与DMDP结构相关的天然亚氨基糖的合成及其生物活性研究

Iminosugars, also refered to as azasugars or polyhydroxylated alkaloids, are an important class of carbohydrate mimetics which posess interesting biological activities. Many iminosugars are found to be inhibitors against glycosidases or glycosyltranferases, and therefore are potentially valuable in the development of new agents for the treatment of many diseases, such as diabetes, cancer and viral infection etc. More than two hundred naturally-ocurring iminosugars have so far been isolated from plants or bacteria. DMDP, the polyhydroxylated pyrrolidine alkaloid with an C2-symmetric and all-trans pyrrolindine ring in its molecule, is a special member in the iminosugar family in that more than thirty naturally-ocurring iminosugars are structurally related to it and can be considered as its deritives. Since DMDP and DMDP-related iminosugars have exhibited some important biological activities and are potentially useful in drug discovery, it is significent to develop efficient synthetic methods for the access of these compounds. The in-depth study on the synthesis and biological evaluation of this kind of iminosugars could be resulted in the discovery of new drug lead compounds. This project is intented to develop a general method for the synthesis of DMDP-related iminosugars with sugar-derived cyclic nitrones as key intermediates. The target of this project is to develop a simple, efficient and general synthetic method for the quick generation of DMDP-related iminosugars, and thereby to build a small molecule library of this kind of iminosugars for the study of their structure-activity relationship. The main tasks of this project include the synthesis of DMDP-related polyhydroxylated pyrrolidines, the synthesis of DMDP-related polyhydroxylated pyrrolizidines and the biological evaluation of these compounds.

亚氨基糖是一类重要的生物活性糖模仿物，其中有许多是高效高选择性的糖苷酶或糖基转移酶抑制剂，在治疗糖尿病、抗癌和抗病毒等新药创制中显示出潜在的巨大应用价值。在迄今已分离到的二百余个天然亚氨基糖生物碱中，吡咯烷类生物碱DMDP是具有代表性的一个：它具有重要的生物活性如糖苷酶抑制活性和杀虫活性；有三十余个天然亚氨基糖生物碱在结构上与其相关，其分子中都含有一个环上全反式取代的吡咯烷分子片段。研究此类生物碱的合成方法并系统评价其生物活性具有重要的意义，有望发现新的药物先导化合物。本课题旨在研究和发展一种以环状硝酮为合成中间体的合成方法。目标是建立一种简便、高效和通用的合成此类生物碱的方法，为系统研究这类化合物的构效关系打下基础。研究内容包括：与DMDP结构相关的多羟基吡咯烷类生物碱的合成、与DMDP结构相关的多羟基双稠吡咯烷类生物碱的合成，以及系统评价所合成化合物的生物活性。

与DMDP结构相关的多羟基生物碱是一类具有代表性的亚氨基糖，是高效、高选择性的糖苷酶或糖基转移酶抑制剂，在治疗糖尿病、抗癌和抗病毒等新药创制中显示出潜在的巨大应用价值。本课题旨在研究和发展一种以环状硝酮为合成中间体的合成方法，建立一种简便、高效和通用的合成此类生物碱的方法，为系统研究这类化合物的构效关系打下基础。主要研究了：与DMDP结构相关的多羟基吡咯烷类生物碱的合成；与DMDP结构相关的多羟基双稠吡咯烷类生物碱的合成；对所合成的化合物进行了系统的生物活性评价。取得了如下结果：以环状硝酮为中间体，发展了一种简便、高效和通用的合成与DMDP结构相关的生物碱的方法；完成了broussonetine S、broussonetine I、broussonetine J、broussonetine J1、broussonetine J2、broussonetine W等天然产物的首次全合成, 并合成了系列类似物；对所成的化合物进行了系统的糖苷酶抑制活性评价，系统研究了与DMDP结构相关的亚氨基糖的构效关系，为基于亚氨基糖的新药设计打下了重要基础；在此基础上设计、合成了系列结构新颖的亚氨基糖，从中发现了数个超高活性的糖苷酶抑制剂，有望成为抗病毒、抗肿瘤、治疗II型糖尿病的候选药物。