[(14) C]-AZD1152 (barasertib) drug substance was prepared in order to support a hADME study that was to be dosed as an intravenous infusion to patients with acute myeloid leukaemia. A long patient recruitment time (1-2 years) was expected, and because of its limited stability several batches of [(14) C]-AZD1152 drug substance needed to be prepared in order to maintain a supply of [(14) C]-AZD1152 in the clinic over this period. A method was developed to purify the [(14) C]-AZD1152 to a GMP-like standard at high specific activity to provide material for each of these batches. This approach to the delivery of the drug substance was successful in supplying the study with radiolabelled drug for over 1 year until all patients had been recruited.

Meeting Summary The 22nd annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK, on Friday, 18 October 2013. The meeting was attended by 65 delegates from academia and industry; the life sciences; and chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral and poster presentations on isotopic chemistry and applications of labelled compounds, or of chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium programme was divided into a morning session chaired by Dr Karl Cable (GlaxoSmithKline, UK) and afternoon sessions chaired by Mr Mike Chappelle (Quotient Biosciences, UK) and by Dr Nick Bushby (AstraZeneca, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

In support of a program to develop an alpha 7 agonist as a treatment for Alzheimer's disease, three drug candidates, 1, 2, and 3, were prepared in labeled forms. Compound 1 was prepared in C-14 labeled form by lithiation of [2,6-(14)C2]2-chloropyridine and subsequent coupling with spirooxirane-2,3'-quinuclidine. When this same coupling was attempted using [3,4,5,6-(2)H4]2-chloropyridine, alcohol [(2)H6]-6 was the major product indicating that the primary isotope effect for the lithiation step was significant enough to shift the reaction pathway. Therefore, an alternate site of labeling was used to prepare [(2)H4]-1. [(13)C5]-2 was prepared in five steps from [(13)C5 ]2-furoic acid, but the C-14 labeled compound used [(14)C2]-1 as the starting material instead. [(14)C2]-3 was prepared in two steps from [carbonyl-(14)C]nicotinic acid.

Blood-protein transacylation/glycosylation reactivity of glucuronides may distinguish beneficial (e.g., ibuprofen) and toxic (e.g., ibufenac) drugs.

Journal of Labelled Compounds and RadiopharmaceuticalsVolume 54, Issue 7 p. 387-398 Abstract 19th international isotope society (UK group) symposium: synthesis & applications of labelled compounds 2010 P. H. Allen, P. H. Allen Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. J. Bloom, A. J. Bloom Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorR. Bragg, R. Bragg Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorR. T. Brown, R. T. Brown Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. Burgos, A. Burgos Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorN. Bushby, N. Bushby Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. L. Clarke, M. L. Clarke Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorL. F. Dudin, L. F. Dudin Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorG. J. Ellames, G. J. Ellames Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. D. Gee, A. D. Gee Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorV. Gouverneur, V. Gouverneur Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorJ. R. Harding, J. R. Harding Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorD. C. Harrowven, D. C. Harrowven Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorJ. M. Herbert, J. M. Herbert Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. J. Hickey, M. J. Hickey Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. Husbands, S. Husbands Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorL. E. Jennings, L. E. Jennings Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. Jones, M. Jones Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. Kealey, S. Kealey Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorD. Killick, D. Killick Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorL. P. Kingston, L. P. Kingston Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. L. Kitson, S. L. Kitson Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. Kohler, A. Kohler Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. L. Kostiuk, S. L. Kostiuk Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorF. Le Strat, F. Le Strat Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. E. Light, M. E. Light Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorW. J. S. Lockley, Corresponding Author W. J. S. Lockley w.lockley@surrey.ac.uk Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKDivision of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorN. J. Long, N. J. Long Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. H. McNeill, A. H. McNeill Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorP. W. Miller, P. W. Miller Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorT. S. Moody, T. S. Moody Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorV. L. Murrell, V. L. Murrell Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorL. Nanson, L. Nanson Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. H. F. Pedersen, M. H. F. Pedersen Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorK. G. Pinney, K. G. Pinney Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorC. Plisson, C. Plisson Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. Schou, S. Schou Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorR. S. Sharma, R. S. Sharma Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorI. Shaw, I. Shaw Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorR. Sherhod, R. Sherhod Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorT. Smith, T. Smith Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. Sriram, M. Sriram Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorJ. Tate, J. Tate Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. Tredwell, M. Tredwell Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. Twiddy, S. Twiddy Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorW. Watters, W. Watters Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. J. P. White, A. J. P. White Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorD. J. Wilkinson, D. J. Wilkinson Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorT. Woodcock, T. Woodcock Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this author P. H. Allen, P. H. Allen Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. J. Bloom, A. J. Bloom Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorR. Bragg, R. Bragg Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorR. T. Brown, R. T. Brown Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. Burgos, A. Burgos Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorN. Bushby, N. Bushby Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. L. Clarke, M. L. Clarke Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorL. F. Dudin, L. F. Dudin Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorG. J. Ellames, G. J. Ellames Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. D. Gee, A. D. Gee Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorV. Gouverneur, V. Gouverneur Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorJ. R. Harding, J. R. Harding Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorD. C. Harrowven, D. C. Harrowven Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorJ. M. Herbert, J. M. Herbert Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. J. Hickey, M. J. Hickey Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. Husbands, S. Husbands Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorL. E. Jennings, L. E. Jennings Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. Jones, M. Jones Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. Kealey, S. Kealey Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorD. Killick, D. Killick Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorL. P. Kingston, L. P. Kingston Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. L. Kitson, S. L. Kitson Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. Kohler, A. Kohler Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. L. Kostiuk, S. L. Kostiuk Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorF. Le Strat, F. Le Strat Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. E. Light, M. E. Light Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorW. J. S. Lockley, Corresponding Author W. J. S. Lockley w.lockley@surrey.ac.uk Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKDivision of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorN. J. Long, N. J. Long Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. H. McNeill, A. H. McNeill Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorP. W. Miller, P. W. Miller Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorT. S. Moody, T. S. Moody Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorV. L. Murrell, V. L. Murrell Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorL. Nanson, L. Nanson Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. H. F. Pedersen, M. H. F. Pedersen Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorK. G. Pinney, K. G. Pinney Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorC. Plisson, C. Plisson Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. Schou, S. Schou Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorR. S. Sharma, R. S. Sharma Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorI. Shaw, I. Shaw Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorR. Sherhod, R. Sherhod Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorT. Smith, T. Smith Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. Sriram, M. Sriram Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorJ. Tate, J. Tate Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorM. Tredwell, M. Tredwell Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorS. Twiddy, S. Twiddy Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorW. Watters, W. Watters Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorA. J. P. White, A. J. P. White Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorD. J. Wilkinson, D. J. Wilkinson Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this authorT. Woodcock, T. Woodcock Division of Chemistry, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UKSearch for more papers by this author First published: 26 April 2011 https://doi.org/10.1002/jlcr.1878Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume54, Issue715 June 2011Pages 387-398 RelatedInformation

(S)-4,4-Dichloro-3-methylbutanoic acid was prepared in 51% overall yield from commercially available starting materials using an organocatalytic transfer hydrogenation to 4,4-dichloro-3-methylbut-2-enal in the key step. The (S)-dichloro acid was used as an intermediate in the first total synthesis of dysideaproline E and a diastereomer confirming the structure of the natural product.

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.

The use of high-performance liquid chromatography/mass spectrometry (HPLC/MS) and proton nuclear magnetic resonance ((1)H NMR) spectroscopy for the kinetic analysis of acyl glucuronide (AG) isomerisation and hydrolysis of the 1-β-O-acyl glucuronides (1-β-O-AG) of phenylacetic acid, (R)- and (S)-α-methylphenylacetic acid and α,α-dimethylphenylacetic acid is described and compared. Each AG was incubated in both aqueous buffer, at pH 7.4, and control human plasma at 37°C. Aliquots of these incubations, taken throughout the reaction time-course, were analysed by HPLC/MS and (1)H NMR spectroscopy. In buffer, transacylation reactions predominated, with relatively little hydrolysis to the free aglycone observed. In human plasma incubations the calculated rates of reaction were much faster than for buffer and, in contrast to the observations in buffer, hydrolysis to the free aglycone was a significant contributor to the overall reaction.A diagnostic analytical methodology based on differential mass spectrometric fragmentation of 1-β-O-AGs compared to the 2-, 3- and 4-positional isomers, which enables selective determination of the former, was confirmed and applied. These findings show that HPLC/MS offers a viable alternative to the more commonly used NMR spectroscopic approach for the determination of the transacylation and hydrolysis reactions of these AGs, with the major advantage of having the capability to do so in a complex biological matrix such as plasma.

Many widely-used non-steroidal anti-inflammatory agents (NSAIDs), e.g. ibuprofen, are extensively metabolised as their acyl glucuronides (AGs), and the reactivity of these AGs raises important questions regarding drug safety and toxicity. In order to understand better the structure-reactivity of these metabolites, we have performed a detailed study of the synthesis, structural analysis and computed transacylation reactivity of a set of acyl glucuronides (AGs) of phenylacetic acids with varying alpha-substitution. A selective acylation procedure was used to prepare all the desired 1-(phenyl)acetyl-beta-D-glucopyranuronic acids 9, 12, 13 and 15 as single 1beta-anomers in good yields. Their reactivity was measured using 1H NMR spectroscopy in pH 7.4 buffer: the dominance of transacylation over hydrolysis in this system was confirmed together with the measurement of half-lives of the 1beta-isomers of the AGs. The half-lives ranged from 20 min for compound 9 to 23 h for 15. The lack of any significant concentration dependence of the reactivity suggests that the main mechanism is intramolecular. A novel computational chemistry and modelling study was performed on both the ground states of the AGs and the transition states for acyl migration to search for correlations with the kinetic data and to probe the mechanistic detail of the acyl transfer. An excellent degree of correlation was found between the calculated activation energies and the rates of transacylation. Especially, transition state analysis provided for the first time a firm mechanistic explanation for the slower kinetics of the (S)-isomer AG 13 compared to the (R)-isomer 12, thus throwing important light on the pharmacokinetic behaviour of marketed NSAIDs.

N-Glucuronides, of various structural types, are frequently encountered as drug metabolites. Efficient chemical synthesis of these compounds, both as analytical standards and for toxicological investigation, is therefore an important goal. Earlier syntheses of N+- glucuronides of aliphatic tertiary amine drugs involved direct reaction of the drug molecule with a bromosugar, but yields were generally low and of poor reproducibility, with many by-products. In addition the final products were often of low stability, hindering effective isolation and purification. We now report that a stable, readily prepared glucuronic acid hemiacetal is a reliable precursor for metabolites of this type and give three pharmaceutically relevant examples. We report further on the stability of the final metabolites and the conditions required for their isolation and purification.

We report convenient syntheses of anomeric quaternary ammonium β-glucosides in both protected and deprotected forms, together with X-ray structural investigations of two of the products. Both the quaternisation of a protected anomeric N,N-(dimethylamino)glucose, derived in two high-yielding steps from the anomeric azide, and the direct reaction of glucose or 6-O-trityl glucose with a secondary amine, followed by protection and quaternisation, are viable routes. We also discuss the significance, in terms of stereoelectronic effects, of the observed C–N bond lengths and the stabilities of the products.

Methapyrilene (MP), a 2-thiophene H1-receptor antagonist, is a model toxicant in the genomic and proteomic analyses of hepatotoxicity. In rats, it causes an unusual periportal necrosis that is hypothetically attributed to chemically reactive and cytotoxic metabolites. We have characterized the bioactivation of MP by hepatic microsomes and primary rat hepatocytes, and we established a possible causal linkage with cytotoxicity. Methapyrilene tritiated at C-2 of the diaminoethane moiety ([3H]MP) was metabolized via an NADPH-dependent pathway to intermediates that combined irreversibly with microsomes (rat > mouse ≈ human). This binding was attenuated by the cytochrome P450 (P450) inhibitor 1-aminobenzotriazole and thiols but not by trapping agents for iminium ions and aldehydes. Reactive intermediates were trapped as thioether adducts of monooxygenated MP. Mass spectrometric and hydrogen/deuterium exchange analysis of the glutathione adduct produced by rat liver microsomes indicated that the metabolite was most probably a thioether of MP S-oxide substituted in the thiophene ring. The glutathione adduct was formed by rat hepatocytes and eliminated in bile by rats administered [3H]MP intravenously. MP produced concentration- and time-dependent cytotoxicity, depleted glutathione, and underwent irreversible binding to the hepatocytes before a significant increase in cell damage was observed. P450 inhibitors reduced turnover of the drug, production of the glutathione adduct, irreversible binding, and cytotoxicity but inhibited glutathione depletion selectively. MP underwent lesser turnover and bioactivation in mouse hepatocytes and was not cytotoxic. Analogs with phenyl and p-methoxyphenyl rings were much less hepatocytotoxic than MP. Hepatotoxicity in rats was diminished by predosing with 1-aminobenzotriazole. For the first time, a thiophene ring substituent is identified as a bioactivation-dependent toxicophore in hepatocytes.

Journal of Labelled Compounds and RadiopharmaceuticalsVolume 51, Issue 6 p. 247-261 Abstract 16th International Isotope Society (UK group) Symposium Synthesis and applications of labelled compounds 2007 G. Åberg, G. ÅbergSearch for more papers by this authorF. I. Aigbirhio, F. I. AigbirhioSearch for more papers by this authorE. Alexakis, E. AlexakisSearch for more papers by this authorN. Al-Maharik, N. Al-MaharikSearch for more papers by this authorM. Almi, M. AlmiSearch for more papers by this authorY. Ambacher, Y. AmbacherSearch for more papers by this authorS. Andersson, S. AnderssonSearch for more papers by this authorA. Athlan, A. AthlanSearch for more papers by this authorG. Badman, G. BadmanSearch for more papers by this authorS. A. Baldwin, S. A. BaldwinSearch for more papers by this authorM. Baumann, M. BaumannSearch for more papers by this authorI. R. Baxendale, I. R. BaxendaleSearch for more papers by this authorN. P. Botting, N. P. 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W. M. Lawrie, K. W. M. LawrieSearch for more papers by this authorS. V. Ley, S. V. LeySearch for more papers by this authorG. Little, G. LittleSearch for more papers by this authorW. J. S. Lockley, Corresponding Author W. J. S. Lockley [email protected] Division of Chemistry, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UKDivision of Chemistry, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UKSearch for more papers by this authorD. Maier, D. MaierSearch for more papers by this authorC. Manning, C. ManningSearch for more papers by this authorA. McNeill, A. McNeillSearch for more papers by this authorD. A. Middleton, D. A. MiddletonSearch for more papers by this authorS. Montgomery, S. MontgomerySearch for more papers by this authorJ. J. Morrison, J. J. MorrisonSearch for more papers by this authorL. Mrzljak, L. MrzljakSearch for more papers by this authorJ. Newman, J. 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Song, C. SongSearch for more papers by this authorL. Tamborini, L. TamboriniSearch for more papers by this authorI. Waterhouse, I. WaterhouseSearch for more papers by this authorA. Watts, A. WattsSearch for more papers by this authorJ. L. Werkheiser, J. L. WerkheiserSearch for more papers by this authorG. Williams, G. WilliamsSearch for more papers by this authorC. L. Willis, C. L. WillisSearch for more papers by this authorP. Woodward, P. WoodwardSearch for more papers by this authorR. Yan, R. YanSearch for more papers by this authorG. Young, G. YoungSearch for more papers by this authorQ. Zhang, Q. ZhangSearch for more papers by this author First published: 28 May 2008 https://doi.org/10.1002/jlcr.1513Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Citing Literature Volume51, Issue6May 2008Pages 247-261 RelatedInformation

Acyl glucuronides are key metabolites for many carboxylic acid-containing drugs, notably those of the non-steroidal anti-inflammatory class. In the processes of drug safety assessment and new drug development, it is essential that acyl glucuronides, if formed in vivo, should be made conveniently available for bioevaluation. We recently showed that selective acylation of allyl glucuronate is a promising method for the synthesis of these metabolites in good yield and with excellent β-anomeric selectivity. We now give fuller details of the allyl ester method and further report that benzyl glucuronate performs at least equally well in the acylation step, offering the advantage of very mild deprotection by catalytic transfer (or conventional) hydrogenation. Depending on the compatibility of other functional groups, as discussed below, this will be the method of choice for many acyl glucuronide syntheses. The value of the method is demonstrated in particular by the synthesis of several acyl glucuronides that are known metabolites of important drugs.

Journal of Labelled Compounds and RadiopharmaceuticalsVolume 50, Issue 5-6 p. 431-432 Short Research Article Synthesis of isotopically labelled ZD4054† Julie A. Bergin, Julie A. Bergin Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorHelen Booth, Helen Booth Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorRyan A. Bragg, Ryan A. Bragg Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorNick Bushby, Nick Bushby Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorJohn R. Harding, Corresponding Author John R. Harding [email protected] Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKIsotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorAngela Jordan, Angela Jordan Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorClare D. King, Clare D. King Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this author Julie A. Bergin, Julie A. Bergin Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorHelen Booth, Helen Booth Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorRyan A. Bragg, Ryan A. Bragg Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorNick Bushby, Nick Bushby Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorJohn R. Harding, Corresponding Author John R. Harding [email protected] Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKIsotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorAngela Jordan, Angela Jordan Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this authorClare D. King, Clare D. King Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKSearch for more papers by this author First published: 30 July 2007 https://doi.org/10.1002/jlcr.1177 † Proceedings of the Ninth International Symposium on the Synthesis and Applications of Isotopically Labelled Compounds, Edinburgh, 16–20 July 2006. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume50, Issue5-6Special Issue: Proceedings of the Ninth International Symposium on the Synthesis and Applications of Isotopically Labelled Compounds, Edinburgh, 16–20 July 2006.April ‐ May 2007Pages 431-432 RelatedInformation