Biological activity of benzylating N-nitroso compounds. Models of activated N-nitrosomethylbenzylamine.

Unsymmetrically substituted N-nitrosomethylbenzylamine is an oesophageal carcinogen with potential methylating and benzylating properties. Whereas the methylating activity of the compound has been investigated, little is known of its potential benzylating properties. In order to elucidate the biological consequences of benzylation, related model compounds which are presumed benzylating agents were synthesized and tested for mutagenicity. N-nitrosobenzylurea and its structural analogue N-nitroso-p-methylbenzylurea were direct acting mutagens in Salmonella typhimurium TA 98. Activity was also present in TA 1535, but it was less pronounced. N-nitroso-alpha-acetoxybenzyl-benzylamine was equally mutagenic in S. typhimurium TA and TA 1535. N-nitroso-acetoxymethyl-benzylamine and N-nitrosoacetoxy-methyl-p-methylbenzylamine are two model compounds which may decompose by hydrolysis or through esterases to yield intermediates also though to arise after alpha-C hydroxylation of the methyl group of the parent nitrosamines. These compounds needed additional activation by enzymes present in the post-mitochondrial supernatant of rat liver. They were distinctly mutagenic in TA 98. Furthermore, all compounds also caused the induction of phage lambda in a qualitative assay with Escherichia coli Br 513. Thus, benzylation of DNA clearly results in a biological consequence. These findings are supportive of the theory that if enzymic attack occurs on the methyl group of N-nitrosomethylbenzylamine, benzylation may also contribute to the overall biological activity of the compound.