The goal of this research is to provide knowledge and practical strategies for the significant reduction of carcinogenesis which may arise from endogenous nitrosation processes which can generate electrophilic species capable of modifying DNA and causing mutations. The principle hypothesis of this proposal is that significant progress toward this goal can be achieved 1) by showing through logical experimentation what can be made; 2) by elucidating the chemistry of processes which may catalyze or otherwise facilitate, as well as block, the N-nitrosation of available substrates and the production of electrophiles, and 3) by providing available markers, such as DNA adducts or other products, of genotoxicity which could be used in epidemiological studies to make connections between endogenous nitrosation chemistry and cancer. Our focus is directed at revealing the role that nitrosation of compounds containing C-N double bonds may play in the generation of cell damaging electrophiles, and how this process, as well as the nitrosation of other substrates, may occur through the reaction of NO with radical cations produced by oxidation processes such as those which occur at inflammation sites. Model substrates and drugs containing the oxazoline, imidazoline, and benzodiazepine rings will be nitrosated under endogenous conditions and the nature of the electrophiles arising from these transformations identified and the nature of their DNA adducts determined when appropriate. Both acidic nitrosation and NO + O2 Dietary aldehydes and ketones, including sugars, will be examined for their ability to catalyze the nitrosative conversion of primary amines, including amino acids, to diazonium ions, alpha-acyloxynitrosamines, or alpha-hydroxynitrosamines. The ability of NO mediated damage to occur by its reaction with radical cations produced by other oxidative processes will be probed. Computational methods will be employed to reveal reaction paths of intermediates and lead to better predictions of the types of compounds which pose a carcinogenic threat through their endogenous nitrosation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085538-02
Application #
6377782
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Poland, Alan P
Project Start
2000-04-01
Project End
2005-03-31
Budget Start
2001-04-16
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$195,750
Indirect Cost
Name
University of Missouri-Columbia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211
Loeppky, Richard N; Shi, Jianzheng (2008) N-nitrosotolazoline: decomposition studies of a typical N-nitrosoimidazoline. Chem Res Toxicol 21:308-18
Loeppky, Richard N; Shi, Jianzheng; Barnes, Charles L et al. (2008) A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug. Chem Res Toxicol 21:295-307
Loeppky, Richard N; Shi, Jianzheng (2008) Nucleoside and DNA adducts from N-nitrosotolazoline. Chem Res Toxicol 21:319-29
Wu, Hong; Loeppky, Richard N; Glaser, Rainer (2005) Nitrosation chemistry of pyrroline, 2-imidazoline, and 2-oxazoline: theoretical Curtin-Hammett analysis of retro-ene and solvent-assisted C-X cleavage reactions of alpha-hydroxy-N-nitrosamines. J Org Chem 70:6790-801
Teuten, Emma L; Loeppky, Richard N (2005) The mechanistic origin of regiochemical changes in the nitrosative N-dealkylation of N,N-dialkyl aromatic amines. Org Biomol Chem 3:1097-108
Loeppky, Richard N; Yu, Hongbin (2004) Amidine nitrosation. J Org Chem 69:3015-24