The mechanism of nucleoside-alkylation by alkylnitrosourea - Reaction of 2'-deoxyguanosine with N-nitroso-N-methyl-N'-phenylurea in methanol

The reaction of 2'-deoxyguanosine with N-nitroso-N-methyl-N'-phenylurea 1 in methanol gave thee alkylated products, N-1-(15%), N-7-(19%) and O-6-(24%)methyl-2'-deoxyguanosine, differing from the result in the reaction with methyl iodide in which only the N-7-methyl derivative was obtained. The random distribution of the products may be due to the formation of a carbonium ion from 1, being capable of the occurrence of the S(N)1 reaction at the nucleophilic sites in the guanine residue. The relative extent of the O-6-alkylation (O-6/N-1, O-6/N-7) was found to be decreased significantly when the water was added to the reaction medium. This observation suggests that the importance of the O-6-alkylation will grow further if the DNA-alkylations by alkylnitrosoureas occur in hydrophobic environments under certain cellular conditions. Thus the evaluation of the carcinogenicity of alkylnitrosoureas may well be achieved with properly defined experimental conditions including a solvent or a dosage method.