ENDOGENOUS NITROSATION CHEMISTRY IN CARCINOGENESIS

本研究的目的是为显著减少内源性亚硝化过程可能产生的致癌作用提供知识和实用策略，该过程可以产生能够修饰DNA并引起突变的亲电物种。这一提议的主要假设是，实现这一目标的重大进展是可以实现的：1)通过逻辑实验表明可以做出什么；2)通过阐明可能催化或以其他方式促进或阻止可用底物的n -亚硝化和亲电试剂的产生的过程的化学过程；3)通过提供可用的标记物，如DNA加合物或其他遗传毒性产物，这些标记物可用于流行病学研究，以建立内源性亚硝化化学与癌症之间的联系。我们的重点是揭示含有C-N双键的化合物的亚硝化可能在产生细胞损伤的亲电试剂中发挥的作用，以及这一过程以及其他底物的亚硝化如何通过氧化过程（如在炎症部位发生的氧化过程）产生的NO与自由基阳离子的反应发生。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，并在适当的时候确定由这些转化产生的亲电试剂的性质及其DNA加合物的性质。将考察膳食醛和酮类（包括糖）催化伯胺（包括氨基酸）转化为重氮离子、α -酰基氧亚硝胺或α -羟基亚硝胺的亚硝化能力。通过与其他氧化过程产生的自由基反应，NO介导的损伤发生的能力将被探索。计算方法将用于揭示中间体的反应路径，并更好地预测通过内源性亚硝化构成致癌威胁的化合物类型。

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.