FREE RADICALS, MEMBRANES, AND ENZYME PHOTOACTIVATION

该提案涉及与人类健康有关的几个重要问题。 和疾病状态。脂质过氧化与肿瘤有关 转化、氧毒性和老化色素的形成。这个 还建议对膜和蛋白质结构进行修饰。 是由自由基的破坏性作用造成的。正因为如此 对氧和自由基毒性的兴趣，脂质的机制 过氧化一直是人们关注的焦点，但仍有 这个问题尚未解决的重要方面。这项建议 解决了与自氧化机制有关的几个问题 类固醇和脂肪酸。高效液-质联用技术将在本研究中得到广泛应用 因为我们已经展示了这种技术特别强大，因为 适用于类固醇和油酸盐过氧化。免费的第二个方面 这项提议涉及的激进化学是对 自由基反应中的立体化学。我们有证据表明 自由基C=C的立体化学控制的一般问题 通过在目标上使用酰胺助剂可以解决加成反应 烯烃碳和自由基中心上的加成反应。这个 在自由基加成反应中发现显著的立体化学控制 考虑迭代自由基过程，例如 齐聚反应，用于构建具有多个 一个反应序列中的立体中心。模板自由基 还提出了使用类固醇模板进行大环化反应 构建长度确定的低聚物。第三个问题是，这 提案涉及的是光可逆丝氨酸的设计和使用 蛋白酶抑制剂。这些很可能在以下方面提供有价值的研究工具 通过将酶的活性囚禁到 光子释放催化的活性部位。我们的战略也可能 为控制重要的血液凝固级联提供了一种新的方法。 我们还将讨论分子如何聚集这一重要问题 例如胶束和脂双层可能会影响有机反应性。 这个问题将通过设计从根本上解决 光学纯三脚架表面活性剂分子的合成。手性 分子聚集体中的识别和底物-模板反应 也可以用这些三脚架分子来研究。

This proposal addresses several important issues relating to human health and disease states. Lipid peroxidation has been implicated in neoplastic transformations, oxygen toxicity, and the formation of age pigments. The modification of membrane and protein structure are also suggested to result from the destructive effects of free radicals. Because of this interest in oxygen and radical toxicity, the mechanism of lipid peroxidation has been the focus of much attention, but there are still important aspects of this problem that are unsolved. This proposal addresses several questions relating to the mechanism of autoxidation of steroids and fatty acids. HPLC/MS will be used extensively in this study because we have shown this technique to be particularly powerful as applied to steroid and oleate peroxidation. A second aspect of free radical chemistry that this proposal addresses is the control of stereochemistry in free radical reactions. We have evidence suggesting that the general problem of stereochemical control in radical C=C addition reactions can be solved by using amide auxiliaries on the target alkene carbon and on the radical center undergoing addition. The discovery of significant stereochemical control in radical addition leads to consideration of iterative free radical processes, such as oligomerizations, for construction of compounds with multiple stereocenters in one reaction sequence. Template radical macrocyclization is also proposed using steroid templates for constructing oligomers of well defined length. A third problem that this proposal addresses is the design and use of photoreversible serine protease inhibitors. These may well provide a valuable research tool in studying enzyme mechanisms by serving to cage the enzyme activity until a photon releases the active site for catalysis. Our strategy may also provide a novel way to control the important blood coagulation cascade. We will also address the important question of how molecular aggregates such as micelles and lipid bilayers may influence organic reactivity. This problem will be approached at the fundamental level via the design synthesis of optically pure tripod surfactant molecules. Chiral recognition and substrate-template reactions in molecular aggregates will also be investigated with these tripod molecules.