Synthesis of a series of phenylacetic acid 1-β-O-acyl glucosides and comparison of their acyl migration and hydrolysis kinetics with the corresponding acyl glucuronides.

Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool, UK L69 7ZD.
Organic & Biomolecular Chemistry (Impact Factor: 3.57). 02/2011; 9(3):926-34. DOI: 10.1039/c0ob00820f
Source: PubMed

ABSTRACT We report the synthesis of the 1-β-O-acyl glucoside conjugates of phenylacetic acid (PAA), R- and S-α-methyl-PAA and α,α'-dimethyl-PAA, and measurement of their transacylation and hydrolysis reactivity by NMR methods. These are analogues of acyl glucuronides, the transacylation kinetics of which could be important in adverse drug effects. One aim of this work was to investigate whether, as previously postulated, the free carboxylate group of the acyl glucuronides plays a part in the mechanism of the internal acyl migration. In addition, such acyl glucosides are known to be endogenous biochemicals in their own right and investigation of their acyl migration propensities is novel. Our previously described selective acylation procedure has proved highly successful for 1-β-O-acyl glucuronide synthesis and when subsequently applied to 6-O-trityl glucose, it gave good yields and excellent anomeric selectivity. Mild acidolysis of the O-trityl intermediates gave the desired acyl glucosides in excellent yield with essentially complete β-selectivity. Measurement of the acyl glucoside transacylation kinetics by (1)H NMR spectroscopy, based simply on the disappearance of the 1-β-isomer in aqueous buffer at pH 7.4, showed marked differences depending on the degree of methyl substitution. Further kinetic modelling of the isomerisation and hydrolysis reactions of the acyl glucosides showed considerable differences in kinetics for the various isomeric reactions. Reactions involving the -CH(2)OH group, presumably via a 6-membered ring ortho-ester intermediate, are facile and the α-glucoside anomers are significantly more reactive than their β-counterparts. By comparison with degradation rates for the corresponding acyl glucuronides, it can be inferred that substitution of the carboxylate by -CH(2)OH in the acyl glucosides has a significant effect on acyl migration for those compounds, especially for rapidly transacylating molecules, and that thus the charged glucuronide carboxylate is a factor in the kinetics.

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    ABSTRACT: Covering: 1998 to 2011. Previous review: Nat. Prod. Rep., 1998, 15, 173-186The fourteen years that have passed since the previous review on this topic have seen a significant increase of interest in many aspects of glucuronide chemistry and biology. Glucuronides are the most important class of phase 2 xenobiotic metabolites and typically act in a detoxifying role. While this is generally true for O-alkyl and O-aryl glucuronides, a number of glucuronides are known to be pharmacologically active per se. Additionally the use of glucuronide prodrugs, notably to ameliorate the cytotoxicity of anticancer agents, has markedly increased. Whereas the previous review covered only the synthesis of O-glucuronides, we now include N-, S- and C-glucuronides also and discuss both synthetic and biological aspects. Synthetic methods for all classes of glucuronides are reviewed and updated, together with advances in the enzymatic synthesis of glucuronides and methods for their detection. Finally we discuss the biological reactivity of glucuronides where known, including the important morphine-6-glucuronide. A lively debate has continued for several years on whether O-acyl glucuronide metabolites of carboxylic acids are toxic, affecting both the safety assessment of well-used drugs and new drug development programmes. We summarise the current understanding, together with other known examples of interaction between glucuronides and macromolecules.
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