杜仲内生菌来源的降糖活性联三苯类化合物的化学多样性研究

Type 2 diabetes is a serious chronic disease, and the α-glucosidase inhibitor is suitable for Chinese patients with carbohydrate as the main source of energy. Oxidative stress plays an important role in the pathogenesis and development of diabetes, and the drugs that inhibit α-glucosidase and reduce oxidative stress may have a good control effect on type 2 diabetes. In the early stage, terphenyls with strong α-glucosidase inhibition and free radical scavenging activity were isolated from endophytic Aspergillus in Eucommia ulmoides. When the Eucommia leaves were added to the medium, the yield of terphenyls increased significantly. The metabolic pathway of the endophytes can be regulated to increase the structural diversity of terphenyls through the mixture culture of endophytes and adding Eucommia ulmoides in the medium. The library of terphenyls will be constructed by chemical modification combined with molecular docking. The structure-activity relationship of terphenyls with hypoglycemic activity will be studied in vitro, and the active molecules were selected to verify the activity in diabetic mice. The project, after the implementation, will be predicted to not only provide new candidate compounds for discovery of antidiabetic drugs with independent intellectual property rights, but also provide basic data for the relationship of active substances between Eucommia and its endophyte.

2型糖尿病是一种严重的慢性疾病，α-葡萄糖苷酶抑制剂类药物适合以碳水化合物为主要热量来源的中国患者。氧化应激在2型糖尿病的发病和发展过程中起着重要作用，具有糖苷酶抑制和降低氧化应激水平的药物可能对糖尿病具有较好的治疗效果。申请者前期从两株杜仲内生曲霉菌代谢提取物中分离得到系列具有较强α-葡萄糖苷酶抑制和自由基清除活性的联三苯类化合物，在菌株的培养基中添加杜仲叶，联三苯类产量明显增加。本项目拟在此基础上，通过杜仲内生菌的混合培养、培养基中添加杜仲叶等策略调控菌株的代谢途径，并结合化学修饰构建联三苯类化合物库；采用体外模型探讨构效关系，优选活性较强的分子进行大鼠体内活性评价。该研究不仅为抗糖尿病自主创新药物的研究提供候选分子，还将为研究杜仲及其内生菌活性物质的相互关系提供基础资料。

联三苯类化合物具有较好的抗氧化和α-葡萄糖苷酶抑制活性，在2型抗糖尿病方面具有很好的应用前景。本项目通过添加宿主植物诱导杜仲内生菌产生结构多样的联三苯类化合物，同时建立了高含量联三苯的高效制备方法。进而通过化学修饰进一步丰富了联三苯类化合物的结构，尤其是完成了具有苯并噻唑骨架的Nocarterphenyl A及其衍生物的合成工作，共获得了61个联三苯类化合物。评价了这些化合物的抗氧化和α-葡萄糖苷酶抑制活性，并初步探讨了构效关系，优选了一个分子进行了小鼠体内降糖活性，具有很好的治疗效果,为抗糖尿病药物的研究提供了新的物质基础。本项目以第一标注发表SCI论文2篇，申请了国家发明专利2件，其中1件已授权，完成了预期的研究目标。