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Stereoisomers of Schisandrin B Are Potent ATP Competitive GSK-3β Inhibitors with Neuroprotective Effects against Alzheimer's Disease: Stereochemistry and Biological Activity.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-07-06 , DOI: 10.1021/acschemneuro.8b00252
Xiao-Long Hu 1 , Cui Guo 1 , Ji-Qin Hou 1 , Jia-Hao Feng 1 , Xiao-Qi Zhang 2 , Fei Xiong 3 , Wen-Cai Ye 2 , Hao Wang 1
Affiliation  

Glycogen synthase kinase-3β (GSK-3β) is a key enzyme in hyperphosphorylation of tau proteins and is a promising therapeutic target in Alzheimer's disease (AD). Here, we reported, for the first time, that the stereoisomers of Schisandrin B (Sch B), (+)-1, (-)-1, (+)-2, and (-)-2, were potent GSK-3β inhibitors. They were demonstrated to selectively target GSK-3β in an orthosteric binding mode, with IC50 values of 340, 290, 80, and 70 nM, respectively. Further study showed that these stereoisomers can significantly increase the expression of p-GSK-3β (Ser9) and decrease the expressions of p-GSK-3β (Tyr216) and p-GSK-3β (Tyr279). Finally, these compounds can alleviate the cell injury induced by Aβ, and the cognitive disorders in AD mice, especially (+)-2 and (-)-2. Collectively, the stereoisomers of Sch B, especially (+)-2 and (-)-2, were found to be potential selective ATP-competitive GSK-3β inhibitors, which further affected their anti-AD effects. These promising findings explained the biological target of Sch B in AD, and bring a new understanding in the stereochemistry and bioactivities of Sch B.

中文翻译:

五味子素B的立体异构体是对ATP具有竞争性的强GSK-3β抑制剂,具有抗阿尔茨海默氏病的神经保护作用:立体化学和生物学活性。

糖原合酶激酶3β(GSK-3β)是tau蛋白过度磷酸化的关键酶,是阿尔茨海默病(AD)的有希望的治疗靶标。在这里,我们首次报道了五味子素B(Sch B),(+)-1,(-)-1,(+)-2和(-)-2的立体异构体是有效的GSK- 3β抑制剂。已证明它们以正构结合模式选择性靶向GSK-3β,IC50值分别为340、290、80和70 nM。进一步的研究表明,这些立体异构体可以显着增加p-GSK-3β(Ser9)的表达,并降低p-GSK-3β(Tyr216)和p-GSK-3β(Tyr279)的表达。最后,这些化合物可以减轻Aβ引起的细胞损伤,以及AD小鼠的认知障碍,尤其是(+)-2和(-)-2。Sch B的立体异构体,特别是(+)-2和(-)-2,被发现是潜在的选择性ATP竞争性GSK-3β抑制剂,这进一步影响了它们的抗AD作用。这些有前途的发现解释了AD中Sch B的生物学目标,并为Sch B的立体化学和生物活性带来了新的认识。
更新日期:2018-06-26
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