Forty−three tricyclic matrinic derivatives with a unique scaffold were prepared and evaluated for their stimulation effects on glucose consumption in HepG2 cells. The structure−activity relationship was systematically elucidated for the first time. Among them, compound 17a exhibited the most promising potency, and dose-dependently increased glucose consumption in L6 myotubes. It significantly lowered blood glucose, glucosylated haemoglobin and AGE level, and improved glucose tolerance and insulin resistance in KK-Ay mice as well. More importantly, 17a effectively ameliorated diabetic nephropathy (DN), as indicated by the improvement of renal function and pathological changes, and decrease of urinary protein. Furthermore, 17a could induce glycolysis but suppressed aerobic oxidation of glucose, in a similar mechanism to Metform. Our results indicated that in addition to hyperglycemia, 17a may be developed to treat diabetic complication such as DN.

制备了具有独特支架的四十三种三环母系衍生物，并评估了它们对HepG2细胞中葡萄糖消耗的刺激作用。第一次系统地阐明了结构-活性关系。其中，化合物17a表现出最有前途的功效，并且在L6肌管中剂量依赖性地增加了葡萄糖的消耗。它显着降低了血糖，糖基化血红蛋白和AGE水平，并且还改善了KK-Ay小鼠的葡萄糖耐量和胰岛素抵抗。更重要的是，17a可有效改善糖尿病肾病（DN），如肾功能和病理变化的改善以及尿蛋白的减少所表明。此外，17a可以诱导糖酵解，但抑制葡萄糖的有氧氧化，其机制与Metform相似。我们的结果表明，除了高血糖症外，还可能开发出17a来治疗糖尿病并发症，例如DN。