From mutagenic to non-mutagenic nitroarenes: effect of bulky alkyl substituents on the mutagenic activity of 4-nitrobiphenyl in Salmonella typhimurium - Part I. Substituents ortho to the nitro group and in 2 '-position

Eleven alkyl substituted derivatives of 4-nitrobiphenyl (4NBp) and two corr esponding nitroso compounds were synthesised and tested for mutagenic poten cy in strains TA98 and TA100 of Salmonella typhimurium. The mutagenicity of compounds substituted ortho to the nitro group (3-methyl-, 3-ethyl-, 3-iso propyl-, 3-tertbutyl-, 3,5-diethyl-, 3,5-di isopropyl-, and 3,5-di tertbuty l-4NBp) decreased with growing steric demand of the alkyl substituents in b oth tester strains. The most sterically hindered compounds were non-mutagen ic even at highest concentrations. This reduction of mutagenicity is correl ated with deviations from the coplanar orientation of the nitro group relat ive to the aromatic plane. Since a comparable decrease of mutagenicity for the nitroso compounds (4NOBp and 3-tertbutyl-4NOBp) was not observed, the f irst reduction step of non-planar nitro groups must be inhibited. Alkyl groups in the 2'-position of 4NBp (2'-methyl-, 2'-ethyl-, 2'-isopropy l-, and 2',4',6'-trimethyl-4NBp) also reduced mutagenic activity with incre asing size and removed it completely for the most sterically hindered speci es (2'-isopropyl-, 2',4',6'-trimethyl-4NBp). In this case, the co-planarity of the nitro group is not affected but the twisting of the two aromatic ri ngs, which is associated with a less effective charge delocalisation of the nitrenium ion. The experimental mutagenicities of all nitro compounds were compared to pre dicted values, that are based on recently developed empirical equations. Wh ile there was reasonable correspondence for the parent compound (4NBp), its ortho methylated derivative (3-methyl-4NBp) and two highly hydrophobic dia lkylated species (3,5-di isopropyl- and 3,5-di tertbutyl- 4NBp), prediction s for all other alkyl substituted compounds were too high. Thus, steric par ameters should be included to improve the general validity of predictions b y means of quantitative structure-activity relationships (QSAR). (C) 2000 E lsevier Science B.V. All lights reserved.