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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

8-羟基喹啉作为多靶点定向配体治疗阿尔茨海默氏病的生物学评估

卷 16, 期 9, 2019

页: [801 - 814] 页: 14

弟呕挨: 10.2174/1567205016666191010130351

价格: $65

摘要

背景：越来越多的证据表明，多靶标定向配体在治疗复杂疾病（例如阿尔茨海默氏病（AD））方面具有巨大潜力。 目的：评价新型嵌合的8-羟基喹啉配体与合并的药效团作为AD的潜在多功能配体。 方法：体外评估了硝基氧代林，PBT2和化合物2-4对组织蛋白酶B，胆碱酯酶和单胺氧化酶的抑制作用。此外，通过基于光谱的分析评估了螯合，抗氧化性能和血脑屏障（BBB）的渗透性，并在免疫分析中确定了对淀粉样β（Aβ）聚集的抑制作用。进行基于细胞的测定以确定细胞毒性，针对毒性Aβ物种的神经保护作用以及化合物2对凋亡级联反应的影响。 结果：化合物2-4竞争性抑制组织蛋白酶Bβ-分泌酶活性，螯合金属离子并且是弱抗氧化剂。根据平行人工膜通透性测定，所有化合物均抑制Aβ聚集，而仅化合物2具有良好的BBB通透性。测试的配体2和3对10μM的SH-SY5Y和HepG2细胞无细胞毒性。化合物2对Aβ毒性具有神经保护作用，减少了caspase-3 / 7的活化并减少了用Aβ1-42处理的细胞的凋亡。 结论：综上所述，我们的数据表明化合物2有望用作AD的多功能配体。

关键词: 8-羟基喹啉，PBT2，硝基氧杂环丁烷，多目标定向配体（MTDL），阿尔茨海默氏病，组织蛋白酶B抑制，金属螯合，神经保护活性。

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