Mutagenicity of electrophilic N-acyloxy-N-alkoxyamides

N-acyloxy-N-alkoxybenzamides are mutagenic in TA100 without the need for me tabolic activation with S9, Electronic effects of substituents on both the benzamide ring in N-acetoxy-N-butoxybenzamides or the benzyloxy ring in N-a cetoxy-N-benzyloxybenzamides do not influence mutagenicity levels. For N-be nzoyloxy-N-benzyloxybenzamides, mutagenicity levels are inversely related t o the electron-withdrawing effect of substituents on the benzoyloxy leaving group. Since reactivities increase with increasing electron-withdrawing ef fects, mutagenicity correlates with stability rather than reactivity of the se 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 n aphthyl group is present. N-acetoxy-N-butoxynaphthamide exhibits a much hig her level of mutagenicity than predicted by its log P value and activity ma y be ascribed to an intercalative binding process with DNA rather than stra ightforward hydrophobic binding in the major or minor groove. Since these a re direct-acting mutagens, structural factors influence binding and reactiv ity towards DNA. (C) 2001 Elsevier Science B.V. All rights reserved.