FREE RADICALS, MEMBRANES, AND ENZYME PHOTOACTIVATION

这项建议涉及到与人类健康有关的几个重要问题 和疾病状态。 脂质过氧化作用与肿瘤 转化、氧毒性和老年色素的形成。 的 膜和蛋白质结构的修饰也被建议， 是由自由基的破坏性作用引起的。 因为如此 感兴趣的氧和自由基毒性，脂质的机制 过氧化反应一直是人们关注的焦点，但仍有 这一问题的重要方面尚未解决。 这项建议 解决了几个有关的自动氧化机制的问题， 类固醇和脂肪酸。 本研究将广泛使用HPLC/MS 因为我们已经证明了这种技术特别强大， 适用于类固醇和油酸过氧化。 自由的第二个方面 这个建议所涉及的自由基化学是控制 自由基反应中的立体化学。 我们有证据表明 自由基C=C中的立体化学控制的一般问题 在目标物上使用酰胺类助剂可以解决加成反应 烯烃碳和进行加成的自由基中心上。 的 在自由基加成中发现了重要的立体化学控制 考虑迭代自由基过程，例如 低聚，用于构建具有多个 在一个反应序列中的立体中心。 模板基 还提出了使用类固醇模板进行大环化， 构建明确长度的寡聚体。 第三个问题是， 建议解决的是光可逆丝氨酸的设计和使用 蛋白酶抑制剂 这些很可能提供一个有价值的研究工具， 研究酶的机制，通过服务，以笼酶的活动，直到 光子释放出催化活性位点。 我们的战略也可能 提供了一种新的方法来控制重要的血液凝固级联。 我们还将讨论分子聚集体如何 例如胶束和脂质双层可以影响有机反应性。 这个问题将通过设计在基本层面上解决， 光学纯的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-模板反应将 也可以用这些三脚架分子进行研究。

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.