Binuclear Copper-O2 Intermediates: Thermodynamic and Mechanistic Insights

项目概要： 与分子氧反应的铜酶对我们的生活至关重要，特别是在转化 生物分子从一种形式转变为另一种形式。然而，在高代谢活动的区域，如大脑， 铜资源的管理不善被认为会导致偶然结合的铜， 分子氧以形成活性分子氧物质（ROS），其导致重要的 生物分子，最终导致衰弱的神经系统疾病。定义连接环境 而偶然结合的铜能够产生ROS的机制是我们的首要目标。 由于铜是生物学中所有氧化还原活性金属中最不稳定的，因此定义了导致这种氧化还原活性的配位。 ROS是一个挑战。铜与分子氧的高度受控配位反应机理 环境，如蛋白质或小铜络合物，提供了一个逻辑起点，以定义什么是 化学上可能的，或者如果不是在不太确定的、管理不善的条件下化学上可能的。我们 假设对分子氧活化和氧化反应性的机械理解将告知如何 最好是在管理不善的铜站点减弱ROS的产生。更具体地说，双核铜位点， 激活O2和氧化困难的底物将进行深入研究。我们使用综合方法， 结构相关的低分子量复合物具有忠实的结构关系， 在小分子水平上详细检查生物位点的氧化反应性，以揭示内在的 结构、电子和性质。由于我们的工作缺乏生物系统的上层建筑，我们使用 极低的溶液温度进行研究。操作的前提是， 将提供重要的机制见解的氧化（Cu（I）+ O2）和还原（Cu-O2 +底物）半- 如果适当的注意力被引导到产生适当的铜连接， 环境.

Project Summary: Copper enzymes that react with dioxygen are essential to our lives especially with respect to transforming biological molecules from one form to another. Yet, in areas of high metabolic activity such as the brain, mismanagement of copper resources is thought to lead to adventitiously bonded copper that reacts with dioxygen to form reactive dioxygen species (ROS) that lead to uncontrolled oxidative degradation of important biological molecules, ultimately leading to debilitating neurological diseases. Defining the ligation environment and the mechanism by which adventitiously bonded copper is able to create ROS is our overarching objective. As copper is the most labile of all redox active metals in biology, defining the coordination that leads to such ROS is challenging. Mechanisms of the reaction of copper with dioxygen in highly controlled coordination environments, such as proteins or in small copper complexes, provide a logical starting point to define what is chemically possible or if not what is chemically probable under less-defined, mismanaged conditions. We postulate that a mechanistic understanding of dioxygen activation and oxidative reactivity will inform on how best to attenuate ROS production at mismanaged copper sites. More specifically, binuclear copper sites that activate O2 and oxidize difficult substrates will be investigated in depth. We use a synthetic approach in our research whereby structurally-related low molecular weight complexes having faithful structural relationships to biological sites are examine for their oxidative reactive at a small molecule level of detail to reveal intrinsic structural, electronic, and properties. As our work lacks the superstructure of the biological systems, we use extremely low solution temperature to perform the investigation. The operating premise is that such complexes will provide important mechanistic insights to the oxidative (Cu(I) + O2) and reductive (Cu-O2 + substrate) half- reactions of biological systems if appropriate attention is directed to creating appropriate copper ligation environments.