Department of Biology, Lewis University, One University Pkwy, Romeoville, IL, 60446, USA.
Department of Chemistry, Lewis University, One University Pkwy, Romeoville, IL, 60446, USA.
J Biol Inorg Chem. 2023 Oct;28(7):643-653. doi: 10.1007/s00775-023-02013-1. Epub 2023 Aug 18.
There is currently an unmet demand for multi-functional precision treatments for Alzheimer's disease (AD) after several failed attempts at designing drugs based on the amyloid hypothesis. The focus of this work is to investigate sulfur-bridged quinoline ligands that could potentially be used in chelation therapies for a subpopulation of AD patients presenting with an overload of labile copper ions, which are known to catalyze the production of reactive oxygen species (ROS) and exacerbate other markers of AD progression. The ligands 1-(2'-thiopyridyl)isoquinoline (1TPIQ) and 2-(2'-thiopyridyl)quinoline (2TPQ) were synthesized and characterized before being electrochemically investigated in the presence of different oxidizing and reducing agents in solution with a physiological pH relevant to the brain. The electrochemical response of each compound with copper was studied by employing both hydrogen peroxide (HO) as an oxidizing agent and ascorbic acid (AA) as an antioxidant during analysis using cyclic voltammetry (CV). The cyclic voltammograms of each quinoline were compared with similar ligands that contained aromatic N-donor groups but no sulfur groups to provide relative electrochemical properties of each complex in solution. In a dose-dependent manner, it was observed that AA exerted dual-efficacy when combined with these chelating ligands: promoting synergistic metal binding while also scavenging harmful ROS, suggesting AA is an effective adjuvant therapeutic agent. Overall, this study shows how coordination by sulfur-bridged quinoline ligands can alter copper electrochemistry in the presence of AA to limit ROS production in solution.
目前，基于淀粉样蛋白假说设计药物的多次尝试都以失败告终，因此对阿尔茨海默病（AD）的多功能精准治疗存在未满足的需求。这项工作的重点是研究硫桥喹啉配体，这些配体可能用于螯合治疗具有不稳定铜离子过载的 AD 患者亚群，已知这些铜离子会催化活性氧（ROS）的产生，并加剧 AD 进展的其他标志物。合成并表征了配体 1-(2'-噻吡啶基)异喹啉（1TPIQ）和 2-(2'-噻吡啶基)喹啉（2TPQ），然后在生理 pH 值相关的脑溶液中，在存在不同氧化还原试剂的情况下进行电化学研究。通过使用过氧化氢（HO）作为氧化剂和抗坏血酸（AA）作为抗氧化剂在分析中使用循环伏安法（CV）研究了每个化合物与铜的电化学响应。将每个喹啉的循环伏安图与含有芳香 N-供体基团但不含硫基团的类似配体进行了比较，以提供每个络合物在溶液中的相对电化学性质。结果表明，AA 以剂量依赖的方式与这些螯合配体结合时表现出双重功效：促进协同金属结合，同时清除有害的 ROS，这表明 AA 是一种有效的辅助治疗剂。总的来说，这项研究表明，硫桥喹啉配体的配位如何在 AA 存在的情况下改变铜的电化学性质，从而限制溶液中 ROS 的产生。
