Design, synthesis and biological evaluation of acridone glycosides as selective BChE inhibitors.
Design, synthesis and biological evaluation of acridone glycosides as selective BChE inhibitors.
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选择性 BChE 抑制剂吖啶酮苷的设计、合成及生物学评价
DOI：
10.1016/j.carres.2020.107977
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发表时间：
2020-05-01
影响因子：
3.1
通讯作者：
Zhang, Guisheng
中科院分区：
文献类型：
--
作者：
Ma, Weiwei;Bi, Jingjing;Zhang, Guisheng
在对丁酰胆碱酯酶（BChE）结构分析的基础上，设计合成了21个吖啶酮苷类化合物，并对其进行了体外抑制BChE和乙酰胆碱酯酶（AChE）活性的评价。D-核糖衍生物6 f对BChE的抑制活性最强（IC_（50）= 6.95 μ M），是选择性最强的BChE抑制剂，其对AChE/BChE的IC_（50）比值为20.59。d-葡萄糖和d-半乳糖衍生物6a和6 b对乙酰胆碱酯酶和乙酰胆碱酯酶均有抑制活性。化合物6a、6 b、6 f和5 t对SHSY 5 Y神经母细胞瘤和HepG 2细胞均无毒性作用，具有明显的神经保护活性。此外，化合物6 f对BChE表现出混合型抑制作用（Ki= 1.76 μ M），这使得6 f成为治疗阿尔茨海默病的潜在药物。这些新的吖啶酮杂合物可能作为有效的探针来揭示配体与BChE之间的关系，并为开发选择性BChE抑制剂以进一步研究阿尔茨海默病的发病机制奠定基础。
Based on structure analyses of butyrylcholinesterase (BChE), a series of 21 acridone glycosides were designed, synthesized and evaluated in vitro for their BChE and acetylcholinesterase (AChE) inhibitory activities. d-ribose derivative 6f exhibited the greatest inhibitory activity on BChE (IC50=6.95muM), and was the most selective inhibitor of BChE with the IC50 ratio of AChE/BChE was 20.59. d-glucose and d-galactose derivatives 6a and 6b showed inhibitory activities against both AChE and BChE. Moreover, compounds 6a, 6b, 6f and 5t were found nontoxic on SHSY5Y neuroblastoma and HepG2 cell and exhibited remarkable neuroprotective activity. Besides, compound 6f showed mixed-type inhibition against BChE (Ki=1.76muM), which renders 6f a potential agent for the treatment of Alzheimer's disease. These novel acridone hybrids might be used as efficient probes to reveal the relationship between ligands and BChE and pave the way for developing selective BChE inhibitors to further study the pathogenesis of alzheimer's disease.