Chemistry and Reactivity of Acyl Glucuronides

Andrew      V. Stachulski

doi:10.2174/138920011795101822

Abstract

This review presents a survey of acyl glucuronides (AGs) from the perspective of a synthetic medicinal chemist. After a brief introduction to the biogenesis of AGs and current attitudes of the pharmaceutical industry towards them, the importance of the availability of pure synthetic AGs as probe molecules is stressed. Current synthetic methods including the selective acylation method and enzymatic procedures are discussed with actual drug examples. The major reaction pathways of AGs, acyl migration and direct acyl transfer, are then examined with consideration of both in vitro and in vivo situations. Both the aglycone and the carbohydrate residue are shown to be important in determining the reactivity of AGs, especially the α-substitution in aryl acetates and propionates and aryl substitution in benzoates. The significance of these effects for important drugs such as the NSAIDs diclofenac and ibuprofen is noted. Appropriate models of the reactivity of AGs with proteins are presented, from short model peptides to body proteins, and examples where AGs clearly interact with protein in vivo (e. g. mycophenolic acid) are presented. Recent results with AGs in plasma, where half-lives differ significantly from their values in aqueous buffer, show the importance of considering the external medium especially when other hydrolytic enzymes are present. Finally, the importance of considering the reactivity of acyl thioesters-which may be formed directly or via AGs as intermediates- is also stressed. This pathway may lead to different protein reactivity than shown for AGs themselves, including interference with the glutathione pathway as shown for NSAID-like carboxylic acids.

Keywords: Drug metabolism, drug toxicity, glucuronides, acyl migration, carbohydrate synthesis, protein reactivity, aglycone, NSAID, mycophenolic acid, acidolysis