Mutagenic N-Acyloxy-N-alkoxyamides: Probes for Drug–DNA Interactions

Abstract

N-acyloxy-N-alkoxyamides are direct-acting mutagens in Salmonella typhimurium TA100 and react with DNA at N7 of guanine and N3 of adenine. From extensive mutagenicity data a quantitative structure–activity relationship (QSAR) has been derived that predicts activity to be dependent upon hydrophobicity (represented by log P) and stability to chemical reactions (through the _pK_A value of the leaving carboxylic acid group). Sterically bulky substituents (represented by Taft E_S parameters) reduce activity. Deviations from this QSAR highlight structural features that can enhance or impede association of small molecules with DNA. Naphthyl, pyrenyl, and fluorenyl substituents raise activity significantly, possibly through an intercalative effect. The influence of a single sterically bulky tert-butyl group remote from the reactive nitrogen is adequately modelled by the QSAR. However, substrates with two or more such groups show radically reduced activity, most likely through a groove exclusion process. Branching close to the reactive centre strongly reduces activity in line with a steric inhibition of reaction with DNA.