Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer's therapy.
Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer's therapy.
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DOI：
10.1021/cb900264w
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发表时间：
2010-06
影响因子：
4
通讯作者：
Hailin Zheng;M. Youdim;M. Fridkin
中科院分区：
文献类型：
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作者：
Hailin Zheng;M. Youdim;M. Fridkin
螯合剂有可能治疗阿尔茨海默病（AD）的潜在病因，但由于其靶向性差、对大脑的渗透性差和/或毒性作用，其治疗用途受到阻碍。在这里，我们报道了一种设计靶向乙酰胆碱酯酶（AChE）和单胺氧化酶（MAO）的位点激活螯合剂的新策略。我们证明了我们的铅2在体外抑制AChE和MAO，但对金属（Fe， Cu和Zn）离子没有亲和力。抑制AChE可激活化合物2，释放活性螯合剂M30。M30已被证明能够调节淀粉样蛋白前体蛋白的调节和β -淀粉样蛋白的还原，抑制氧化应激，并钝化过量的金属离子（铁、铜和锌）。化合物2比脑渗透螯合剂M30具有更小的细胞毒性和更强的亲脂性。我们的新策略相对简单，通常生产具有类似药物性质的小而简单的分子；因此，它在设计更安全、更有效的位点激活多功能螯合剂方面具有潜在的用途，可用于治疗其他与金属相关的疾病，如帕金森病和癌症，这些疾病需要在癌细胞中特异性消除金属。
Chelators have the potential to treat the underlying cause of Alzheimer's disease (AD), but their therapeutic use is hampered by their poor targeting and poor permeability to the brain and/or toxic effects. Here, we report a new strategy for designing site-activated chelators targeting both acetylcholinesterase (AChE) and monoamine oxidase (MAO). We demonstrated that our lead 2 inhibited both AChE and MAO in vitro, but with little affinity for metal (Fe, Cu, and Zn) ions. Compound 2 can be activated by inhibition of AChE to release an active chelator M30. M30 has been shown to be able to modulate amyloid precursor protein regulation and beta-amyloid reduction, suppress oxidative stress, and passivate excess metal ions (Fe, Cu, and Zn). Compound 2 was less cytotoxic and more lipophilic than the brain-permeable chelator M30. Our new strategy is relatively simple and generally produces small and simple molecules with drug-like properties; it thus holds a potential use in designing site-activated multifunctional chelators with safer and more efficacious properties for treating other metal-related diseases such as Parkinson's disease and cancer where specific elimination of metals in cancer cells is required.