N-ALKYL-N-NITRO-NITROSOGUANIDINES AND ALKANE DIAZOTATES

N-烷基-N-硝基-亚硝基胍和烷烃重氮酸盐

• 批准号: 3197732
• 负责人: JAMES C FISHBEIN
• 金额: $ 10.48万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-08 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3197732
• 关键词: alkanes; alkylating agents; alkylation; chemical carcinogen; chemical kinetics; chemical structure function; diazo compound; hydrolysis; mutagens; nitrosamines; nitrosoguanidines; nitrosourea; stop flow technique; water solution

The ultimate general objective of the research described in the present proposal is a complete understanding of the chemistry of decomposition of N-alkyl-N'-nitro-N-nitrosoguanidines (ANNG) in aqueous solutions. Compounds of this class are extremely potent direct-acting carcinogens and number of them have been shown to have substantia chemotherapeutic potential. The parent methyl compound, MNNG, plays a central role in studies of chemical carcinogenesis. The biological activity of these compounds is believed to be due to the generation, upon decomposition of a highly reactive alkylating moiety, an alkane diazotate. There are two major focal elements encompassed by this objective: 1) The proposal describes experiments that will determine the rates and products of decomposition of ANNGs, employing kinetic and analytical techniques. In particular, it will focus on what factors control the novel partitioning of the parent compound MNNG between alkylating and non- alkylating products. This study may then define conditions and structural features by which the potent mutagenic and carcinogenic activities of these compounds can be mitigated, and it may delineate ways in which these and related compounds can be beneficially manipulated. 2) The proposal describes experiments that will define ,in a quantitative way, the fate of the alkylating moiety produced by the decomposition of ANNGs- the alkane diazotates. These intermediates are common to the activities of all N-nitroso compounds-those that are harmful as well as those that are beneficial. Alkane diazotates were first synthesized almost 90 years ago but there have been no attempts to make direct determinations of the rates and rate laws that govern the fate of these crucial compounds. I propose to carry out such a study employing both standard and rapid mix techniques. The study will encompass both simple alkane diazotates and substituted benzyl diazotates--the latter in order to better assess the effect of electronic perturbations on the reaction rates and mechanisms.

本研究描述的最终总体目标 提案是对分解化学的完整理解 水溶液中的 N-烷基-N'-硝基-N-亚硝基胍 (ANNG)。 此类化合物是极强的直接致癌物， 其中许多人已被证明具有实质性化疗 潜在的。 母体甲基化合物 MNNG 在 化学致癌作用的研究。 这些物质的生物活性 化合物被认为是由于分解时产生的 高反应性烷基化部分，烷烃重氮化物。 该目标包含两个主要焦点要素： 1) 该提案描述了将确定速率和 ANNG 分解产物，采用动力学和分析方法 技术。 特别是，它将关注哪些因素控制着小说 母体化合物 MNNG 在烷基化和非烷基化之间的分配 烷基化产品。 然后，这项研究可以定义条件和结构 这些特征具有强致突变和致癌活性 化合物可以得到缓解，并且它可以描述这些和 可以有益地操纵相关化合物。 2) 该提案描述了将定量定义 的实验 方式，分解产生的烷基化部分的命运 ANNGs-烷烃重氮化物。 这些中间体是常见的 所有 N-亚硝基化合物的活性 - 那些有害的以及 那些有益的。 烷烃重氮化物在大约 90 年前首次被合成，但 没有尝试直接确定利率和利率法 决定这些关键化合物的命运。 我建议进行 此类研究同时采用标准和快速混合技术。 研究 将涵盖简单的烷烃重氮化物和取代的苄基 重氮化物——后者是为了更好地评估电子的影响 反应速率和机制的扰动。