Chemical and mutagenic properties of alpha-phosphonooxynitrosamines

The chemical and mutagenic properties of the products of solvolysis of alpha-acetoxynitrosamines in phosphate buffer were investigated. alpha-Acetoxynitrosamines decomposed in two ways: O-acyl fission yielded alpha-hydroxynitrosamines, which decomposed into aldehydes and alcohols, while O-alkyl fission gave a resonance hybrid of alpha-N-nitrosocarbonium and -iminium ions, which was trapped with phosphate and afforded alpha-phosphonooxynitrosamine. Formation of alpha-phosphonooxynitrosamines was dependent on the structure of alpha-acetoxynitrosamines; those with a secondary alpha-phosphonooxy group, including cyclic nitrosamines, were easily formed, while among those with a primary phosphonooxymethyl group, only those with an alkyl group containing a branched alpha-carbon as isopropyl, sec-butyl and tert-butyl were isolated. They were good substrates of alkaline phosphatase and showed a nuclear magnetic resonance spectrum due to the presence of a phosphorus atom. They were decomposed by acid catalysis, and the rate was dependent on the structure. They were directly mutagenic in bacterial tester strains, except for a compound with a tert-butyl group. The activity was similar or stronger in Salmonella typhimurium TA1535 and much weaker in Escherichia coli WP2 and WP2 hcr- than those of alpha-acetoxynitrosamines. Stability in neutral aqueous solution and the strong mutagenicity of alpha-phosphonooxynitrosamines suggested their possible involvement in metabolic activation as a precursor of alpha-hydroxynitrosamines, and also in the organotropic carcinogenicity of N-nitrosodialkylamines as a transport form.