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

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Abstract
Unsymmetrically substituted N-nitrosomethylbenzylamine is an esophageal 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, presumed benzylating agents, were synthesized and tested for mutagenicity. N-nitrosobenzylurea and its structural analog 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 98 and TA 1535. N-nitroso-acetoxymethyl-benzylamine and N-nitroso-acetoxy-methyl-p-methylbenzylamine were 2 model compounds which may have decomposed by hydrolysis of through esterases to yield intermediates also thought 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. All compounds also caused the induction of phage .lambda. in a qualitative assay with Escherichia coli Br 513. Benylation of DNA resulted in a biological consequence. These findings supported the theory that if enzymic attack occurred on the methyl group of N-nitrosomethylbenzylamine, benzylation may have also contributed to the overall biological activity of the compound.

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