Combating Alzheimer's disease with multifunctional molecules designed for metal passivation
Combating Alzheimer's disease with multifunctional molecules designed for metal passivation
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DOI：
10.1002/anie.200603866
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Orvig, Chris
中科院分区：
文献类型：
--
作者：
Schugar, Harvey;Green, David E.;Orvig, Chris
阿尔茨海默病（AD）的两个生物化学特征是细胞内氧化应激和微量金属离子水平升高，特别是Fe III、Cu II和Zn II。[1]这两种因素都参与了通常用于AD死后诊断的脑组织学特征的形成，即β-淀粉样蛋白（Aβ）斑块和神经元缠结。目前在其他地方研究的治疗干预包括氯碘羟喹[2]和去铁胺[3]，它们是靶向大脑中升高的痕量金属离子的金属螯合剂，尽管它们既不打算直接影响氧化应激，也不靶向大脑。抗氧化剂补充剂已被单独研究，作为缓解AD症状的唯一缓解措施。[4]在此，我们首次提出了AD治疗的三功能方法。修饰和官能化的二齿羟基吡啶酮前配体（方案1）解决了AD中固有的金属离子和氧化失衡，同时结合了葡萄糖受体靶向特征。这些前药被设计为穿过血脑屏障（BBB），通过酶裂解失去侧链碳水化合物，钝化脑中过量的金属离子，并且还保护神经元细胞免受活性氧（ROS）的影响。这些功能中的每一个都已得到证实，从而确立了三功能原则作为AD治疗的有效目标。前药策略通过使用碳水化合物作为掩蔽和定向取代基解决了过早金属结合的潜在问题。在神经退行性疾病（包括AD）中重建正常金属离子稳态的经验支持越来越多的背景下，三功能方法允许选择性的组织依赖性金属结合作为定制的生物相容性治疗。
Two of the biochemical features of Alzheimer s disease (AD) that contribute to neurodegeneration are intracellular oxidative stress and elevated levels of trace metal ions, especially FeIII, CuII, and ZnII.[1] Both are factors involved in formation of the histological features in the brain used typically for postmortem diagnosis of AD, namely β-amyloid (Aβ) plaques and neurofibrillary tangles. Therapeutic interventions under current investigation elsewhere include clioquinol [2] and desferrioxamine,[3] which are metal chelators that target elevated trace-metal ions in the brain, although neither are intended to affect oxidative stress directly and nor are they targeted to the brain. Antioxidant supplements have been studied separately as palliative-only measures for alleviation of the symptoms of AD.[4]Herein, we present for the first time a trifunctional approach to AD therapy. Modified and functionalized bidentate hydroxypyridinone pro-ligands (Scheme 1) address both the metal-ion and the oxidative imbalances inherent in AD while incorporating a glucose-receptor targeting feature. These prodrugs are designed to cross the blood–brain barrier (BBB), lose the pendant carbohydrate by enzymatic cleavage, passivate excess metal ions in the brain, and also protect neuronal cells against reactive oxygen species (ROS). Each of these functionalities has been demonstrated, thereby establishing the trifunctional principle as a valid goal in AD therapy. The prodrug strategy solves the potential problem of premature metal binding by using carbohydrates as both masking and directing substituents. In the context of increasing empirical support for re-establishing normal metal-ion homeostasis in neurodegenerative diseases, including AD, the trifunctional approach permits selective, tissue-dependent metal binding as a tailor-made, biologically compatible therapy.