SCREENING OF COMPOUNDS STRUCTURALLY AND FUNCTIONALLY RELATED TO N-METHYL-N'-NITRO-N-NITROSOGUANIDINE, A GASTRIC CARCINOGEN

Abstract

In view of a potent gastric carcinogenicity of the well-known mutagen, N-methyl-N'-nitro-N-nitrosoguanidine, a screening of compounds related to it was attempted by examining the mutagenicity of various nitrosated guanidine derivatives for a strain of Salmonella typhimurium at neutral pH. Among naturally occurring guanidines so far tested, nitrosated methylguanidine was the most mutagenic, and nitrosated agmatine and γ-guanidinobutyric acid were moderately mutagenic, while nitrosated L-arginine and acetyl-L-arginine were weakly mutagenic. Regarding synthetic guanidines, nitrosated benzoyl-L-arginineamide, acetyl-L-arginineamide, and γ-guanidinobutyric acid amide showed a powerful mutagenic activity and were as active as or more so than nitrosated N-methyl-N'-nitroguanidine. Nitrosated L-arginineamide, β-guanidinopropionic acid, homoarginine, and benzoyl-L-arginine ethyl ester were weakly active. Some arginine-containing di- or tri-peptides and salmine hydrolysate, when nitrosated, also showed moderately or weakly mutagenic activity. Some urea derivatives revealed weak or slight mutagenicity after nitrosation. Several amino acids except arginine, which were treated with nitrite in the same manner, failed to show mutagenic activity. The mutagenic principle of nitrosated acetyl-L-arginineamide was identified as N-nitroso-4-acetamido-4-carboxamidobutylcyanamide. Based on these findings, the structural specificity involved in the mutagenicity of nitrosated guanidine derivatives is discussed.