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

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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.