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

Abstract

Derivatives of 4-nitrobiphenyl, 4-nitrosobiphenyl, 2-phenyl-5-nitropyridine (2-aza-4-nitrobiphenyl) and 2-nitrofluorene, bearing various alkyl substituents far away from the nitro group (4′-position in nitrobiphenyls, 7-position in 2-nitrofluorenes) were synthesised and tested for mutagenic potency in strains TA98 and TA100 of Salmonella typhimurium. In the absence of S9 in both strains, mutagenicity of all compounds decreased with increasing steric demand of the attached alkyl groups as, e.g., for the 4-nitrobiphenyl series in the order 4′-H>4′-Me>4′-Et>4′-nBu>4′-iPr>4′-tBu>4′-Ad (Ad=adamantyl). Changes of the molecular shape from ‘planar’ to non-planar caused by the bulk of the introduced substituents (without influencing the twisting of the nitro substituent or the phenyl rings in the biphenyl compounds) 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 the preceding paper) that mutagenicity of alkyl-substituted nitroaromatics cannot be predicted by hydrophobicity and LUMO-energies alone without including steric parameters.