多功能金属螯合剂的设计及其治疗阿尔茨海默病的分子机制

项目名称： 多功能金属螯合剂的设计及其治疗阿尔茨海默病的分子机制

项目编号： No.21271101

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 王晓勇

作者单位： 南京大学

项目金额： 84万元

中文摘要： 阿尔茨海默病（AD）严重影响老年人的生活质量，现有药物只能缓解症状不能终止病程，所以研制抗AD药物具有重大的现实意义。大脑皮层和海马区神经细胞外β-淀粉样蛋白（Aβ）聚集是AD的病理特征，因此抑制Aβ聚集是治疗AD的关键。大脑内锌、铜离子含量升高是诱发AD的主要因素之一，它们不仅诱导Aβ聚集，还与之结合诱导产生羟基自由基，对脑组织造成氧化损伤。His-6、-13、-14和Met-35是Aβ结合金属离子的主要位点。乙酰胆碱酯酶能水解神经递质乙酰胆碱，终止冲动传递，导致认知功能障碍，因此抑制其活性亦可改善认知功能。本项目拟设计合成一类多功能螯合剂，其中一个功能单元是螯合锌、铜离子的大环多胺，另一个功能单元是对His和Met残基有特异性结合能力的脂溶性平面芳香铂、钯配合物，两者通过连接体相联形成复合多功能分子，它们同时具备金属螯合剂、Aβ性能调控剂和酶抑制剂等性质，是一类潜在的多靶点AD治疗剂。

中文关键词： 阿尔茨海默病；多功能螯合剂；Aβ聚集；金属配合物；治疗诊断剂

英文摘要： Alzheimer's disease (AD) is a progressive neurodegenerative disorder that badly affects the life of senior citizens. Existing drugs can only alleviate the symptoms, but cannot terminate the pathogenic processes of the disease. Therefore, further development of anti-AD drugs has great practical significance. The pathological hallmark of AD is the aggregation of amyloid β-peptides (Aβ) in the hippocampus area of the cortex in the brain. Thus, the inhibition of Aβ aggregation is crucial to the therapy of AD. The increase in the content of zinc and copper ions in the brain plays a major role in the pathogenesis of AD. These ions not only induce the Aβ aggregation, but also elicit the production of hydroxyl free radicals, causing oxidative damage to brain tissues. The main metal binding sites locate at His-6, -13, -14 and Met-35 amino acid residues in Aβ. Acetylcholinesterase is the enzyme responsible for hydrolyzing the neurotransmitter acetylcholine, thereby facilitating the termination of impulse transmission and leading to cognitive dysfunction. Consequently, the inhibitor of this enzyme can improve the cognitive function of AD patients. In this project, we will design and construct a series of multifunctional metal chelators. At least two functional units are included in these chelators: a macrocyclic amine resp

英文关键词： Alzheimer's disease；Multifunctional chelator；Aβ aggregation；Metal complex；Theranostic agent