Structural effects upon the mutagenicity of N-acyloxy-N-alkoxyamides

Abstract

N-Acyloxy-N-alkoxyamides are members of a recently discovered class of compounds known as anomeric amides, amides bearing two heteroatoms at nitrogen. They possess unusual characteristics such as pyramidality at nitrogen, reduced amide resonance and are able to undergo SN2 reactions at nitrogen, which has been shown to be the mechanism by which they exhibit biological activity. They are direct-acting mutagens in Salmonella typhimurium TA100. To date the extent to which structural features contribute to their biological activity has been quantified in a limited Quantitative Structure Activity Relationship (QSAR). In previously reported studies of steric effects on the amide and acyloxyl side-chains, branching resulted in significant diminution of activity. In this thesis the study of the role of proximal steric effects has been completed. It has been shown that, in contrast, branching on the alkoxyl side-chain has little impact upon the mutagenic activity of N-acyloxy-N-alkoxyamides. Incorporation of eight new compounds from this series led to a revised linear QSAR.