From mutagenic to non-mutagenic nitroarenes: effect of bulky alkyl substituents on the mutagenic activity of nitroaromatics in Salmonella typhimurium- Part II. Substituents far away from the nitro group

Derivatives of 4-nitrobiphenyl, 4-nitrosobiphenyl, 2-phenyl-5-nitropyridine (2-aza-4-nitrobiphenyl) and 2-nitrofluorene, bearing various alkyl substit uents far away from the nitro group (4'-position in nitrobiphenyls, 7-posit ion in 2-nitrofluorenes) were synthesised and tested for mutagenic potency in strains TA98 and TA100 of Salmonella typhimurium. In the absence of S9 i n both strains, mutagenicity of all compounds decreased with increasing ste ric demand of the attached alkyl groups as, e.g., for the 4-nitrobiphenyl s eries in the order 4'-H > 4'-Me > 4'-Et > 4'-nBu > 4'-iPr > di-tBu > 4'-Ad (Ad = adamantyl). Changes of the molecular shape from 'planar' to non-plana r caused by the bulk of the introduced substituents (without influencing th e twisting of the nitro substituent or the phenyl rings in the biphenyl com pounds) may be responsible for this effect by interfering with an efficient intercalation into DNA. A comparison between experimental and theoretical values as calculated from recently developed equations (QSAR) confirmed our previous results (see th e preceding paper) that mutagenicity of alkyl-substituted nitroaromatics ca nnot be predicted by hydrophobicity and LUMO-energies alone without includi ng steric parameters. (C) 2000 Elsevier Science B.V. All rights reserved.