The ultimate general objective of the research described in the present proposal is a complete understanding of the chemistry of decomposition of N-alkyl-N'-nitro-N-nitrosoguanidines (ANNG) in aqueous solutions. Compounds of this class are extremely potent direct-acting carcinogens and number of them have been shown to have substantia chemotherapeutic potential. The parent methyl compound, MNNG, plays a central role in studies of chemical carcinogenesis. The biological activity of these compounds is believed to be due to the generation, upon decomposition of a highly reactive alkylating moiety, an alkane diazotate. There are two major focal elements encompassed by this objective: 1) The proposal describes experiments that will determine the rates and products of decomposition of ANNGs, employing kinetic and analytical techniques. In particular, it will focus on what factors control the novel partitioning of the parent compound MNNG between alkylating and non- alkylating products. This study may then define conditions and structural features by which the potent mutagenic and carcinogenic activities of these compounds can be mitigated, and it may delineate ways in which these and related compounds can be beneficially manipulated. 2) The proposal describes experiments that will define ,in a quantitative way, the fate of the alkylating moiety produced by the decomposition of ANNGs- the alkane diazotates. These intermediates are common to the activities of all N-nitroso compounds-those that are harmful as well as those that are beneficial. Alkane diazotates were first synthesized almost 90 years ago but there have been no attempts to make direct determinations of the rates and rate laws that govern the fate of these crucial compounds. I propose to carry out such a study employing both standard and rapid mix techniques. The study will encompass both simple alkane diazotates and substituted benzyl diazotates--the latter in order to better assess the effect of electronic perturbations on the reaction rates and mechanisms.
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