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: 3.56). 02/2011; 9(3):926-34. DOI: 10.1039/c0ob00820f
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.
- [Show abstract] [Hide abstract]
ABSTRACT: UDP-glycosyltransferases (UGTs) are an important group of enzymes that participate in phase II metabolism of xenobiotics and use the cofactor UDP-glucuronic acid for the production of glucuronides. When acting on molecules bearing a carboxylic acid they can form acyl glucuronides, a group of metabolites that has gained significant interest in recent years because of concerns about their potential role in drug toxicity. In contrast, reports about the production of drug acyl glucosides (which might also display high reactivity) have been scarce. In this study, we discovered the formation of acyl glycoside metabolites of R- and S-ibuprofen (Ibu) by human liver microsomes supplied with the cofactor UDP-glucose. Subsequently, human UGT2B7*1 and UGT2B7*2 recombinantly expressed in fission yeast Schizosaccharomyces pombe could be shown to catalyze these reactions. Moreover, we could enhance the glucoside production rate in fission yeast by overexpressing the fission yeast gene SPCC1322.04, a potential UDP-glucose pyrophosphorylase (UGPase), but not by overexpression of SPCC794.10, and therefore suggest to name this gene fyu1 for fission yeast UGPase1. It was interesting to note that pronounced differences between the two polymorphic UGT2B7 variants were observed with respect to acyl glucoside production. Finally, using the metabolic precursor [(13)C(6)]glucose, we demonstrated the production of stable isotope-labeled reference standards of Ibu acyl glucoside and Ibu acyl glucuronide by whole-cell biotransformation in fission yeast.Drug metabolism and disposition: the biological fate of chemicals 08/2011; 39(12):2174-81. DOI:10.1124/dmd.111.041640 · 3.25 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: This chapter reviews computational and experimental studies of pericyclic and pseudopericyclic reactions that show sequential transition structures on the potential energy surfaces. It has been reported that Cplex-isoelectronic theory predicts endo selectivity in Diels–Alder reactions. The chapter presents a review of the use of electrocyclic reactions in synthesis. It also talks about the origin of the torquoselectivity in the thermal ring opening of cyclobutenes based on the Cplex-isoelectronic theory and expanded Robinson electronic theory. A reaction sequence involving a Nazarov cyclization followed by two sequential Wagner–Meerwein migrations has been reported to give spirocyclic compounds from divinyl ketones in the presence of copper(II) complexes. The Beckmann rearrangement has been used for the synthesis of glycoside-derived lactams from oxime precursors. The chapter discusses the role of acid-promoted palladium-catalysed isomerization in the skeletal rearrangement of cyclic amines.12/2012: pages 393-417;
- [Show abstract] [Hide abstract]
ABSTRACT: An increased reaction rate for lipase-catalyzed N-acylation of amino alcohols relative to that of monofunctionalized amines can be explained by a hydrogen shuttling mechanism that avoids nitrogen inversion in the transition state. The mechanism does not involve acyl migration from an ester intermediate that would be formed first, an explanation that permeates the literature. Our suggested reaction mechanism is dependent on the preference of amino alcohols to form intramolecular hydrogen bonds and the capability of the enzyme to accommodate and exploit the specific hydrogen bonding pattern provided by the ligand during catalysis. Our proposed proton shuttle mechanism involves the transfer of two protons in the transition state concomitant with a nucleophilic attack on the acyl enzyme and provides an explanation for the high reaction rate and chemoselectivity for lipase-catalyzed N-acylation of amino alcohols. Moreover, the proton shuttle mechanism explains the increased reaction rate for the enzyme-catalyzed Nacylation of diamines and of methoxy-2-propylamine, for which O- to N-acyl migration is impossible. A linear free-energy relationship analysis based on the experimental results showed that all of our investigated difunctionalized amine substrates afforded a substrate-assisted rate acceleration of the N-acylation by the same reaction mechanism. Furthermore, the results of the analysis were consistent with partial proton transfer in the rate-limiting transition state, which further supports our suggested proton shuttle mechanism.ChemCatChem 02/2013; 5(7):1842. DOI:10.1002/cctc.201200751 · 4.56 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.