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

善与恶之间持续斗争的分子水平研究：抗氧化剂和氧化剂

• 批准号: 315330-2011
• 负责人: Pratt, Derek
• 金额: $ 3.28万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=548864
• 关键词: Molecular; level; studies; ongoing; battle

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.

生物分子（如脂质、蛋白质、核酸和碳水化合物）的氧化，由所谓的活性氧（ROS）介导，几乎与所有退行性疾病有关，从心血管疾病到阿尔茨海默病再到癌症。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，如润滑油、燃料、橡胶和塑料——基本上是每一种石油衍生材料。拟议的研究涉及两个方向的研究，最终目的是更好地理解氧化和抗氧化反应之间的平衡。第一个方向：阐明ROS从生物分子中产生和与生物分子反应的动力学和机制。这一方向的研究活动包括研究线粒体中ROS的生成作为细胞呼吸的功能，从抗体产生ROS作为免疫反应的一部分，到ROS与胆固醇的反应表征，这些反应负责形成高细胞毒性胆固醇衍生化合物。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，这样这些见解可以用于设计更有效的化合物，用于工业和/或治疗应用。在这个方向上，目前特别感兴趣的是进一步开发我们最先进的细胞环境中的吡啶醇和嘧啶醇抗氧化剂，以及研究植物衍生的硫代亚硫酸盐和工业中常用的芳香胺。拟议的研究项目为未来的高素质人员提供了极好的培训机会，导致有机合成和反应机制研究方面的专门知识的发展，以便将其应用于生物和工业化学问题。