Flavonoid derivatives synthesis and anti-diabetic activities
Flavonoid derivatives synthesis and anti-diabetic activities
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DOI：
10.1016/j.bioorg.2019.103501
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发表时间：
2020-01-01
影响因子：
5.1
通讯作者：
Qin, Nan
中科院分区：
文献类型：
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作者：
Chen, Ying;Cheng, Feng-Bo;Qin, Nan
在高脂饮食诱导的肥胖小鼠中，铁线蕨苷的黄酮衍生物Fla-CN具有抗高血糖作用，可以改善胰岛素敏感性，改善代谢脂质紊乱，并且有益于以胰岛素抵抗为特征的某些疾病。Fla-CN是发现抗糖尿病和抗肥胖药物的新型先导化合物。本研究报告了Fla-CN的优化，以获得新的衍生物10 b，其在胰岛素抵抗（IR）HepG 2细胞中以纳摩尔水平（EC 50 = 0.3 nM）改善葡萄糖消耗。10 b还增加HepG 2细胞的糖原含量和葡萄糖摄取，同时抑制HepG 2细胞的糖原合成。Western blotting结果显示，10 B能显著增强HepG 2细胞AMPK（AMP活化蛋白激酶）和AS 160（160 kDa蛋白激酶B底物）的磷酸化，降低细胞凋亡关键酶PEPCK（磷酸烯醇丙酮酸羧激酶）和G6 P（葡萄糖6-磷酸酶）的水平。10 b可能的分子机制是激活AMPK/AS 160和AMPK/PEPCK/G6 P通路。我们的结论是，10 b可能是一个有价值的候选人，发现抗糖尿病药物。
In high fat diet-induced obese mice, the flavonoid derivative of tiliroside, Fla-CN, has antihyperglycemic effects, can improve insulin sensitivity, ameliorate metabolic lipid disorders, and benefits certain disorders characterized by insulin resistance. Fla-CN is a novel lead compound to discovery anti-diabetic and anti-obesity drugs. The present study reported the optimization of Fla-CN to obtain a new derivative, 10b, which has improved glucose consumption at the nanomolar level (EC50 = 0.3 nM) in insulin resistant (IR) HepG2 cells. 10b also increased the glycogen content and glucose uptake, and concurrently inhibited gluconeogenesis in HepG2 cells. Western blotting showed that 10b markedly enhanced the phosphorylation of AMPK (AMP-activated protein kinase) and AS160 (protein kinase B substrate of 160 kDa) and reduced the levels of the gluconeogenesis key enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6P (glucose 6-phosphatase) in HepG2 cells. The potential molecular mechanism of 10b may be activation of the AMPK/AS160 and AMPK/PEPCK/G6P pathways. We concluded that 10b might be a valuable candidate to discover anti-diabetic drugs.