Molecular level studies of the ongoing battle between good and evil: antioxidants and oxidants

由所谓的活性氧（ROS）介导的生物分子（例如脂质、蛋白质、核酸和碳水化合物）的氧化几乎涉及每一种退行性疾病，从心血管疾病到阿尔茨海默病到癌症。这些氧化发生的机制通常是自由基反应，涉及具有一个（或多个）未配对电子的物质。这些活性中间体也参与工业材料的氧化，例如润滑油、燃料、橡胶和塑料-基本上每一种石油衍生材料。拟议的研究涉及两个方向的研究，最终目标是更好地了解氧化和抗氧化反应之间的平衡。第一个方向：阐明活性氧从生物分子产生并与生物分子反应的动力学和机制。在这一方向的研究活动范围从研究在线粒体中产生的ROS作为细胞呼吸的功能，从抗体产生的ROS作为免疫反应的一部分，到表征ROS与胆固醇的反应，负责形成高细胞毒性的胆固醇衍生化合物。第二个方向：进一步考虑自由基捕获抗氧化剂的动力学和机制，使得这些见解可用于设计用于工业和/或治疗应用的更有效的化合物。在这个方向上，目前特别感兴趣的是我们最先进的吡啶醇和嘧啶醇抗氧化剂在细胞环境中的进一步发展，以及植物衍生的硫代亚磺酸盐和工业中常用的芳香胺的研究。拟议的研究项目为未来的高素质人才提供了极好的培训机会，从而发展了有机合成的专业知识和反应机理的研究，使其能够应用于生物和工业化学中的问题。

The oxidation of biological molecules (e.g. lipids, proteins, nucleic acids and carbohydrates), mediated by so-called reactive oxygen species (ROS), has been implicated in virtually every degenerative disorder, ranging from cardiovascular disease to Alzheimer's to cancer. The mechanisms by which these oxidations occur are generally free radical reactions, involving species with one (or more) unpaired electron(s). These reactive intermediates are also involved in the oxidation of industrial materials, such as lubricating oils, fuels, rubbers and plastics - essentially every petroleum derived material. The proposed research involves studies aimed in two directions with the ultimate objective of a better understanding of the balance between oxidative and antioxidative reactions. The first direction: the elucidation of the kinetics and mechanisms by which ROS are generated from, and react with, biomolecules. The research activities in this direction span from studies on the generation of ROS in mitochondria as a function of cellular respiration, to the generation of ROS from antibodies as part of the immune response, to the characterization of reactions of ROS with cholesterol that are responsible for the formation of highly cytotoxic cholesterol-derived compounds. The second direction: further consideration of the kinetics and mechanisms of radical-trapping antioxidants, such that these insights can be used to design more effective compounds for industrial and/or therapeutic applications. Of particular current interest in this direction are the further development of our state-of-the-art pyridinol and pyrimidinol antioxidants in cellular contexts, as well as studies of plant-derived thiosulfinates and the aromatic amines commonly used in industry. The proposed research projects offer excellent training opportunities for future highly qualified personnel, leading to the development of expertise in organic synthesis and the interrogation of reaction mechanisms, such that they can be applied to problems in biological and industrial chemistry.