The broad goal of this research is to significantly reduce cancer incidence by preventing exposure to carcinogenic N-nitroso compounds or electrophilic species produced in nitrosation reactions. The principal hypothesis of this proposal is that significant progress toward this goal can be achieved through the development of chemistry for 1) the specific destruction of nitrosamines, 2) the specific scavenging of nitrosating agents, and 3) an understanding of the structural features which lead to rapid nitrosation an nitrosamine formation. Since in vivo nitrosation occurs in all humans, one of the objectives of this research is to discover and elucidate the structural characteristics of various nitrogen containing compounds which predispose them to the rapid formation of N- nitroso compounds and/or highly reactive diazonium ions from limited quantities of nitrosating agents. Of particular concern are nitrogen containing compounds found in drugs, pesticides, household chemicals, or dietary constituents to which humans are exposed.
The specific aims or this research are: 1) To test our hypothesis that the """"""""nitrosative solvolysis"""""""" mechanism and the addition of HNO2 across the C=N is responsible for the rapid formation of nitrosamines and highly reactive diazonium ions from amidines, imidates, thioimidates, geminal diamines and their S and O analogs, and certain benzylic-like amines linked to indoles, or other electron rich aromatic or heteroaromatic groups. The reactivity of specific drugs containing these structural characteristics toward common nitrosating agents will be examined and the structure of N-nitroso containing products elucidated. 2) To test our hypothesis that a nitrosation mechanism involving the production of radical cations is significantly responsible for the rapid production of nitrosamines from N,N-dialkyl aromatic amines and to determine which structural features significantly reduce the reactivity of these oft-used commercial chemicals. 3) To test our hypothesis that molecules containing the 1 ,2- pyrazol-5-ones ring are capable of blocking nitrosation reactions and to explore the synthesis and characterization of polymers containing pyrazolones as effective agents for blocking N-nitrosation. 4) To carefully elucidate the nature of the reaction of nitrosamines with acylating agents with the goal of developing effective agents for the catalytic destruction of specific nitrosamines. This research in """"""""preventive chemical toxicology"""""""" should lead to practical measures for reducing carcinogen exposure to humans and the prevention of cancer.
