The effect of hydrophobicity upon the direct mutagenicity of N-acyloxy-N-alkoxyamides - bilinear dependence upon LogP

Abstract

N-Acyloxy-N-alkoxyamides 1 are direct-acting mutagens for which a bilinear QSAR has been established, which predicts with accuracy their activity in the Ames reverse mutation assay in 'Salmonella typhimurium' TA100, based upon their hydrophobicity (LogP), reactivity (pKA of the carboxylic acid of the N-carboxyl group) and TAFT steric parameters. From activity data for 55 congeners and incorporating five mutagens bearing long-chain hydrocarbons on the alkoxyl and acyloxyl groups, designed for this study, a maximal LogPo, is found to be LogP = 6.4. Mutagens with LogP < than this value show a linear hydrophobic dependence (h = 0.24) relating to their binding to bacterial DNA and those with LogP > LogPo undergo lipid entrapment which masks the DNA binding effect. The QSAR has been used to differentiate between lipophilicity and steric inhibition to groove binding in a series of outliers bearing large tert-butyl groups as well as to confirm the enhancement to DNA binding of the naphthalene moiety, which is shown to be equivalent to about 3.5 LogP units.