Efficient synthesis of 1β-O-acyl glucuronides via selective acylation of allyl or benzyl d-glucuronate

Bowkett, Elizabeth R.; Harding, John; Maggs, James L.; Park, B. Kevin; Perrie, Jennifer A.; Stachulski, Andrew V.

doi:10.1016/j.tet.2007.05.050

Cited by 35 publications

(24 citation statements)

References 22 publications

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“…The observation that (a) 13 C NMR shift can be reliably predicted; (b) in combination with steric descriptors, ester hydrolysis rates can be predicted and (c) this is correlated with AG degradation rate led us to conclude that a purely in silico prediction of AG reactivity could be achieved. Due to the limited data sets of AG degradation data available in the literature, the novel methodology that we have described allows the ranking of future diverse chemistry targets with a strong association to gold-standard AG reactivity data.…”

Section: Discussionmentioning

confidence: 93%

“…While 13 . 7) to predict methyl ester hydrolysis rate shows good predictivity over a 2.5 log unit range in reactivity, and the independent test set of NSAIDs is well predicted.…”

Section: Discussionmentioning

confidence: 99%

“…Our approach firstly involved using readily synthesised methyl esters of carboxylic acids as a surrogate for the corresponding AG and establishing a correlation between AG degradation rate and the hydrolysis rate of the corresponding methyl ester of the parent carboxylic acid. Secondly, a correlation was observed between methyl ester hydrolysis rates of a large structurally diverse set of compounds and the measured 13 [13] by or by biosynthesis as described below.…”

Section: Introductionmentioning

confidence: 99%

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In silico prediction of acyl glucuronide reactivity

Potter

Lewis

Luker

et al. 2011

J Comput Aided Mol Des

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Drugs and drug candidates containing a carboxylic acid moiety, including many widely used non-steroidal anti-inflammatory drugs (NSAIDs) are often metabolized to form acyl glucuronides (AGs). NSAIDs such as Ibuprofen are amongst the most widely used drugs on the market, whereas similar carboxylic acid drugs such as Suprofen have been withdrawn due to adverse events. Although the link between these AG metabolites and toxicity is not proven, there is circumstantial literature evidence to suggest that more reactive acyl glucuronides may, in some cases, present a greater risk of exhibiting toxic effects. We wished therefore to rank the reactivity of potential new carboxylate-containing drug candidates, and performed kinetic studies on synthetic acyl glucuronides to benchmark our key compounds. Driven by the desire to quickly rank the reactivity of compounds without the need for lengthy synthesis of the acyl glucuronide, a correlation was established between the degradation half-life of the acyl glucuronide and the half life for the hydrolysis of the more readily available methyl ester derivative. This finding enabled a considerable broadening of chemical property space to be investigated. The need for kinetic measurements was subsequently eliminated altogether by correlating the methyl ester hydrolysis half-life with the predicted (13)C NMR chemical shift of the carbonyl carbon together with readily available steric descriptors in a PLS model. This completely in silico prediction of acyl glucuronide reactivity is applicable within the earliest stages of drug design with low cost and acceptable accuracy to guide intelligent molecular design. This reactivity data will be useful alongside the more complex additional pharmacokinetic exposure and distribution data that is generated later in the drug discovery process for assessing the overall toxicological risk of acidic drugs.

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Section: Discussionmentioning

confidence: 93%

“…While 13 . 7) to predict methyl ester hydrolysis rate shows good predictivity over a 2.5 log unit range in reactivity, and the independent test set of NSAIDs is well predicted.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In silico prediction of acyl glucuronide reactivity

Potter

Lewis

Luker

et al. 2011

J Comput Aided Mol Des

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“…The chemical synthesis of diclofenac 1-b AG via a modified form of the method of Bowkett et al (2007) is described in Supplemental Scheme 1.…”

Section: Methodsmentioning

confidence: 99%

Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from a Drug Acyl Glucuronide Metabolite: Multiple Albumin Adductions in Diclofenac Patients

Hammond

Meng

Jenkins

et al. 2014

J Pharmacol Exp Ther

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Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in liver and plasma of experimental animals and humans. However, in the absence of definitive molecular characterization, and specifically, identification of signature glycation conjugates retaining the glucuronyl and carboxyl residues, it cannot be assumed any of these adducts is derived uniquely or even fractionally from AG metabolites. We have therefore undertaken targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-derived structures and, thereby, for the first time, have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. These analyses were informed by a thorough understanding of the reactions of HSA with diclofenac AG in vitro. HSA from six patients without drug-related hypersensitivities had either a single drug-derived adduct or one of five combinations of 2-8 adducts from among seven diclofenac N-acylations and three AG glycations on seven of the protein's 59 lysines. Only acylations were found in every patient. We present evidence that HSA modifications by diclofenac in vivo are complicated and variable, that at least a fraction of these modifications are derived from the drug's AG metabolite, and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association.

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“…The configuration of the glycosidic linkage was confirmed by 1 H NMR (6.17 ppm, br s, H-1 0 ). Therefore, we turned to another approach recently developed by Stachulski and co-workers 26,27 allowing the stereoselective formation of b-glucuronides. As shown in Scheme 1, the selective acylation of allyl glucuronate (6) with betulinic acid (1) was tried using O-(7-azabenzotriazol-1-yl)-N,N,N 0 ,N 0 -tetramethyluronium hexafluorophosphate (HATU) and N-methylmorpholine (NMM) in acetonitrile (CH 3 CN).…”

mentioning

confidence: 99%