Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer's disease
Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer's disease
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DOI：
10.1016/j.ejmech.2015.02.063
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发表时间：
2015-04-13
影响因子：
6.7
通讯作者：
Deng, Yong
中科院分区：
文献类型：
--
作者：
Sang, Zhipei;Qiang, Xiaoming;Deng, Yong
设计、合成并测试了一系列灯盏乙素-O-烷基胺衍生物，作为治疗阿尔茨海默病（AD）的多功能药物。结果表明，这些化合物大多数表现出良好的多功能活性。其中，化合物16d表现出显着的金属螯合特性、中等的乙酰胆碱酯酶（AChE）抑制和抗氧化活性，对自身诱导的Aβ（1-42）聚集、Cu2+诱导的Aβ（1-42）聚集、人AChE诱导的Aβ（1-40）聚集和解体Cu2+诱导的结构良好的Aβ（1-42）原纤维聚集具有优异的抑制作用。 AChE 抑制的动力学分析和分子模型研究表明 16d 同时与 AChE 的催化活性位点和外周阴离子位点结合。此外，化合物16d对H2O2诱导的PC12细胞损伤表现出良好的保护作用，且对SH-SY5Y细胞的毒性较低。此外，降压被动回避测试表明，这种化合物可以显着逆转东莨菪碱引起的小鼠记忆缺陷。因此，16d被证明是一种值得进一步研究的有趣的多功能先导化合物。 (C) 2015 Elsevier Masson SAS。版权所有。
A series of scutellarein-O-alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 16d demonstrated significant metal chelating properties, moderate acetylcholinesterase (AChE) inhibitory and anti-oxidative activity, and excellent inhibitory effects on self-induced A beta(1-42) aggregation, Cu2+-induced A beta(1-42) aggregation, human AChE-induced A beta(1-40) aggregation and disassembled Cu2+-induced aggregation of the well-structured A beta(1-42) fibrils. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that 16d binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Moreover, compound 16d showed a good protective effect against H2O2-induced PC12 cell injury, with low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Thus, 16d was shown to be an interesting multifunctional lead compound worthy of further study. (C) 2015 Elsevier Masson SAS. All rights reserved.