The role of steric effects in the direct mutagenicity of N-acyloxy- N-alkoxyamides

Abstract

Electrophilic N-acyloxy- N-alkoxyamides are mutagenic in Salmonella typhimurium TA100 without the need for S9 metabolic activation and they react with DNA at guanine—N7 at physiological pH. Since these are direct-acting mutagens, structural factors influence binding and reactivity with DNA. Mutagenicity in TA100 can be predicted by a QSAR incorporating hydrophobicity (log P), stability to substitution reactions at nitrogen (p K a of the leaving acid) and steric effects of para-aryl substituents ( E s). A number of mutagens exhibit activities that deviate markedly from the predicted values and they fall into two classes: di- tert-butylated N-benzoyloxy- N-benzyloxybenzamides, which – because of their size – are most probably excluded from the major groove or are unable to achieve a transition state for reaction with DNA, and N-benzoyloxy- N-butoxyalkylamides with branching α-to the amide carbonyl, which are resistant to S N2 reactions at the amide nitrogen.