NMR IDENTIFICATION OF AN <i>S</i>-LINKED GLUCURONIDE OF A TRIAZOLE  THIONE FORMED IN VITRO

Martin, Iain; Lewis, Richard J.; Bonnert, Roger V.; Cage, Peter; Moody, Graeme C.

doi:10.1124/dmd.31.6.694

Cited by 14 publications

(10 citation statements)

References 11 publications

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“…These data confirm that the benzoxazine-2-thione (N(CϭS)O) of tanaproget did not rearrange to a thionocarbamate (N(CϭO)S) group before glucuronidation. Key 1 H and 13 C NMR chemical shift data reported above for the S-glucuronide 3 were similar to those reported in the literature for two other S-␤-(D)-glucuronides (Ethell et al, 2003;Martin et al, 2003).…”

Section: Resultssupporting

confidence: 72%

“…The synthetic glucuronide 3 that was determined to be S-glucuronide was found to have retention times identical to that of metabolite M1 under all 10 HPLC conditions. Literature reports of glucuronide conjugation through an S-linkage are rare (Jeffcoat et al, 1980;Nakaoka et al, 1989;Smith et al, 1992;Ethell et al, 2003;Martin et al, 2003), with little data available on their structural characterization or the UDP-glucuronosyltransferases (UGTs) catalyzing their formation. N-and O-glucuronides are more commonly observed (Green and Tephly, 1998;Hawes, 1998;Kuehl and Murphy, 2003;Tricker, 2003).…”

Section: Resultsmentioning

confidence: 99%

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NMR CHARACTERIZATION OF AN S-LINKED GLUCURONIDE METABOLITE OF THE POTENT, NOVEL, NONSTEROIDAL PROGESTERONE AGONIST TANAPROGET

Keating

McConnell²,

Zhang³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Tanaproget is a first-in-class nonsteroidal progesterone receptor agonist that is being investigated for use in contraception. A major in vitro and in vivo metabolite of tanaproget formed in humans was initially characterized as a glucuronide of tanaproget. However, whether the glucuronide was linked to the nitrogen or sulfur of the benzoxazine-2-thione group in tanaproget could not be determined by liquid chromatography/mass spectrometry (LC/MS) and LC-tandem mass spectrometry analysis. To obtain additional structural details for this metabolite, additional quantities were generated from rat liver microsomal incubations and purified by high-performance liquid chromatography (HPLC) for NMR analysis. The NMR data for the metabolite confirmed that the glucuronide was covalently bound to either the sulfur or the nitrogen of the benzoxazine-2-thione moiety. The lack of key through-bond (scalar) and through-space (dipolar) one-dimensional (1D) and twodimensional (2D) NMR couplings and correlations in the metabolite spectra (due primarily to low sample concentration) precluded an unambiguous structure elucidation. Subsequent synthesis of the S-and N-glucuronides of tanaproget from tanaproget facilitated the unambiguous regio-and stereochemical assignment of the metabolite by comparison of 1D NMR chemical shifts and scalar coupling constants, 2D NMR correlations, and HPLC and LC/MS characteristics between the synthetic compounds and the metabolite. From extensive comparison of the spectral and chromatographic data of the microsomally derived metabolite and the synthetic compounds, the metabolite has been determined to be the S-(␤)-D-glucuronide of tanaproget.Tanaproget is a potent, first-in-class nonsteroidal progesterone receptor agonist being investigated at Wyeth for use in contraception (Fensome et al., 2005;Zhang et al., 2005). Earlier studies indicated that a major conjugated metabolite (Ͼ10%), referred to here as M1, was formed in rat and human liver microsomal incubations, and initially characterized by LC/MS as a glucuronide of tanaproget. The glucuronic acid group was proposed to be either on the nitrogen or the sulfur of the benzoxazine-2-thione moiety of tanaproget (1, Scheme 1). Oxidative metabolism represented a minor metabolic pathway of 1 in both in vitro and in vivo studies.Analysis of the initial NMR data of M1 from rat liver microsomes confirmed that the glucuronide was covalently bound to either the Sor the N-form of the benzoxazine-2-thione moiety. However, due to an insufficient amount (approximately a few micrograms) of the sample in solution, we could not record complete scalar and dipolar 1D and 2D NMR couplings and correlations for an unambiguous structure elucidation. The NMR analysis was especially challenging because of the lack of protons in the benzoxazine-2-thione moiety, particularly in the scenario of an S-glucuronide conjugate of tanaproget, since most heteronuclear correlations between the sugar and the parent molecule would be too long range to be observed.Because of the ch...

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Section: Resultssupporting

confidence: 72%

Section: Resultsmentioning

confidence: 99%

NMR CHARACTERIZATION OF AN S-LINKED GLUCURONIDE METABOLITE OF THE POTENT, NOVEL, NONSTEROIDAL PROGESTERONE AGONIST TANAPROGET

Keating

McConnell²,

Zhang³

et al. 2006

Drug Metab Dispos

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“…The two-dimensional NMR experiments clearly demonstrated that the glucuronic acid linkage to BMS-204352 is through the amide nitrogen. Recently, two tautomeric S-glucuronides formed from thio-amides were reported (Ethell et al, 2003;Martin et al, 2003). Smith and Williams (1949) identified the first N-glucuronide of aniline in urine of rabbit dosed with aniline.…”

Section: Discussionmentioning

confidence: 99%

AMIDE N-GLUCURONIDATION OF MAXIPOST CATALYZED BY UDP-GLUCURONOSYLTRANSFERASE 2B7 IN HUMANS

Zhang¹,

Zhao²,

Roongta³

et al. 2004

Drug Metab Dispos

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“…AR-C133611XX, a CXCR2 receptor antagonist, has been shown to be metabolized to an S-linked conjugate in dog hepatocytes as a major metabolic pathway. Structure elucidation by NMR revealed the Sglucuronide to be present on triazole thione moiety in the molecule (Martin et al, 2003). Finally, phenotyping information on formation of S-glucuronides is scarce.…”

Section: Sulfur-linked Glucuronidesmentioning

confidence: 99%

Unusual Glucuronides

Argikar¹

2012

Drug Metab Dispos

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ABSTRACT:Glucuronidation reaction is catalyzed by mammalian uridine diphosphoglucuronosyl transferases by using uridine diphosphoglucuronic acid as a cosubstrate. Conjugation of glucuronic acid to nucleophilic functional groups in chemical entities results in formation of glucuronides. As anticipated, a number of nucleophilic functional groups such as hydroxyl, phenolic, acyl, primary secondary and tertiary amino, etc. in a diverse set of chemical compounds are known to form the corresponding glucuronides. Glucuronides have been reported to be formed at carbon atoms, selenium atoms, and upon N-carbamoylation of primary and secondary amino groups. Glucuronides are also believed to be the end products of metabolism. However, there are examples where glucuronidation results in further oxidative or conjugative biotransformation reactions. The objective of this review is to highlight unusual glucuronide conjugates. Diglucuronide conjugates reported in the literature fall under two distinct categories. Use of prefixes such as "bis" versus "di" has been previously proposed for separating the two types of diglucuronides. In spite of this, literature reports for diconjugative glucuronide metabolites reflect interchangeable use of "bisglucuronides" and "diglucuronides." Furthermore, the application of such prefixes does not adhere to recommendations of International Union of Pure and Applied Chemistry nomenclature for substituent groups. Therefore, an effort is made in this review to document the historic reports for diglucuronides into two distinct types for sake of clarity and to allow differentiation between the two types of diconjugative metabolites. Overall, this commentary centers on unusual glucuronide metabolites that result from conjugation at uncommon functional groups, glucuronides undergoing ensuing oxidative or conjugative metabolic transformations. Structural and mechanistic aspects are also discussed.

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NMR IDENTIFICATION OF AN S-LINKED GLUCURONIDE OF A TRIAZOLE THIONE FORMED IN VITRO

Cited by 14 publications

References 11 publications

NMR CHARACTERIZATION OF AN S-LINKED GLUCURONIDE METABOLITE OF THE POTENT, NOVEL, NONSTEROIDAL PROGESTERONE AGONIST TANAPROGET

NMR CHARACTERIZATION OF AN S-LINKED GLUCURONIDE METABOLITE OF THE POTENT, NOVEL, NONSTEROIDAL PROGESTERONE AGONIST TANAPROGET

AMIDE N-GLUCURONIDATION OF MAXIPOST CATALYZED BY UDP-GLUCURONOSYLTRANSFERASE 2B7 IN HUMANS

Unusual Glucuronides

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