Development of bifunctional stilbene derivatives for targeting and modulating metal-amyloid-β species.
Development of bifunctional stilbene derivatives for targeting and modulating metal-amyloid-β species.
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DOI：
10.1021/ic2012205
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发表时间：
2011-11-07
影响因子：
4.6
通讯作者：
Lim MH
中科院分区：
文献类型：
--
作者：
Braymer JJ;Choi JS;DeToma AS;Wang C;Nam K;Kampf JW;Ramamoorthy A;Lim MH
淀粉样蛋白β（Aβ）肽及其金属相关的综合态已在阿尔茨海默氏病的发病机理中实现，尽管AD的病因仍然不确定，但了解金属Aβ物种的作用可以提供对发作和发作的见解疾病的发展。通过合理结构的设计原理研究金属Aβ相关事件的工具，涉及将金属结合位点掺入Aβ相互作用分子的结构，我们设计了Silbene衍生物（L1-A和L1-A）和尤其是对金属Aβ物种的反应性。 UV-VIS，X射线晶体学，高分辨率2D NMR和对接研究。通过UV-VIS和2D NMR，具有Zn2+-Aβ物种的L1-B表明，与Aβ肽的配体和/或金属配体相互作用的金属螯合可能是驱动因素观察到的金属Aβ聚集途径的调制总体上，此处介绍的研究表明，结构相互作用的关系对于设计小分子以靶向金属Aβ物种的重要性，从而可以调节金属诱导的Aβ反应性和神经毒性。
Amyloid-β (Aβ) peptides and their metal-associated aggregated states have been implicated in the pathogenesis of Alzheimer’s disease (AD). Although the etiology of AD remains uncertain, understanding the role of metal-Aβ species could provide insights into the onset and development of the disease. To unravel this, bifunctional small molecules that can specifically target and modulate metal-Aβ species have been developed, which could serve as suitable chemical tools for investigating metal-Aβ-associated events in AD. Through a rational structure-based design principle involving the incorporation of a metal binding site into the structures of Aβ interacting molecules, we devised stilbene derivatives (L1-a and L1-b) and demonstrated their reactivity toward metal-Aβ species. In particular, the dual functions of compounds with different structural features (e.g., with or without a dimethylamino group) were explored by UV-vis, X-ray crystallography, high-resolution 2D NMR, and docking studies. Enhanced bifunctionality of compounds provided greater effects on metal-induced Aβ aggregation and neurotoxicity in vitro and in living cells. Mechanistic investigations of the reaction of L1-a and L1-b with Zn2+-Aβ species by UV-vis and 2D NMR suggest that metal chelation with ligand and/or metal-ligand interaction with the Aβ peptide may be driving factors for the observed modulation of metal-Aβ aggregation pathways. Overall, the studies presented herein demonstrate the importance of a structure-interaction-reactivity relationship for designing small molecules to target metal-Aβ species allowing for the modulation of metal-induced Aβ reactivity and neurotoxicity.
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影响因子：
--
作者：
Braymer JJ;Detoma AS;Choi JS;Ko KS;Lim MH
通讯作者：
Lim MH
影响因子：
46.2
作者：
DeToma AS;Salamekh S;Ramamoorthy A;Lim MH
通讯作者：
Lim MH
影响因子：
3.9
作者：
Deraeve, Celine;Pitie, Marguerite;Meunier, Bernard
通讯作者：
Meunier, Bernard
影响因子：
2.9
作者：
Garrett, DS;Seok, YJ;Gronenborn, AM
通讯作者：
Gronenborn, AM
影响因子：
3.4
作者：
Choi, Jung-Suk;Braymer, Joseph J.;Lim, Mi Hee
通讯作者：
Lim, Mi Hee