RCDA, N-NITROSAMINES AND ALKANE DIAZOATES

该RCDA是为了寻求建立一个一流的计划， 阐明和理解化学的分子方面 致癌作用 候选人是维克森林的助理教授 大学，一个小型的文科大学，具有浓厚的传统， 教学卓越。 化学系有12个全职员工， 大约15年前建立了一个博士学位项目， 在过去的7年里， 学术研究的声誉。 据认为，RCDA将对候选人的选举产生重大影响。 建立一个持续的，国家认可的计划，主要是 提供从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有关。 几 潜在的领域都在里面。 候选人打算执行 在适当的实验室进行短期实习， 吸收特定的基本实验技术， 解决分子生物学领域各个层面的问题至关重要， 化学致癌作用。 目前和近期，研究的重点是化学 亚硝胺和接受亚硝胺致癌作用的中间体。 当前R 01补助金的竞争性更新提出了详细的， 水分解化学的定量理解 参与N-甲基-N-苯并咪唑烷基化活性的反应性中间体 亚硝胺诱变剂、致癌物和癌症化疗剂。 研究分为两大问题领域。 A.强大的 致癌、致突变和癌症化疗活性， 亚硝基-N-烷基化合物被认为在很大程度上是由于 这些化合物通过烷烃重氮盐的中间作用分解。 链烷重氮酸酯随后分解成亲电的 物种被认为是负责DNA烷基化活性的 N-亚硝基-N-烷基家族的所有生物活性成员 化合物. 通过结合动力学和产品分析研究： 重氮烷烃在水介质中的寿命;反应 它们分解的机制和中间体;以及 反应机理和烷基化选择性将重氮化结构 将被量化。 B。无环化合物的致癌性和致突变性 N-亚硝基-二烷基胺是由于它们是酶促的 活化成不稳定的α-羟基-N-亚硝基二烷基胺， 分解并排出重氮酸盐，然后烷基化 DNA. a-羟基的命运-所描述的重氮盐，将作出 α-取代-N-亚硝基二烷基胺的组成化学 为了确定结构的哪些元素控制寿命， 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.