Relationship of carcinogenicity, mutagenicity, and K-region reactivity in benz[c]acridines.
Benz[c]acridine and its 10 methyl-substituted derivatives were examined for chemical reactivity with osmium tetroxide and mutagenic activity on Salmonella typhimurium, and the results were contrasted with the electronic charge in the K region and the carcinogenic activity of benz[c]acridines. The addition of osmium tetroxide took place at the K region of benz[c]acridines. A linear relationship was established between the charge in the K region and the rate constant of the second-order reaction between osmium tetroxide and benz[c]acridines except the 5,7-dimethyl derivative whose substituent in the 5-position sterically hindered the reaction. Benz[c]acridines showed mutagenic activity in the presence of S-9 Mix, but not in the absence of S-9 Mix. There was a corresponding relationship among the K-region reactivity, mutagenic activity, and carcinogenic activity in benz[c]acridines. The only exception for this was the 7,11-dimethyl derivative in which the 11-methyl group had a steric effect on the ring-nitrogen atom. It was suggested that a common mechanism with regard to the reactivity of the K region is working in both carcinogenesis and mutagenesis. It was concluded that benz[c]acridines are activated, before they display a carcinogenic or mutagenic activity, to a proximate form such as 5,6-epoxides, through a metabolic process in which the nucleophilic property of the K region to react with electrophilic reagents plays an important role.
D000166:Acridines / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens; D055598:Chemical Phenomena; D002621:Chemistry; D007700:Kinetics; D008297:Male; D009153:Mutagens; D009993:Osmium Tetroxide; D051381:Rats; D013329:Structure-Activity Relationship
D000166:Acridines; D002273:Carcinogens; D009153:Mutagens; D009993:Osmium Tetroxide