Novel Tacrine-8-Hydroxyquinoline Hybrids as Multifunctional Agents for the Treatment of Alzheimer's Disease, with Neuroprotective, Cholinergic, Antioxidant, and Copper-Complexing Properties
Novel Tacrine-8-Hydroxyquinoline Hybrids as Multifunctional Agents for the Treatment of Alzheimer's Disease, with Neuroprotective, Cholinergic, Antioxidant, and Copper-Complexing Properties
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DOI：
10.1021/jm100329q
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发表时间：
2010-07-08
影响因子：
7.3
通讯作者：
Isabel Rodriguez-Franco, Maria
中科院分区：
文献类型：
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作者：
Isabel Fernandez-Bachiller, Maria;Perez, Concepcion;Isabel Rodriguez-Franco, Maria
他克林和 PBT2（一种 8-羟基喹啉衍生物）是众所周知的药物，它们分别通过与氧化还原活性金属络合来抑制胆碱酯酶并降低 β-淀粉样蛋白 (Aβ) 水平。在这项工作中，新型他克林-8-羟基喹啉杂化物被设计、合成并评估为治疗阿尔茨海默病的潜在多功能药物。在纳摩尔和亚纳摩尔浓度下，它们可抑制人乙酰胆碱酯酶和丁酰胆碱酯酶（AChE 和 BuChE），比他克林更有效。它们还取代了 AChE 外周阴离子位点的碘化丙啶，因此能够抑制 AChE 促进的 Aβ 聚集。它们表现出比 Trolox（维生素 E 中负责自由基捕获的芳香部分）更好的抗氧化特性，并显示出针对线粒体自由基的神经保护特性。此外，根据体外血脑屏障模型，它们选择性地络合 Cu(II)，显示出低细胞毒性，并且能够穿透中枢神经系统。
Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (A beta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer's disease. At nano- and subnanomolar concentrations they inhibit human acetyl- and butyrylcholinesterase (AChE and BuChE), being more potent than tacrine. They also displace propidium iodide from the peripheral anionic site of AChE and thus could be able to inhibit A beta aggregation promoted by AChE. They show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals. In addition, they selectively complex Cu(II), show low cell toxicity, and could be able to penetrate the CNS, according to an in vitro blood brain barrier model.