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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710380
• 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 -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主要导致所有化石燃料衍生的产品（例如润滑剂，橡胶，塑料和特种化学品）的恶化。因此，抑制自氧化的添加剂 - 抗氧化剂（AOS）是化学工业必不可少的一部分。尽管必须将大量的AO（重量为1-15％）添加到石油衍生产品中，以确保它们具有有用的终生，但工业AO技术的创新已经停滞了一段时间。缺乏重大的新事态发展可以追溯到缺乏必要的情况：化石燃料长期以来一直被视为一种无限资源，并最大程度地提高了它们的使用效率并不是当务之急。显然，这种观点已经改变。我们建议利用我们小组的最新机械见解来开发新型的AO，这些AO在广泛的条件下表现出催化效率。这将使新技术的设计通过最大限度地提高其从中衍生的产品的寿命来最大程度地减少化石燃料消耗，并允许设计更有效的燃烧发动机，目前，该发动机在所需的较高温度下受到过度润滑的润滑氧化的限制。 碳氢化合物自氧化也与生物体中的衰老，癌症和退化性疾病（DD）有关。因此，据信抗氧化剂（AOS）在人类健康中起关键的预防作用。长期以来，流行病学研究表明，饮食中富含AOS的人群的寿命增加和DD的发展降低，但临床研究很少支持AOS在治疗和/或预防DD中的作用。关于AOS的绝大多数临床研究都检查了天然产物，例如维生素E，维生素C和 - 胡萝卜素（> 2000条目出现在这三种的在线NIH临床试验数据库中！）。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，因为尚未确定更好的选择。我们建议提供更好的选择，以促进该悖论的解决。具体而言，我们旨在对新发现的脂质氧化抑制剂进行动力学和机械研究，以指导针对临床候选者的进一步优化。此外，我们旨在根据我们对工业环境中AO活动的基本研究来设计和开发全新的化合物，以抑制铁毒性。最后，我们建议确定与生理相关的固醇氧化机制，以建立特定的铁毒细胞死亡的生物标志物，以阐明DD病原体中自氧化，牛roptsis及其抑制之间的联系。