals the molecular mechanism. The project has certain significance for a new design and the development of the inorganic medicines to treat diabetes drugs of inorganic.

三价铬(III)离子能增强胰岛素功能，促进糖、蛋白质和脂肪的代谢，在糖尿病的治疗中发挥着重要作用，分子机理不明。我们首次合成了单体水杨酸铬配合物，发现水杨酸对铬的转运具有促进作用，并在预实验中观察到了二者的协同降糖作用。本项目将选择降糖活性和安全性更好的多聚水杨酸（水杨酸二聚体、三聚体），合成具有特定晶型的多聚水杨酸铬(III)配合物20余种。然后以糖尿病老鼠为模型,利用生物学方法进行高通量药物筛选、降糖实验、毒理实验和肠道菌群实验，筛选活性物种；同时利用分子生物学手段进行配合物生物利用率、胰岛素增强效应、相关靶肽酶的选择和铬如何跨出细胞内囊泡的通道定位实验，揭示降糖机理。实验囊括了结构-活性-机理三层次，总计十项实验，最终筛选出几种高效低毒的多聚水杨酸铬配合物，并从分子机理上诠释降糖效应。该项目立足于新型含铬药物的设计和研发，对肥胖症及糖尿病的治疗具有重要意义。

铬(III)离子能增强胰岛素功能，促进糖、蛋白质和脂肪的代谢，在糖尿病的治疗中发挥着重要作用，但是作用机制不明确。首先合成了单体水杨酸铬配合物，发现水杨酸对铬的转运具有明显促进作用，并在预实验中观察到了二者的协同降糖作用。在此基础上，选择降糖活性和安全性更好的多聚水杨酸（水杨酸二聚体、三聚体），合成具有特定晶型的水杨酸铬(III)配合物40余种,研究了他们的理化性质。然后以糖尿病老鼠为模型, 利用生物学方法进行药物筛选、降糖实验、毒理实验和肠道菌群实验，筛选活性物种；同时利用分子生物学手段进行配合物生物利用率、胰岛素增强效应、相关靶肽酶的选择和铬如何跨出细胞内囊泡的通道定位实验，研究表明，与传统药物吡啶甲酸铬比较起来，多聚水杨酸铬具有良好的降糖减肥效果，初步认为降糖机理为氧化机理。实验囊括了结构-活性-机理三层次，总计十项实验，最终筛选出3种高效低毒的多聚水杨酸铬配合物，并从分子机理上诠释了降糖效应。总之，水杨酸铬作为降糖药物具有良好的降糖效果和较小的生物副作用，具有诱人的应用前景。