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 (logP), stability to substitution reactions at nitrogen (pK(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 alpha-to the amide carbonyl, which are resistant to S(N)2 reactions at the amide nitrogen.
Andrews
Luke E
LE
Division of Chemistry, School of Biological, Biomedical and Molecular Sciences, University of New England, Armidale, NSW 2351, Australia.
Bonin
Antonio M
AM
Fransson
Linda E
LE
Gillson
Ashley-Mae E
AM
Glover
Stephen A
SA
D001549:Benzamides / Q000138:chemical synthesis / Q000633:toxicity*; D001665:Binding Sites; D004269:DNA, Bacterial / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D009152:Mutagenicity Tests; D009153:Mutagens / Q000138:chemical synthesis / Q000633:toxicity*; D053284:Polyunsaturated Alkamides / Q000138:chemical synthesis / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D013329:Structure-Activity Relationship
D001549:Benzamides; D004269:DNA, Bacterial; D009153:Mutagens; D053284:Polyunsaturated Alkamides; D006147:Guanine