ENDOGENOUS NITROSATION CHEMISTRY IN CARCINOGENESIS

本研究的目的是提供知识和实用的策略，显着减少致癌作用，可能会出现从内源性亚硝化过程，可以产生亲电物种能够修饰DNA和引起突变。 这一建议的基本假设是，朝着这一目标取得重大进展可以实现1）通过显示通过逻辑实验可以做什么; 2）通过阐明可催化或以其它方式促进以及阻断可用底物的N-亚硝化和亲电体的产生的过程的化学，以及3）通过提供可用的标记物，如DNA加合物或其它产物，遗传毒性，可用于流行病学研究，使内源性亚硝化化学和癌症之间的联系。我们的重点是揭示的作用，含C-N双键的化合物的亚硝化可能在细胞损伤亲电体的产生中发挥作用，以及如何这个过程，以及其他底物的亚硝化，可能会发生通过NO与自由基阳离子的反应产生的氧化过程，如那些发生在炎症部位。含有恶唑啉、咪唑啉和苯二氮卓环的模型底物和药物将在内源性条件下进行亚硝化，并确定这些转化产生的亲电试剂的性质，并在适当时确定其DNA加合物的性质。酸性亚硝化和NO + O2将检查膳食醛和酮（包括糖）催化伯胺（包括氨基酸）亚硝化转化为重氮离子、α-酰氧基亚硝胺或α-羟基亚硝胺的能力。NO介导的损伤发生的能力，其与其他氧化过程产生的自由基阳离子反应将被探测。计算方法将被用来揭示中间体的反应路径，并导致更好的预测类型的化合物，通过其内源性亚硝化构成致癌威胁。

The goal of this research is to provide knowledge and practical strategies for the significant reduction of carcinogenesis which may arise from endogenous nitrosation processes which can generate electrophilic species capable of modifying DNA and causing mutations. The principle hypothesis of this proposal is that significant progress toward this goal can be achieved 1) by showing through logical experimentation what can be made; 2) by elucidating the chemistry of processes which may catalyze or otherwise facilitate, as well as block, the N-nitrosation of available substrates and the production of electrophiles, and 3) by providing available markers, such as DNA adducts or other products, of genotoxicity which could be used in epidemiological studies to make connections between endogenous nitrosation chemistry and cancer. Our focus is directed at revealing the role that nitrosation of compounds containing C-N double bonds may play in the generation of cell damaging electrophiles, and how this process, as well as the nitrosation of other substrates, may occur through the reaction of NO with radical cations produced by oxidation processes such as those which occur at inflammation sites. Model substrates and drugs containing the oxazoline, imidazoline, and benzodiazepine rings will be nitrosated under endogenous conditions and the nature of the electrophiles arising from these transformations identified and the nature of their DNA adducts determined when appropriate. Both acidic nitrosation and NO + O2 Dietary aldehydes and ketones, including sugars, will be examined for their ability to catalyze the nitrosative conversion of primary amines, including amino acids, to diazonium ions, alpha-acyloxynitrosamines, or alpha-hydroxynitrosamines. The ability of NO mediated damage to occur by its reaction with radical cations produced by other oxidative processes will be probed. Computational methods will be employed to reveal reaction paths of intermediates and lead to better predictions of the types of compounds which pose a carcinogenic threat through their endogenous nitrosation.