RCDA, N-NITROSAMINES AND ALKANE DIAZOATES

寻求RCDA是为了建立一个一流的计划 阐明和理解化学物质的分子方面 致癌。这位候选人是维克森林大学的助理教授 大学，一所具有深厚传统的小型文科大学 卓越的教学水平。化学系有12个FTE，并且有 大约15年前建立了一个博士项目，取得了长足的进步 在过去的7年里，朝着一个重要的 学术研究的声誉。 据认为，RCDA将对候选人的 能够建立持续的、国家认可的计划，主要是 在为相对沉重的教学负担提供释放时间方面。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有关。几个 潜在的领域在中有详细介绍。候选人打算执行 在适当的实验室做几个短期的学徒 吸收特定的基本实验技术，将是 对于解决分子领域所有层面的问题至关重要 化学致癌的几个方面。 目前和近期的研究重点是化学 亚硝胺类化合物和亚硝胺致癌中间体。 目前R01赠款的竞争性续签提出了一项详细的、 对水溶液分解化学的定量认识 N-烷基化活性中的活性中间体 亚硝胺诱变剂、致癌物和癌症化疗药物。 本研究分为两个主要问题领域。A.有权势的 N-二氮杂环己烷的致癌、致突变和抗癌化疗活性 亚硝基-N-烷基化合物被认为很大程度上是由于 这些化合物通过烷烃重氮酸盐的中间体进行分解。 烷烃重氮酸盐随后分解成亲电性 物种被认为是导致DNA烷化活性的原因 N-亚硝基-N-烷基的所有生物活性成员 化合物。通过动力学和产物分析相结合的研究： 烷烃重氮酸盐在水介质中的寿命；反应 它们的分解机制和中间体；以及它们之间的关系 反应机理和烷基化选择性将重氮化结构 将会被量化。B.无环化合物的致癌性和致突变性 N-亚硝基-二烷胺是由于它们在酶作用下 活化到不稳定的α-羟基-N-亚硝基二烷胺 通过排出可随后烷化的重氮酸盐而分解 DNAA-羟基的命运--为重氮酸盐所描述的--将会被制造出来 α-取代-N-亚硝基二烷胺的组成化学 为了确定哪些结构元素控制生命周期 以及这些活性中间体的分解机理。

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.