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.
| Mesic', M; Peuralahti, J; Blans, P et al. (2000) Mechanisms of decomposition of alpha-hydroxydialkylnitrosamines in aqueous solution. Chem Res Toxicol 13:983-92 |
