Synthesis and properties of novel bifunctional nitrosamines with ω-chloroalkyl groups

Novel N-nitroso-N-(acetoxymethyl)-ω-chloroalkylamines were synthesized and their chemical and biological properties were evaluated. The nitrosamines were expected to decompose through ω-chloroalkyldiazohydroxides in aqueous solution, and then to alkylate various cellular macromolecules. N-Nitroso-N-(acetoxymethyl)-2-chloroethylamine rapidly decomposed in aqueous solution, and the reaction rate was apparently independent of the pH of the solution. On the other hand, the rate of decomposition of chloropropyl and chlorobutyl homologs was pH-dependent, and increased in alkaline solution. When mutagenicity was assayed in Salmonella typhimurium TA1535 and TA92 for preliminary evaluation, all three compounds were directly mutagenic. The mutagenicity in Salmonella typhimurium TA1535, which can detect base-pair change mutation, clearly showed that these compounds induced DNA alkylation in vivo. The increase of alkyl chain length in chloroalkyl compounds increased the mutagenic activity, and the activities were stronger than those of the corresponding simple α-acetoxy nitrosamines lacking a chloro group, N-nitroso-N-(acetoxymethyl)alkylamines. Furthermore, the positive result in TA92 suggested that chlorinated nitrosamines cross-linked DNA like antitumor chloroethylnitrosoureas and that they are expected to be new lead compounds for antitumor agents.