Structure–antimutagenic activity relationships of benzalacetone derivatives against UV-induced mutagenesis in E. coli WP2 uvrA and γ-induced mutagenesis in Salmonella typhimurium TA2638

Abstract

The antimutagenic activities of benzalacetone (4-phenyl-3-buten-2-one) and its structurally-related compounds were evaluated through their use as post-treatments for the UV-induced mutagenesis in Escherichia coli WP2s ( uvrA) and the γ-induced mutagenesis in Salmonella typhimurium TA2638, the latter of which is sensitive to oxidants. Structure–activity relationships were studied between IC 50 activity values, i.e. the dose (μmol/ml) at which the mutation frequency is reduced to 50% of the control, and electronic and hydrophobicity properties of the studied molecules. Benzalacetone and benzalacetone analogs, cinnamaldehyde and trans-1,1,1-trifluoro-4-phenyl-3-buten-2-one (TF), inhibited both forms of mutagenesis, but methyl cinnamate, cinnamic acid and cinnamamide did not. The IC 50 values of TF, for UV-induced mutagenesis and γ-induced mutagenesis, were 0.028 and 0.045 μmol/ml, respectively, and one order of magnitude lower than those of cinnamaldehyde and benzalacetone. The three antimutagenic analogs listed in order of decreasing activity are: TF⪢cinnamaldehyde>benzalacetone. This order is proportional to the electron-withdrawing property of the terminal group attached to an α,β-unsaturated carbonyl moiety in the side chain that is known to play an important role in the antimutagenicities of benzalacetone and related compounds. In UV-induced mutagenesis in E. coli WP2s, mono-substituted benzalacetones — the ring-substituents of which have electron-withdrawing properties — showed antimutagenic activity that correlated with their electronic property. In γ-induced mutagenesis in S. typhimurium TA2638, the antimutagenic activities of mono-substituted benzalacetones were proportional to the substituent hydrophobicities ( π). The different effects on both the mutation-induced systems is suggested to be related to the relative permeability of the cell membranes and the different sensitivities to mutagens between E. coli WP2s and S. typhimurium TA2638. In addition, the antimutagenic activity against γ-induced mutagenesis could be due to the ability of parent compounds or their derivatives to scavenge long-lived organic radicals; the radicals have been described to be generated as a result of the X-irradiation of cells by Koyama et al. [Mutat. Res. 421 (1998) 45].