The general aim of this proposal is 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. 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 with diazoate structure will be quantitated. These factors determine: whether a diazoate has a sufficient lifetime to diffuse to a particular target; whether the diazoate is sufficiently selective toward alkylation of a given target compared to other potential targets; whether there are mechanisms of decomposition by which the given lifetime or selectivity is enhanced or diminished; and whether there are manipulatable elements of structure by which selectivity and lifetime can be rationally altered. 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 diazoate that can subsequently alkylate DNA. The fate of the alpha-hydroxy-N- nitrosodialkylamines is dependent upon several competing reactions. They may decompose with N-C bond cleavage to generate aIkylating equivalents but may also be converted in vivo into more stable forms by O- glucoronylation, or by trapping as an alpha-thioether - presumably by any of the various biological thiols. These forms can then in some cases be exported from the body or alternatively travel to distant sites where they may be reconverted to the alpha-hydroxycompounds which subsequently decompose with the generation of alkylating equivalents. A quantitative analysis, similar to that described for the diazoates, will be made of the decomposition 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. It is evident that an understanding of the detailed aqueous decomposition chemistry of the alpha-substituted-N-nitrosodialkylamines is essential to determining the fate of the alkylating equivalents born in the N-nitroso-N-alkylgroups of these compounds.
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