Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
Metallomics. 2011 Mar;3(3):284-91. doi: 10.1039/c0mt00077a. Epub 2011 Jan 6.
Metal ions associated with amyloid-β (Aβ) species have been suggested to be involved in neurodegeneration leading to the progression of Alzheimer's disease (AD). The role of metal-involved Aβ 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 Aβ 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 Aβ interaction) was confirmed. These bifunctional IMPY derivatives showed preferential reactivity toward metal-induced Aβ 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 Aβ species.
金属离子与淀粉样蛋白-β（Aβ）物种的结合被认为与神经退行性变有关，导致阿尔茨海默病（AD）的进展。然而，金属参与的 Aβ物种在 AD 神经发病机制中的作用尚未完全阐明。为了深入了解这一点，并为 AD 的治疗开发做出贡献，最近人们越来越关注基于合理结构设计的、专门针对 Aβ物种周围金属离子的小分子。迄今为止，为此目的设计的化合物还很少。在此，我们报告了新型双功能 IMPY 衍生物 K1 和 K2 的设计策略、合成、表征和反应性。通过紫外可见光谱和高分辨率二维（2D）NMR 光谱，证实了 K1 和 K2 的双功能性（金属螯合和 Aβ相互作用）。在体外抑制和去聚集实验中，这些双功能 IMPY 衍生物在金属诱导的 Aβ聚集方面表现出比金属自由条件下更高的反应活性。综上所述，这项研究提供了另一个可以针对与 Aβ物种相关的金属离子的双功能小分子框架的例子。
