Improved Synthesis of the Food Mutagen 2-Amino-3,7,8-trimethyl-3H-imidazo[4,5-f]quinoxaline and Activity in a Mammalian DNA Repair System

Abstract

A simplified, direct synthesis of 2-amino-3,7,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (7,8-Me2IQx) is described. Reaction of butane-2,3-dione with 4-nitro-l,2-phenylenediamine yielded 87% 2,3-dimethyl-6-nitroquinoxaline, which in three convenient steps gave 6-(methylamino)-2,3-dimethylquinoxaline (51% yield). Nitration and separation of the two nitrated isomers provided the needed 5-nitro derivative (42%) that upon catalytic reduction and reaction with cyanogen bromide gave 7,8-Me2IQxin 65% yield. 7,8-Me2IQxhas about 50% of the mutagenicity of 2-amino-3-methyl-3H-imidazo [4,5-f] quinoline (IQ) in Salmonella typhimurium TA98 with biochemical activation and also in the Williams test, the induction of unscheduled DNA synthesis in rat hepatocytes. Thus, 7,8-Me2IQxis genotoxic, and most likely carcinogenic, as are most chemicals with reliable activity in both tests. © 1987, American Chemical Society. All rights reserved.