Synthesis and biological evaluation of 3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-(indol-3-yl)-maleimides as potent, selective GSK-3β inhibitors and neuroprotective agents.
Synthesis and biological evaluation of 3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-(indol-3-yl)-maleimides as potent, selective GSK-3β inhibitors and neuroprotective agents.
复制标题
DOI：
10.1016/j.bmc.2014.12.026
复制
发表时间：
2015-03
影响因子：
3.5
通讯作者：
Q. Ye;Wei-wei Mao;Yubo Zhou;Lei Xu;Qiu Li;Yuan-xue Gao;Jing Wang;Chenhui Li;Ya-zhou Xu;Yuan Xu;H. Liao;Luyong Zhang;Jian-rong Gao;Jia Li;Tao Pang
中科院分区：
文献类型：
--
作者：
Q. Ye;Wei-wei Mao;Yubo Zhou;Lei Xu;Qiu Li;Yuan-xue Gao;Jing Wang;Chenhui Li;Ya-zhou Xu;Yuan Xu;H. Liao;Luyong Zhang;Jian-rong Gao;Jia Li;Tao Pang
设计、制备了一系列新的3-（[1,2,4]三唑[4,3- A]吡啶-3-基）-4-（吲哚-3-基）-马来酰亚胺，并对其GSK-3β抑制活性进行了评价。大多数化合物对GSK-3β具有高选择性抑制作用。其中化合物7c、7f、7h、7land7m显著降低了原代神经元中GSK-3β底物Tau蛋白Ser396位点的磷酸化，显示出对细胞GSK-3β的抑制作用。在体外神经元损伤模型中，化合物7c、7f、7h、7land7m7可预防与脑缺血相关的谷氨酸、氧葡萄糖剥夺和营养血清剥夺导致的神经元死亡。在体内脑缺血动物模型中，化合物7可使脑梗死面积减少15%，改善局灶性脑缺血后的神经功能缺损。这些发现可能为开发具有潜在神经保护活性的新型GSK-3β抑制剂提供新的见解。
A series of novel 3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-(indol-3-yl)-maleimides were designed, prepared and evaluated for their GSK-3β inhibitory activities. Most compounds showed high potency to GSK-3β inhibition with high selectivity. Among them, compounds7c,7f,7h,7land7msignificantly reduced GSK-3β substrate Tau phosphorylation at Ser396 in primary neurons, showing the inhibition of cellular GSK-3β. In the in vitro neuronal injury models, compounds7c,7f,7h,7land7mprevented neuronal death against glutamate, oxygen–glucose deprivation and nutrient serum deprivation which are associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound7freduced infarct size by 15% and improved the neurological deficit following focal cerebral ischemia. These findings may provide new insights into the development of novel GSK-3β inhibitors with potential neuroprotective activity.