新型碳糖类化合物的设计、合成及活性评价

Diabetes is a kind of disabled and highly-fataled common metabolic diseases, and is seriously harmful to human health. As one type of hypoglycemic drugs, α-glucosidase inhibitor, such as voglibose, can control the concentration of the patients' blood glucose via inhibiting the production of intestinal monosaccharide. Based on the results of the structure-activity relationship of the known voglibose, and with the help of computer-aided homology modeled and molecular docked technology, here are designed and synthesized some novel types of carbasugars, especially the amino-carbasugars, by the modification of the substituents and their configurations in the position of C1-C3 on the six-membered ring.Starting from our invented cyclohexenone 15, the designed carbasugars can be synthesized by employing the selective 1,4-Michael addition, and the reductive amination or 1,2-addition of the formed cyclohexanone 18 as the key steps. After the enzyme- and animal-level evaluation of the activity of the carbasugars and the study of the structure-activity relationship, it will be expected here to get a new active lead..It will be also very important for this project to develop the novel synthetic methodology of carbasugars, to know more about their properties, and to discover some new hypoglycemic drugs.

糖尿病是致残、致死率高的常见代谢性疾病，严重危害人类身体健康。α-葡萄糖苷酶抑制剂类降糖药如Voglibose通过抑制肠道单糖的产生来控制患者的血糖浓度。本项目在总结Voglibose的构效关系基础上、借助计算机辅助的同源模建和分子对接技术，对其碳环的1-位、2-位和3-位取代基种类和构型的变换等，设计、合成结构多样性的碳糖尤其是氨基碳糖目标物。以我们发现的环己烯酮15为原料，经选择性1,4-Michael加成、相应环己酮18的还原胺化或羰基加成反应为关键步骤，可完成这些目标物的合成。通过酶及动物水平的活性评价，总结构效关系，期望发现新的活性先导物。.本项目的顺利开展，对碳糖合成策略的拓展、碳糖性质的理解及发现新的糖尿病治疗药物具有重要意义。