RCDA, N-NITROSAMINES AND ALKANE DIAZOATES

RCDA、N-亚硝胺和烷烃重氮酸盐

• 批准号: 2717144
• 负责人: JAMES C FISHBEIN
• 金额: $ 6.64万
• 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/2717144
• 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以建立一流的计划 阐明和理解化学的分子方面 致癌作用。 候选人是Wake Forest的助理教授 大学，一所小型文科大学，具有强烈的传统 卓越的教学。 化学部门有12英尺，有 大约15年前建立了博士学位课程，取得了长足的进步 在过去的7年中，发展重要 学术研究的声誉。 据认为，他的RCDA将对候选人的 能够建立一个持续的，全国认可的计划的能力 在提供相对繁重的教学负载的释放时间。 这 发布时间将用于建立新领域和方法论 与化学癌变的一般问题区域有关。 一些 潜在区域在其中详细介绍。 候选人打算进行 适当的实验室中的一些短期学徒 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 化学癌变的各个方面。 对于目前和近期，研究重点是化学 亚硝胺并接受亚硝胺癌发生的中间体。 当前R01赠款的竞争更新提出了详细的， 对水分解化学的定量理解 反应性中间体参与N-的烷基化活性 亚硝胺诱变剂，致癌物和癌症化学治疗剂。 该研究分为两个主要问题领域。 答：强大的 N-的致癌，诱变和癌症化学治疗活性 硝基n-烷基化合物被认为很大程度上是由于事实 这些化合物通过烷烃重生的介体分解。 随后的烷烃重生对亲电的分解 据信物种是造成DNA烷基化活性的原因 N-硝基-N-烷基家族的所有生物活性成员 化合物。 通过动力学和产品分析研究的结合： Alkane Rizoo的生命是在水性介质中；反应 它们分解的机制和中间体；和相关性 反应机理和烷基化选择性将重射生结构 将被定量。 B.无环的致癌性和诱变性 N-硝基二烷基胺是由于它们是酶上的 被激活为不稳定的α-羟基-N-硝基二烷基胺，该胺的激活 通过排出的重量材料分解，后来可以烷基化 脱氧核糖核酸。 将重量码描述的A-羟基的命运将成为 α-取代的N-硝基二烷基胺的组成化学 为了确定结构的哪些元素控制生命 这些反应性中间体的分解机制。