Exploring the reactivity of flavonoid compounds with metal-associated amyloid-β species.
Exploring the reactivity of flavonoid compounds with metal-associated amyloid-β species.
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DOI：
10.1039/c2dt12207c
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发表时间：
2012-06-07
期刊：
影响因子：
--
通讯作者：
Lim MH
中科院分区：
文献类型：
--
作者：
He X;Park HM;Hyung SJ;DeToma AS;Kim C;Ruotolo BT;Lim MH
与淀粉样蛋白-β (Aβ) 肽相关的金属离子被认为与阿尔茨海默病 (AD) 的发展有关，但这仍然不清楚且存在争议。为了更好地理解该假设，人们尝试合理设计或选择具有金属螯合和 Aβ 相互作用（即双功能）结构部分的小分子。为了为这些努力做出贡献，根据双功能原理合理选择了四种合成黄酮衍生物FL1 – FL4，并利用物理方法和生物测定研究了它们螯合金属离子、与Aβ相互作用、抑制金属诱导的Aβ聚集、清除自由基和调节活性氧（ROS）形成的能力。化合物 FL1 – FL3 能够螯合金属离子，但在缓冲水溶液中溶解度有限。对于与水性条件最相容的 FL4，通过溶液形态研究获得了其对 Cu2+ 和 Zn2+ 的结合亲和力（分别为 nM 和 μM）。通过核磁共振波谱和质谱监测，FL4 和 Aβ 单体之间的直接相互作用很弱。使用 FL1 – FL4，没有观察到对金属介导的 Aβ 聚集的明显抑制作用。在FL1 – FL4中，FL3具有3-OH、4-氧代和4'-N(CH3)2基团，表现出与维生素E类似物Trolox和ca相似的抗氧化活性。在氧气 (O2) 和还原剂存在下，Cu2+-Aβ 产生的过氧化氢 (H2O2) 量减少 60%。总体而言，这里的研究表明，尽管根据预期的双功能性选择了四种黄酮类分子，但它们的性质和金属-Aβ反应性根据结构差异而变化，这表明必须很好地调整双功能性才能提供所需的反应性。
Metal ions associated with amyloid-β (Aβ) peptides have been suggested to be involved in the development of Alzheimer’s disease (AD), but this remains unclear and controversial. Some attempts to rationally design or select small molecules with structural moieties for metal chelation and Aβ interaction (i.e., bifunctionality) have been made to gain a better understanding of the hypothesis. In order to contribute to these efforts, four synthetic flavonoid derivatives FL1 – FL4 were rationally selected according to the principles of bifunctionality and their abilities to chelate metal ions, interact with Aβ, inhibit metal-induced Aβ aggregation, scavenge radicals, and regulate the formation of reactive oxygen species (ROS) were studied using physical methods and biological assays. The compounds FL1 – FL3 were able to chelate metal ions, but showed limited solubility in aqueous buffered solutions. In the case of FL4, which was most compatible with aqueous conditions, its binding affinities for Cu2+ and Zn2+ (nM and μM, respectively) were obtained through solution speciation studies. The direct interaction between FL4 and Aβ monomer was weak, which was monitored by NMR spectroscopy and mass spectrometry. Employing FL1 – FL4, no noticeable inhibitory effect on metal-mediated Aβ aggregation was observed. Among FL1 – FL4, FL3, having 3-OH, 4-oxo, and 4′-N(CH3)2 groups, exhibited similar antioxidant activity to the vitamin E analogue, Trolox, and ca. 60% reduction in the amount of hydrogen peroxide (H2O2) generated by Cu2+-Aβ in the presence of dioxygen (O2) and a reducing agent. Overall, the studies here suggest that although four flavonoid molecules were selected based on expected bifunctionality, their properties and metal-Aβ reactivity were varied depending on the structure differences, demonstrating that bifunctionality must be well tuned to afford desirable reactivity.
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影响因子：
20.6
作者：
Alderighi, L;Gans, P;Vacca, A
通讯作者：
Vacca, A
影响因子：
--
作者：
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Lim MH
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Lim MH
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作者：
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作者：
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通讯作者：
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