Yao Dahong, Wang Jing, Wang Guan, Jiang Yingnan, Shang Lei, Zhao Yuqian, Huang Jian, Yang Shilin, Wang Jinhui, Yu Yamei
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
Department of Neurology, Liaocheng People's Hospital and Liaocheng Clinical School of Taishan Medical University, Liaocheng 252000, China.
Bioorg Chem. 2016 Oct;68:112-23. doi: 10.1016/j.bioorg.2016.07.013. Epub 2016 Jul 27.
A novel series of coumarin derivatives were designed, synthesized and investigated for inhibition of cholinesterase, including acetyl cholinesterase (AChE) and butyrylcholinesterase (BuChE). This biological study showed that these compounds containing piperazine ring had significant inhibition activities on AChE rather than BuChE. Further study suggested that 9x, as one of this kind of structure derivative, showed the strongest inhibition activity on AChE with an IC50 value of 34nM. Moreover, molecular docking, flow cytometry (FCM), and western blot assay suggested that 9x could induce cytoprotective autophagy to attenuate H2O2-induced cell death in human neuroblastoma SH-SY5Y cells. These findings highlight a new approach for the development of a novel potential neuroprotective compound targeting AChE with autophagy-inducing activity in future Alzheimer's disease (AD) therapy.
设计、合成并研究了一系列新型香豆素衍生物对胆碱酯酶的抑制作用，包括乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）。该生物学研究表明，这些含哌嗪环的化合物对AChE具有显著的抑制活性，而对BuChE的抑制活性不明显。进一步研究表明，作为这类结构衍生物之一的9x对AChE表现出最强的抑制活性，IC50值为34nM。此外，分子对接、流式细胞术（FCM）和蛋白质印迹分析表明，9x可诱导细胞保护性自噬，以减轻H2O2诱导的人神经母细胞瘤SH-SY5Y细胞死亡。这些发现突出了一种新方法，用于开发一种新型潜在的神经保护化合物，该化合物在未来阿尔茨海默病（AD）治疗中靶向具有自噬诱导活性的AChE。
