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

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 (pKa of the leaving acid) and steric effects of para-aryl substituents (Es). 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 SN2 reactions at the amide nitrogen.