Transformation of mutagenic aromatic amines into non-mutagenic species by alkyl substituents. Part II: alkylation far away from the amino function.
Alkyl and trifluoromethyl derivatives of 4-aminobiphenyl (1) (4ABP) and 2-aminofluorene (7) (2AF) were synthesised and assayed for mutagenicity using Salmonella typhimurium tester strains TA98 and TA100 with and without the addition of S9 mix. Modification of 1 was achieved by attachment of alkyl groups (methyl, ethyl, iso-propyl, n-butyl, tert-butyl) and a trifluoromethyl group (CF(3)) in the 4'-position, the 3'-position (Me, CF(3)) and the 3'-, 5'-positions (DiMe, DiCF(3)). Compound 7 was modified by introduction of alkyl groups (methyl, tert-butyl, adamantyl) and a trifluoromethyl group (CF(3)) in the 7-position. The derivatives of 1 and 7 show for groups with growing steric demand decreased mutagenic activity. The bulkiest groups (CF(3), tert-butyl and adamantyl) induce the strongest effects on the mutagenicity. It was even possible to eliminate the mutagenicity of 1 and 7 by introduction of such substituents. In the last part of the work, we compared the experimental mutagenicities with calculated values derived from QSAR correlations. Our findings show that the predictions for aromatic amines with bulky substituents were generally too high. The strongest deviations were observed in the case of the CF(3)-, tert-butyl- and the adamantyl-group. Only the parent compounds and derivatives with small alkyl groups were predicted well. These investigations show that "large" substituents have an influence on the mutagenicity caused by their steric demand. To predict the correct mutagenicities of such compounds, it is necessary to introduce steric parameters in the respective QSAR equations which will be done in a forthcoming paper.
Glende
Carsten
C
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Str., 35032, Marburg, Germany.
Klein
Markus
M
Schmitt
Heimo
H
Erdinger
Lothar
L
Boche
Gernot
G
D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D000478:Alkylation; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D000611:Aminobiphenyl Compounds / Q000737:chemistry / Q000633:toxicity; D005449:Fluorenes / Q000737:chemistry / Q000633:toxicity; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D011237:Predictive Value of Tests; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
D000588:Amines; D000611:Aminobiphenyl Compounds; D005449:Fluorenes; D009153:Mutagens; C006757:4-biphenylamine; C012177:2-aminofluorene; D015081:2-Naphthylamine