RCDA, N-NITROSAMINES AND ALKANE DIAZOATES

RCDA、N-亚硝胺和烷烃重氮酸盐

• 批准号: 2330856
• 负责人: JAMES C FISHBEIN
• 金额: $ 6.61万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-03-11 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2330856
• 关键词: acidity /alkalinity; alkanes; alkylating agents; analytical chemistry; chemical addition; chemical carcinogen; chemical kinetics; chemical structure function; chemical substitution; chemical synthesis; diazo compound; hydroxides; mutagens; nitrosamines; nitroso compounds; solvents; solvolysis; thermodynamics; thioether; water

The RCDA is sought in order to establish a first-rate program for elucidating and understanding molecular aspects of chemical carcinogenesis. The candidate is an assistant professor at Wake Forest University, a small liberal arts University with a strong tradition of teaching excellence. The Chemistry department has 12 FTEs and, having established a Ph.D program some 15 years ago, has made great strides within the last 7 years towards the development of a significant reputation for academic research. It is considered that he RCDA will have a major impact on the candidate's ability to establish a sustained, nationally recognized program mainly in providing release time from a comparably heavy teaching load. This release time will be used to establish new areas and methodologies relevant to the general problem area of chemical carcinogenesis. Several potential areas are detailed within. The candidate intends to carry out a few short term apprenticeships in appropriate laboratories to assimilate specific essential experimental techniques that will be critical to addressing problems at all levels of the field of molecular aspects of chemical carcinogenesis. For the present and the near term, of focus of research is the chemistry of nitrosamines and receive intermediates in nitrosamine carcinogenesis. The competitive renewal of the current R01 grant proposes a detailed, quantitative understanding of the aqueous decomposition chemistry of reactive intermediates involved in the alkylating activity of N- nitrosamine mutagens, carcinogens and cancer chemotherapeutic agents. The research is divided into two major problems areas. A. The powerful carcinogenic, mutagenic and cancer-chemotherapeutic activities of N- nitroso-N-alkyl compounds are thought to be due in large part to the fact that these compounds decompose via the intermediacy of alkane diazoates. The subsequent decomposition of the alkane diazoate to an electrophilic species is believed to be responsible for the DNA alkylating activity of all biologically active members of the N-nitroso-N-alkyl family of compounds. By a combination of kinetic and product-analytical studies: the lifetimes of alkane diazoates in aqueous media; the reaction mechanisms and intermediates by which they decompose; and the correlation of reaction mechanisms and alkylating selectivity will diazote structure will be quantitated. B. The carcinogenicity and mutagenicity of acyclic N-nitroso-dialkylamines is due to the fact they are enzymatically activated to unstable alpha-hydroxy-N-nitrosodialkylamines which decompose with expulsion of a diazoate that can subsequently alkylate DNA. The fate of the a-hydroxy-described for the diazoates, will be made of the composition chemistry of alpha-substituted-N-nitrosodialkylamines in order to determine what elements of structure control the lifetimes and mechanisms of decomposition of these reactive intermediates.

寻求 RCDA 是为了建立一流的计划 阐明和理解化学的分子方面 致癌作用。 该候选人是维克森林大学的助理教授 大学，一所小型文科大学，具有浓厚的传统 教学卓越。 化学系有 12 名 FTE， 大约15年前设立了博士项目，取得了长足的进步 在过去的7年里，我们致力于发展一个重要的 学术研究的声誉。 RCDA被认为将对候选人产生重大影响 建立持续的、国家认可的计划的能力，主要是 提供从相对繁重的教学负担中解脱出来的时间。 这 发布时间将用于建立新的领域和方法 与化学致癌的一般问题领域相关。 一些 潜在领域详见内。 候选人打算执行 在适当的实验室进行一些短期学徒 吸收特定的基本实验技术 对于解决分子领域各个层面的问题至关重要 化学致癌作用的各个方面。 当前和近期的研究重点是化学 亚硝胺并接受亚硝胺致癌作用的中间体。 当前 R01 拨款的竞争性更新提出了详细的、 定量理解水分解化学 参与 N- 烷基化活性的反应中间体 亚硝胺诱变剂、致癌剂和癌症化疗剂。 该研究分为两个主要问题领域。 A、强者 N-的致癌、致突变和癌症化疗活性 亚硝基-N-烷基化合物被认为很大程度上是由于以下事实 这些化合物通过烷烃重氮酸酯的中间作用分解。 随后烷烃重氮酸酯分解为亲电化合物 据信该物种负责 DNA 烷基化活性 N-亚硝基-N-烷基家族的所有生物活性成员 化合物。 通过动力学和产物分析研究的结合： 烷烃重氮酸盐在水介质中的寿命；反应 它们分解的机制和中间体；和相关性 重氮结构的反应机理和烷基化选择性 将被量化。 B.无环的致癌性和致突变性 N-亚硝基二烷基胺是因为它们是酶促的 活化为不稳定的α-羟基-N-亚硝基二烷基胺， 分解并排出重氮酸盐，随后可烷基化 脱氧核糖核酸。 重氮酸酯中描述的α-羟基的命运将由 α-取代-N-亚硝基二烷基胺的化学组成 以确定结构的哪些元素控制寿命 以及这些反应中间体的分解机制。