深海土曲霉中α-葡萄糖苷酶抑制剂的发现、结构优化及构效关系研究

Diabetes is among the top 10 causes of death globally. The latest diabetes atlas announced by International Diabetes Federation revealed that China had 121 million people with diabetes. The current clinical medication is limited and unsatisfied with some complication. Therefore, the development of new highly effective drugs for diabetes is of urgent significance. In recent years, deep-sea fungi are considered to have great potential for the development of lead compounds. In our previous study, a series of highly conjugated steroids and butenolides were obtained from the deep-sea derived fungus Aspergillus terreus. Bioactivity study indicated several compounds exhibited promising inhibitory effects against α-glucosidase, more active than the commercial drugs acarbose. In our ongoing project, we intend to make an intensive study of the α-glucosidase inhibitors of the strain and to study the structure modification, structure-activity relationship, and the in vivo pharmacodynamic activity. Our study will provide new ideas and scientific basis for the development of new drugs for diabetes.

糖尿病是全球 10 大死因之一，我国糖尿病患者数量约1.21亿。临床高效低毒药物较少。寻找新型和高效抗糖尿病先导物具有迫切性。深海真菌在药物先导化合物开发上具有巨大潜力。课题前期从深海来源土曲霉中获得一系列高度共轭甾体类化合物及丁烯酸内酯类同系物，部分化合物具有较强的抑制α-葡萄糖苷酶作用，活性显著强于阳性对照药物阿卡波糖。本课题拟深入开展该菌株抑制α-葡萄糖苷酶新颖成分挖掘，对活性成分进行结构修饰和构效关系探讨，并开展体内药效评价，为抗糖尿病治疗药物研发提供新型先导分子。

α-葡萄糖苷酶是抗糖尿病药物研发的重要靶点。海洋真菌是新颖和活性分子的重要来源。课题前期发现从海洋来源土曲霉Aspergillus terreus中获得的部分化合物具有较好的α-葡萄糖苷酶抑制活性。实验中发现曲霉菌Aspergillus flavipes、Aspergillus versicolor、Aspergillus fumigatus、青霉菌Penicillium thomii的发酵物显著抑制α-葡萄糖苷酶。在项目执行的三年间，对以上5株真菌中α-葡萄糖苷酶抑制成分进行了深入的挖掘，发表71个化合物，包括新化合物29个。10余个化合物活性显著强于阳性对照阿卡波糖（临床常用药物），其中1个化合物是阿卡波糖活性的44倍，分子对接实验表明活性化合物与酶的活性氨基酸残基具有一定的相互作用。部分化合物在uM浓度下对多株肿瘤细胞株、铁死亡细胞、磷酸二酯酶4表现出较强活性，其中1个化合物显著抑制铁死亡（IC50 0.1 uM），对其进行了衍生物的制备。本项目为开发海洋来源α葡萄糖苷酶抑制剂奠定了化学及活性基础，为以该酶为靶点的抗糖尿病药物的研发提供了理论基础。课题发表相关SCI论文7篇。