Structure-antimutagenic activity relationships of benzalacetone derivatives against UV-induced mutagenesis in E-coli WP2uvrA and gamma-induced mutagenesis in Salmonella typhimurium TA2638

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 gamma -induced mutagenesis in Salmonella typhimurium TA2638, the la tter of which is sensitive to oxidants. Structure-activity relationships we re studied between IC50 activity values, i.e, the dose (mu mol/ml) at which the mutation frequency is reduced to 50% of the control, and electronic an d hydrophobicity properties of the studied molecules. Benzalacetone and ben zalacetone analogs, cinnamaldehyde and trans-1,1,1-trifluoro-4-phenyl-3-but en-2-one (TF), inhibited both forms of mutagenesis, but methyl cinnamate, c innamic acid and cinnamamide did not. The IC50 values of TF, for UV-induced mutagenesis and gamma -induced mutagenesis, were 0.028 and 0.045 mu mol/ml respectively, and one order of magnitude lower than those of cinnamaldehyd e and benzalacetone. The three antimutagenic analogs listed in order of dec reasing activity are: TF >> cinnamaldehyde > benzalacetone. This order is p roportional to the electron-withdrawing property of the terminal group atta ched to an alpha.beta -unsaturated carbonyl moiety in the side chain that i s known to play an important role in the antimutagenicities of benzalaceton e and related compounds. In UV-induced mutagenesis in E. coli WP2s, mono-su bstituted benzalacetones - the ring-substituents of which have electron-wit hdrawing properties - showed antimutagenic activity that correlated with th eir electronic property. In gamma -induced mutagenesis in S. typhimurium TA 2638, the antimutagenic activities of mono-substituted benzalacetones were proportional to the substituent hydrophobicities (pi). The different effect s on both the mutation-induced systems is suggested to be related to the re lative permeability of the cell membranes and the different sensitivities t o mutagens between E. coli WP2s and S, typhimurium TA2638. In addition, the antimutagenic activity against gamma -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 re sult of the X-irradiation of cells by Koyama et al. [Mutat. Res. 421 (1998) 45]. (C) 2001 Elsevier Science B.V. All rights reserved.