Synthesis and characterization of IMPY derivatives that regulate metal-induced amyloid-β aggregation
Synthesis and characterization of IMPY derivatives that regulate metal-induced amyloid-β aggregation
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DOI：
10.1039/c0mt00077a
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发表时间：
2011-01-01
期刊：
影响因子：
3.4
通讯作者：
Lim, Mi Hee
中科院分区：
文献类型：
--
作者：
Choi, Jung-Suk;Braymer, Joseph J.;Lim, Mi Hee
与淀粉样β（β）物种相关的金属离子已被认为与神经变性有关，导致阿尔茨海默氏病的发展（AD）。然而，金属涉及β物种在AD神经病发生中的作用尚未完全阐明。为了促进这种理解并有助于AD的治疗发展，基于理性的小分子的设计专门针对被β种包围的金属离子的设计，最近受到了越来越多的关注。迄今为止，为此目的仅制定了几种化合物。在此，我们报告了新的双功能衍生物K1和K2的设计策略，合成，表征和反应性。使用UV-VIS和高分辨率二维（2D）NMR光谱，确认K1和K2（金属螯合和AB相互作用）的双函数。在体外抑制和分解实验中，这些双功能的iNMING衍生物对金属诱导的β诱导的β诱导的聚集的优先反应性比无金属条件。综上所述，这项研究提供了一个双功能小分子框架的另一个例子，该框架可以针对与β物种相关的金属离子。
Metal ions associated with amyloid-beta (A beta) species have been suggested to be involved in neurodegeneration leading to the progression of Alzheimer's disease (AD). The role of metal-involved A beta species in AD neuropathogenesis, however, is not fully elucidated. In order to advance this understanding and contribute to the therapeutic development for AD, the rational structure-based design of small molecules that specifically target metal ions surrounded by A beta species has recently received increased attention. To date, only a few compounds have been fashioned for this purpose. Herein, we report the design strategy, synthesis, characterization, and reactivity of new bifunctional IMPY derivatives K1 and K2. Using UV-vis and high-resolution two-dimensional (2D) NMR spectroscopy, the bifunctionality of K1 and K2 (metal chelation and Ab interaction) was confirmed. These bifunctional IMPY derivatives showed preferential reactivity toward metal-induced A beta aggregation over metal-free conditions in both in vitro inhibition and disaggregation experiments. Taken together, this study provides another example of a bifunctional small molecule framework that can target metal ions associated with A beta species.