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

自由基氧化：从化石燃料衍生产品到生命物质的战斗

• 批准号: RGPIN-2016-06741
• 负责人: Pratt, Derek
• 金额: $ 6.63万
• 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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=662583
• 关键词: Free; Radical; Oxidation; Taking; Battle

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 β-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.**

碳氢化合物的自由基氧化是所有化石燃料衍生产品（例如润滑剂、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（AO）——是化学工业中不可或缺的一部分。尽管必须在石油衍生产品中添加大量 AO（按重量计 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：长期以来，化石燃料一直被视为无限的资源，最大限度地提高其使用效率并不是一个优先事项。显然，这种观点已经改变。我们建议利用我们小组最新的机理见解来开发新型 AO，在广泛的条件下表现出催化效率。这将使新技术的设计能够通过最大限度地延长由此衍生的产品的寿命来最大限度地减少化石燃料消耗，并允许设计更高效的内燃机，而目前内燃机在所需的较高温度下受到禁止性润滑剂氧化的限制。***碳氢化合物自氧化还与生物体的衰老、癌症和退行性疾病（DD）有关。因此，抗氧化剂（AO）被认为在人类健康中发挥着关键的预防作用。流行病学研究早已证明，饮食中富含所谓 AO 的人群可以延长寿命并减少 DD 的发生，但临床研究很少支持 AO 在治疗和/或预防 DD 中的作用。绝大多数关于 AO 的临床研究都检查了维生素 E、维生素 C 和 β-胡萝卜素等天然产品（NIH 在线临床试验数据库中仅针对这三种物质就出现了超过 2000 条条目！）。尽管有明确的证据表明它们不是理想的 AO，但对这些（和其他）天然产品的临床研究仍在继续，因为尚未找到更好的选择。我们建议提供更好的选择来帮助解决这一悖论。具体来说，我们的目标是对新发现的脂质氧化相关细胞死亡（铁死亡）抑制剂进行动力学和机制研究，以指导临床候选药物的进一步优化。此外，我们的目标是基于我们对工业环境中 AO 活性的基础研究，设计和开发全新的化合物来抑制铁死亡。最后，我们建议确定甾醇氧化的生理相关机制，以便建立铁死亡细胞死亡的特异性生物标志物，最终目标是阐明自氧化、铁死亡及其在 DD 发病机制中的抑制之间的联系。 **