School of Pharmacy, Tianjin Medical University, Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theragnostic), Tianjin, People's Republic of China.
School of Pharmacy, Tianjin Medical University, Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theragnostic), Tianjin, People's Republic of China; Department of Pharmacy, Tianjin Children's Hospital, People's Republic of China.
Fitoterapia. 2020 Apr;142:104499. doi: 10.1016/j.fitote.2020.104499. Epub 2020 Feb 10.
3-O-[(E)-4-(4-cyanophenyl)-2-oxobut-3-en-1-yl] kaempferol is a novel lead compound to discover anti-diabetic and anti-obesity drugs. The present study reported the scaffold hopping of the lead compound to obtain a new isoxazole derivative, C45, which has improved glucose consumption at the nanomolar level (EC = 0.8 nM) in insulin resistant (IR) HepG2 cells. Western blotting showed that C45 markedly enhanced the phosphorylation of AMPK (AMP-activated protein kinase) and reduced the levels of the gluconeogenesis key enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose 6-phosphatase) in HepG2 cells. The potential molecular mechanism of C45 may be activation of the AMPK/PEPCK/G6Pase pathways. We concluded that C45 might be a valuable candidate to discover anti-diabetic drugs.
3-O-[(E)-4-(4-氰基苯基)-2-氧代丁-3-烯-1-基]山柰酚是一种新型的抗糖尿病和抗肥胖药物的先导化合物。本研究报道了该先导化合物的骨架跃迁，得到了一种新的异噁唑衍生物 C45，它在胰岛素抵抗（IR）HepG2 细胞中以纳摩尔级（EC=0.8 nM）的水平显著提高葡萄糖的消耗。Western blot 结果表明，C45 明显增强了 AMPK（AMP 激活的蛋白激酶）的磷酸化，并降低了 HepG2 细胞中糖异生关键酶 PEPCK（磷酸烯醇丙酮酸羧激酶）和 G6Pase（葡萄糖 6-磷酸酶）的水平。C45 的潜在分子机制可能是激活 AMPK/PEPCK/G6Pase 途径。我们得出结论，C45 可能是一种有价值的抗糖尿病药物候选物。
