School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Korea.
Int J Mol Sci. 2022 Apr 1;23(7):3927. doi: 10.3390/ijms23073927.
Ginkgolic acid (C13:0) (GA), isolated from Ginkgo biloba, is a potential therapeutic agent for type 2 diabetes. A series of GA analogs were designed and synthesized for the evaluation of their structure-activity relationship with respect to their antidiabetic effects. Unlike GA, the synthetic analog exhibited improved inhibitory activity against PTPN9 and significantly stimulated glucose uptake via AMPK phosphorylation in differentiated 3T3-L1 adipocytes and C2C12 myotubes; it also induced insulin-dependent AKT activation in C2C12 myotubes in a concentration-dependent manner. Docking simulation results showed that had a better binding affinity through a unique hydrophobic interaction with a PTPN9 hydrophobic groove. Moreover, ameliorated palmitate-induced insulin resistance in C2C12 cells. This study showed that increases glucose uptake and suppresses palmitate-induced insulin resistance in C2C12 myotubes via PTPN9 inhibition; thus, it is a promising therapeutic candidate for treating type 2 diabetes.
银杏酸（C13:0）（GA）从银杏中分离得到，是 2 型糖尿病的潜在治疗药物。为了评估其对糖尿病作用的构效关系，设计并合成了一系列 GA 类似物。与 GA 不同，合成的类似物 对 PTPN9 的抑制活性得到了改善，并且能够通过 AMPK 磷酸化显著刺激分化的 3T3-L1 脂肪细胞和 C2C12 肌管中的葡萄糖摄取；它还能够以浓度依赖的方式诱导 C2C12 肌管中胰岛素依赖的 AKT 激活。对接模拟结果表明， 通过与 PTPN9 疏水沟的独特疏水相互作用， 具有更好的结合亲和力。此外， 改善了 C2C12 细胞中棕榈酸引起的胰岛素抵抗。本研究表明， 通过抑制 PTPN9， 在 C2C12 肌管中增加葡萄糖摄取并抑制棕榈酸引起的胰岛素抵抗；因此，它是治疗 2 型糖尿病的有前途的治疗候选药物。
