Mechanisms of Peroxyl Radical Addition Reactions

在这项由化学系化学结构、动态和机理B计划资助的项目中，华盛顿大学药物化学系的徐立斌教授旨在开发化学工具来了解具有生物重要性的脂质氧化的反应活性和反应机理。了解脂质过氧化的基础化学具有广泛的影响，因为脂质过氧化在人类病理中发挥着重要作用，如衰老、动脉粥样硬化和退行性疾病。该项目位于物理有机化学和生物有机化学的交界处，利用现代分析化学技术，非常适合不同培训背景的科学家的教育。该研究小组还旨在将教育与研究计划相结合，通过向高中生和教师宣传脂质过氧化知识，并吸引来自不同背景的本科生进入研究领域。脂质过氧化的速率决定步骤是过氧基的传播步骤，通常发生两种类型的反应：a)氢原子从给体转移到过氧基；b)过氧基与碳-碳双键的加成。氢原子转移机理已经得到了很好的研究，但对过氧基-自由基加成反应的反应性和产物却知之甚少。这个项目的目的是阐明控制过氧基与双键加成的反应活性的因素，以及这一机制对一些生物重要脂质过氧化的贡献，包括胆固醇生物合成前体、脂溶维生素和多不饱和脂肪酸。研究目的有三个：1)建立自由基时钟，测量氢原子转移和过氧基自由基加成反应的速率常数；2)评价控制过氧基双键加成反应的因素；3)阐明生物重要脂质自由基过氧化的产物和反应机理。

In this project, funded by the Chemical Structure, Dynamic & Mechanism B Program of the Chemistry Division, Professor Libin Xu of the Department of Medicinal Chemistry at the University of Washington aims to develop chemical tools to understand the reactivities and reaction mechanisms of oxidation of biologically important lipids. Understanding the fundamental chemistry underneath lipid peroxidation has broad impacts because lipid peroxidation plays significant roles in human pathologies, such as aging, atherosclerosis, and degenerative diseases. The project lies at the interface of physical organic chemistry and bioorganic chemistry and utilizes modern analytical chemistry techniques, and is well suited to the education of scientists with different training backgrounds. This research group also aims to integrate education with the research plan by disseminating the knowledge of lipid peroxidation through outreach to high school students and teachers and attracting undergraduates from diverse backgrounds to the research field. The rate-determining step in lipid peroxidation is the propagation step of the peroxyl radical, where generally two types of reactions occur: a) hydrogen-atom transfer from a donor to the peroxyl radical; b) peroxyl-radical addition to a carbon-carbon double bond. The hydrogen-atom transfer mechanism is well studied, but much less is known about the reactivities and products of peroxyl-radical addition reactions. The goal of this project is to elucidate factors governing the reactivity of peroxyl-radical addition to a double bond and the contribution of this mechanism to peroxidation of a number of biologically important lipids, including cholesterol biosynthetic precursors, fat-soluble vitamins, and polyunsaturated fatty acids. There are three research objectives: 1) Establish a "radical clock" to measure the rate constants of both hydrogen-atom transfer and peroxyl-radical addition; 2) Evaluate factors controlling the reactivities of peroxyl-radical addition to a double bond; 3) Elucidate the products and reaction mechanisms of free radical peroxidation of biologically important lipids.