Free Radical Oxidation: Taking the Battle from Fossil Fuel-Derived Products to Living Matter

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The free radical oxidation of hydrocarbons is primarily responsible for the deterioration of all fossil fuel-derived products (e.g. lubricants, rubbers, plastics and specialty chemicals). Accordingly, additives that inhibit autoxidation - antioxidants (AOs) - are an indispensable part of the chemical industry. Although substantial quantities of AO (1-15% by weight) must be added to petroleum-derived products to ensure they have a useful lifetime, innovation in industrial AO technology has been stagnant for some time. The lack of significant new developments can be traced to a perceived lack of necessity: fossil fuels have long been viewed as an infinite resource and maximizing how efficiently they are used has not been a priority. Clearly, this view has changed. We propose to utilize recent mechanistic insights made by our group to develop novel AOs that exhibit catalytic efficiency under a broad range of conditions. This will enable the design of new technology to minimize fossil fuel consumption by maximizing the life of products derived therefrom, and permit the design of more efficient combustion engines, which is currently limited by prohibitive lubricant oxidation at the higher temperatures which are required. Hydrocarbon autoxidation has also been implicated in aging, cancer and degenerative disease (DD) in living organisms. Accordingly, antioxidants (AOs) are believed to play key preventive roles in human health. Epidemiological studies have long demonstrated increased longevity and decreased DD development in populations where diets are rich in purported AOs, but clinical studies rarely support a role for AOs in the treatment and/or prevention of DD. The overwhelming majority of clinical studies on AOs have examined natural products such as Vitamin E, Vitamin C and -carotene (>2000 entries appear in the online NIH clinical trials database for these three alone!). Despite clear evidence that they are not ideal AOs, clinical studies on these (and other) natural products continue because better options have yet to be identified. We propose to provide better options to contribute to a resolution of this paradox. Specifically, we aim to carry out kinetic and mechanistic studies on newly discovered inhibitors of lipid oxidation associated cell death (ferroptosis) in order to guide further optimization for clinical candidates. Moreover, we aim to design and develop completely new compounds to inhibit ferroptosis based on our fundamental studies of AO activity in industrial contexts. Finally, we propose to determine physiologically-relevant mechanisms of sterol oxidation in order to establish specific biomarkers of ferroptotic cell death, with the ultimate objective of clarify the link between autoxidation, ferroptsis and its inhibition in the pathogenesis of DD.