Design, synthesis and anti-AD effects of dual inhibitor targeting glutaminyl cyclase/GSK-3β.
Design, synthesis and anti-AD effects of dual inhibitor targeting glutaminyl cyclase/GSK-3β.
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DOI：
10.1016/j.ejmech.2023.115089
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发表时间：
2023-01
影响因子：
6.7
通讯作者：
Yazhou Xie; Chen-Chen-Chen;Shujing Lin;Xi Yu;Shuixian Ye;Xiaojie Chen;Na Ouyang;Wei Xiong;Chenyang Li;Chenshu Xu;Guoli Song;Haiqiang Wu
中科院分区：
文献类型：
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作者：
Yazhou Xie; Chen-Chen-Chen;Shujing Lin;Xi Yu;Shuixian Ye;Xiaojie Chen;Na Ouyang;Wei Xiong;Chenyang Li;Chenshu Xu;Guoli Song;Haiqiang Wu
阿尔茨海默病（Alzheimer's disease，AD）是一种多因素疾病，是痴呆的最常见形式之一，临床上抗AD药物的疗效有限。近年来，研究发现，上调的β-氨基环化酶（QC）和糖原合成酶激酶-3 β（GSK-3β）是AD发病的两个关键因素。本文设计并合成了一系列含马来酰亚胺和咪唑基序的化合物，作为QC和GSK-3β的双重抑制剂。基于初步筛选，化合物2（2.26 μM），5（2.37 μM），8（1.34 μM），21（2.44 μM），25（0.36 μM），27（1.76 μM），28（1.04 μM），33（2.08 μM）和34（2.33 μM）显示出显著的人QC（hQC）抑制效力，而化合物1（0.014 μM）、7（0.04 μM）、8（0.057 μM）、19（0.034 μM）、24（0.014 μM）、32（0.032 μM）、38（0.051 μM）、39（0.044 μM）、44（0.048 μM）、47（0.011 μM）、49（0.021 μM）等具有明显的GSK-3β抑制活性。这些化合物对hQC和GSK-3β均有明显的抑制作用，如化合物1（2.80和0.014 μM），8（1.34和0.057 μM），25（0.36和0.15 μM），27（1.76和0.069 μM），28（1.04和0.090 μM），33（2.08和0.19 μM），34（2.33和0.11 μM），35（2.55和0.14 μM），36（2.34和0.11 μM），体内实验结果表明，化合物8能减轻3 × Tg-AD小鼠的认知障碍，减少焦虑样行为。治疗通过抑制QC活性降低AD小鼠脑中pE-Aβ和Aβ的积累，并通过降低GSK-3β水平降低Tau的过度磷酸化。这些新化合物有望成为以QC和GSK-3β为靶点的抗AD药物。
Alzheimer's disease (AD), multifactorial disease, is recognized as one of the most common forms of dementia, and the efficacy of anti-AD drugs is limited clinically. Up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3β (GSK-3β) have been identified as two critical elements involved in AD recently. Here, a series of novel chemicals containing maleimide and imidazole motif were designed and synthesized as dual inhibitors targeting QC and GSK-3β. Based on primary screening, compound2(2.26 μM),5(2.37 μM),8(1.34 μM),21(2.44 μM),25(0.36 μM),27(1.76 μM),28(1.04 μM),33(2.08 μM) and34(2.33 μM) exhibited notable human QC (hQC) inhibitory potency, while compound1(0.014 μM),7(0.04 μM),8(0.057 μM),19(0.034 μM),24(0.014 μM),32(0.032 μM),38(0.051 μM),39(0.044 μM),44(0.048 μM),47(0.011 μM),49(0.021 μM) and so on showed remarkable GSK-3β inhibitory activities. And as expected, these chemicals possessed significant inhibitory potency on both hQC and GSK-3β, such as compound1(2.80 and 0.014 μM),8(1.34 and 0.057 μM),25(0.36 and 0.15 μM),27(1.76 and 0.069 μM),28(1.04 and 0.090 μM),33(2.08 and 0.19 μM),34(2.33 and 0.11 μM),35(2.55 and 0.14 μM),36(2.34 and 0.11 μM), etc. Subsequentin vivostudies demonstrated that compound8attenuated cognitive deficits and decreased the anxiety-like behavior in 3 × Tg-AD mice. The treatment decreased both pE-Aβ and Aβ accumulation by inhibiting the activity of QC, and decreased the hyperphosphorylation of Tau by reducing the levels of GSK-3β in the brains of AD mice. Results obtained in this research suggested that these novel compounds could be supposed as potential anti-AD agents targeting QC and GSK-3β.