Transformation of mutagenic aromatic amines into non-mutagenic species by alkyl substituents Part I.: Alkylation ortho to the amino function

Alkyl-substituted derivatives of 2-aminonaphthalene (2-AN) 1, 2-aminofluorene (2-AF) 6 and 4-aminobiphenyl (4-ABP) 11 were synthesized and the mutagenic activity of these compounds determined in Salmonella typhimurium strains TA98 and TA100 with and without S9 mix. In the case of the ortho-substituted 4-aminobiphenyls 12-15 (3-alkyl = ethyl, iso-propyl, n-butyl, tert-butyl) the substituent with the strongest steric demand (3-tert-butyl) shows the strongest influence on the decrease of mutagenicity if compared with the parent compound. In the series of the bis-ortho-disubstituted compounds 16-18 (3,5-dimethyl-, 3,5-diethyl- and 3,5-diisopropyl-4-aminobiphenyl) generation of non-mutagenic species occurs already with the introduction of two ethyl groups. For the 4-aminobiphenyl derivatives 12-15 and 16-18, as well as for the 1-alkylated 2-aminofluorenes 7-10 and the 1-alkylated 2-aminonaphthalenes 2-5 a smaller mutagenicity was observed if compared with predicted mutagenicities as calculated by the QSAR equations of Debnath et al. (Environ. Mol. Mutagen. 19 (1992) 37). The largest differences resulted in the cases of the tert-butyl substituted compounds. Only with smaller alkyl groups like ethyl the QSAR predictions and the experimentally determined mutagenicities come close to each other. Thus, these results show that appropriate alkyl substitution reduces (eliminates) mutagenicity, secondly, it is necessary to introduce steric parameters to predict the mutagenicity of such compounds correctly. (C) 2001 Elsevier Science B.V. All rights reserved.