Kwak Jimin, Yi Yelim, Park Seongmin, Lim Mi Hee
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) Daejeon 34141 Republic of Korea
Chem Sci. 2024 Dec 3;16(2):889-900. doi: 10.1039/d4sc06417h. eCollection 2025 Jan 2.
Designing multi-target chemical tools is a vital approach to understanding the pathology of Alzheimer's disease (AD), which involves a complex network of pathological factors, such as free organic radicals, amyloid-β (Aβ), and metal-bound Aβ (metal-Aβ). The pyrogallol moiety, known for its ability to lower redox potentials and interact with both Aβ and metal ions, presents a promising framework for this molecular design. Here we show how simple structural variations of pyrogallol can be used to enhance its ability to scavenge free organic radicals and regulate the aggregation of both metal-free Aβ and metal-Aβ. By incorporating multiple pyrogllol units into a macrocyclic scaffold methylene bridges, we achieve synergistic reactivity against several pathological targets. Our structure-reactivity relationship studies also reveal that the macrocyclic structure noticeably improves antioxidant activity as well as interactions with both Aβ and metal ions, leading to oxidation of Aβ peptides and influencing their conformation and aggregation in both the absence and presence of metal ions. This work demonstrates the potential of simple redox-active structural entities in developing multifunctional chemical reagents that effectively manage the pathological components associated with AD.
设计多靶点化学工具是理解阿尔茨海默病（AD）病理学的重要方法，AD涉及一个复杂的病理因素网络，如游离有机自由基、淀粉样β蛋白（Aβ）和金属结合的Aβ（金属-Aβ）。邻苯三酚部分以其降低氧化还原电位以及与Aβ和金属离子相互作用的能力而闻名，为这种分子设计提供了一个有前景的框架。在此，我们展示了邻苯三酚的简单结构变化如何用于增强其清除游离有机自由基的能力，并调节无金属Aβ和金属-Aβ的聚集。通过将多个邻苯三酚单元并入大环支架亚甲基桥中，我们实现了对多个病理靶点的协同反应性。我们的结构-反应性关系研究还表明，大环结构显著提高了抗氧化活性以及与Aβ和金属离子的相互作用，导致Aβ肽氧化，并在有无金属离子的情况下影响其构象和聚集。这项工作证明了简单的氧化还原活性结构实体在开发有效管理与AD相关病理成分的多功能化学试剂方面的潜力。
