Mutagenicity of electrophilic N-acyloxy- N-alkoxyamides

Abstract

N-acyloxy- N-alkoxybenzamides are mutagenic in TA100 without the need for metabolic activation with S9. Electronic effects of substituents on both the benzamide ring in N-acetoxy- N-butoxybenzamides or the benzyloxy ring in N-acetoxy- N-benzyloxybenzamides do not influence mutagenicity levels. For N-benzoyloxy- N-benzyloxybenzamides, mutagenicity levels are inversely related to the electron-withdrawing effect of substituents on the benzoyloxy leaving group. Since reactivities increase with increasing electron-withdrawing effects, mutagenicity correlates with stability rather than reactivity of these mutagens. Hydrophobicity is the dominant factor controlling mutagenicity levels and data for all mutagens correlate with computed log P values with a lower dependence ( h=0.22) than that recorded for indirect mutagens ( h=1.0), except where a sterically demanding p- tert-butyl substituent or a naphthyl group is present. N-acetoxy- N-butoxynaphthamide exhibits a much higher level of mutagenicity than predicted by its log P value and activity may be ascribed to an intercalative binding process with DNA rather than straightforward hydrophobic binding in the major or minor groove. Since these are direct-acting mutagens, structural factors influence binding and reactivity towards DNA.