Alpha-acetoxy derivatives of methyl-2-oxopropylnitrosamine: synthesis, hydrolysis rate and bacterial mutagenicity

Abstract

N-Methyl-N-2-oxopropylnitrosamine (MOP) induces pancreatic tumors in hamsters. As models for the putative proximate carcinogenic alpha-hydroxy derivatives, we studied N-acetoxymethyl-N-2-oxopropylnitrosamine (AMOP) and N-methyl-N-(1-acetoxy-2-oxopropyl)nitrosamine (MAOP). AMOP was synthesized from aminoacetone by the method of Roller et al. [1975), Tetrahedron Lett., 25, 2065-2068) and MAOP was synthesized by acetoxylation of MOP with lead tetraacetate. The half-lives of AMOP, MAOP and acetoxymethylmethylnitrosamine (ADMN) in aqueous buffer decreased as the pH rose from 5 to 9, with values at pH 5 of 2.8 X 10(4) min for AMOP, 3.2 X 10(3) min for ADMN, and 23 min for MAOP. Mutagenicity was examined in Salmonella typhimurium TA1535, using a pre-incubation at pH 5 without microsomal activation. The mutagenic potency, expressed as revertants/mumole, was 56 for AMOP, 150 for ADMN, and 4.5 X 10(4) for MAOP. Hence, hydrolysis rates at pH 5 were probably important in determining the relative mutagenicity.