Mutagenic activities of the series of N-methyl-N′-aryl-N-nitrosoureas (I-X) and N-methyl-N′-aryl-N′-methyl-N-nitrosoureas (II-Y) on Salmonella typhimurium TA 1535 have been investigated. All I-X compounds had strong mutagenic potency without metabolic activation, and their effectiveness was even greater than that of N-methyl-N-nitrosourea. The mutagenicity at a given concentration of the compounds (3.35 × 10−2 µmol) was compared with the chemical alkylating activity on 4-(p-nitrobenzyl)pyridine. A positive parallelism between them was observed in the cases of N-methyl-N′-(p-methoxyphenyl)-N-nitrosourea, N-methyl-N′-(p-methylphenyl)-N-nitrosourea, N-methyl-N′-phenyl-N-nitrosourea, and N-methyl-N′-(p-chlorophenyl)-N-nitrosourea, whereas this correlation broke down with N-methyl-N′-(p-acetylphenyl)-N-nitrosourea and N-methyl-N′-(p-nitrophenyl)-N-nitrosourea. These observations were discussed in terms of both the inductive effect and hydrogen-bonding nature of the substituents (X) and the difference in the chemical and biological processes. On the other hand, the II-Y compounds which are the methyl-substituted derivatives on the second nitrogen (N′) had no significant or weaker mutagenicity when compared to the corresponding I-X compounds. This was also in agreement with the results of the chemical alkylation. The dose-response curves of the I-X and II-Y compounds showed that all mutagenicities with the exception of N-methyl-N′-phenyl-N′-methyl-N-nitrosourea increased similarly in accordance with an increase in their concentrations, indicating that the lethal effect might not influence the observed mutagenicity. Mechanistically, it has been suggested that removal of the hydrogen on N′ may be involved in the transition state of both the chemical and mutagenic actions of the I-X compounds. With the II-Y compounds, however, further investigations are needed to elucidate the observed results since other factors such as inductive and steric effects by the methyl group on N′ may also be of importance.

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