Design and synthesis of phenolic acid analogues as inhibitors of fatty acid metabolism

炎症是一种正常的防御机制，通过启动病原体杀伤和组织修复过程来保护宿主免受感染。然而，当炎症反应变得过度时，许多常见的情况和疾病就会发生，以炎性代谢物水平升高为特征的病理状态可能会发生。在这些代谢物中，有一种是由脂肪酸衍生的炎症的脂质介质。脂肪酸代谢通过多种机制影响炎症。阐明化合物抑制代谢脂肪酸的酶的作用方式是理解这些机制的一个有希望的策略。酚酸是一种分布广泛的天然化合物，将作为构建这些酶的特异性和高效抑制剂的基础。申请人的实验室所报告的一些基于酚酸的化合物的观察到的作用使他建议从这些简单和自然可用的化合物中创造和优化分子多样性。拟议的计划涉及合成和药物化学的方法学，同时还包括分子建模和与生物化学家的合作。在接下来的五年里，4名研究生和10名本科生将接受有机和药物化学艺术以及其他研究相关技能的高质量培训。除了提供强化的HQP培训外，该计划还将扩大可用于合成生物相关的酚酸类似物的方法的数量，这些方法对分子多样性的需求很大。致力于酚酸类化合物开发的药物化学界和人群将从拟议研究的这一方面的结果中受益。

Inflammation is a normal defence mechanism protecting the host from infections by the initiation of pathogen killing and tissue repair processes. However, many common conditions and diseases occur when the inflammatory response becomes excessive, and pathological states characterised by elevated levels of inflammatory metabolites can occur. Amongst these metabolites are lipid mediators of inflammation that are derived from fatty acids.Fatty acid metabolism influences inflammation through a variety of mechanisms. Elucidating the mode of action by which compounds inhibit enzymes that metabolize fatty acids is a promising strategy to understand these mechanisms. Phenolic acids, which are widely distributed natural compounds, will be used as building blocks to construct specific and efficient inhibitors of these enzymes. The observed action of some phenolic acid based compounds as reported by the applicant's laboratory led him to propose the creation and optimization of molecular diversity from these simple and naturally available compounds. The proposed program involves methodology in synthesis and medicinal chemistry while including molecular modeling and collaborations with biochemists. For the next five years, 4 graduate and 10 undergraduate students will receive high quality training in the art of organic and medicinal chemistry, and other research related skills. In addition to imparting intensive HQP training, this program will expand the number of approaches available for the synthesis of biologically relevant analogues of phenolic acids where molecular diversity is in great demand. The medicinal chemistry community working on the development of phenolic acid based compounds and the population will benefit from the outcome of this aspect of the proposed research.