The influence of conformational factors on the metabolic conjugation of aryloxyacetates

Among p-chlorophenoxyalkanoic acids, the acetate and 2-propionate are essentially inert towards metabolic conjugation, whereas the isobutyrate (clofibric acid) undergoes extensive glucuronidation, as well as amino acid conjugation in carnivores. To try to explain these differences, the conformational behaviour of three model compounds was studied by quantum mechanical calculations (PCILO method). All three compounds prefer syn (folded) conformers, but the isobutyrate, in contrast to its two lower homologues, also has anti (extended) conformers of relatively low energy. Based on these results, a hypothetical topographical model is proposed for the binding site of glucuronyltransferase.