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

碳氢化合物的自由基氧化是所有化石燃料衍生产品（如润滑剂、橡胶、塑料和特种化学品）变质的主要原因。因此，抑制自氧化的添加剂——抗氧化剂（AOs）——是化学工业不可缺少的一部分。虽然必须在石油衍生产品中添加大量的AO（按重量计为1-15%）以确保其使用寿命，但工业AO技术的创新已经停滞了一段时间。缺乏重大的新发展可以追溯到人们认为缺乏必要性：化石燃料长期以来一直被视为一种无限的资源，最大限度地提高它们的使用效率一直不是一个优先事项。显然，这种观点已经改变。我们建议利用我们小组最近的机制见解来开发在广泛条件下表现出催化效率的新型AOs。这将使新技术的设计能够通过最大限度地延长衍生产品的使用寿命来最大限度地减少化石燃料的消耗，并允许设计更有效的内燃发动机，而目前的限制是在所需的更高温度下禁止润滑剂氧化。

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 ß-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.