Glucuronide conjugates of Soraprazan (BY359), a new potassium-competitive acid blocker (P-CAB) for the treatment of acid-related diseases

Glucuronide conjugates of Soraprazan (BY359), a potent novel anti-secretory drug (currently in Phase II clinical trials), were not directly accessible synthetically. This was due to the relative instability of Soraprazan under the harsh Lewis acid conditions employed in popular glucuronidation methodologies and a lack of reactivity under alternative, Koenigs-Knorr, coupling conditions. We have now devised a successful synthesis using the novel N-acetylated Soraprazan to access the required glucuronide metabolites on gram scale. Coupling of this novel aglycone with methyl 1-O-trichloroacetimidoyl-2,3,5-tri-O-isobutyryl-α-d-glucopyran-uronate in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) gave the protected glucuronide intermediates. A one-pot two-step deprotection involving hydrolysis of the ester functionalities and removal of the N-acetyl group with alkaline hydrazine delivered the title compounds in satisfactory yield.     

Liquid chromatography–electrospray tandem mass spectrometry investigations of fragmentation pathways of biliary 4,4′-methylenedianiline conjugates produced in rats

4,4′-methylenedianiline (DAPM) is the main building block for production of 4,4′-methylenediphenyldiisocyanate that has been widely used in the manufacturing of polyurethane materials including medical devices. Although it was revealed that damage to biliary epithelial cells of the liver and common bile duct occurred upon acute exposure to DAPM, the exact mechanism of DAPM toxicity is not fully understood. Both phase I and II biotransformations of DAPM, some of which generate reactive intermediates, are characterized in detail by liquid chromatography electrospray tandem mass spectrometry. The two most prominent metabolites found in rat bile (M2 and M7) implicated glutathione, glucuronic acid, and glycine conjugations (phase II) following hydroxylation, and N-oxidation (phase I). Their decomposition pathways, as evidenced by MS ⁿ experiments, have been elucidated in detail. Figure Proposed fragmentation pathways of a DAPM metabolite     

Strategies for reducing solvent toxicity in extractive ethanol fermentation

A glucuronide of a novel cholesterol absorption inhibitor was synthesized on a 200-mg scale in one step via bovine liver glucuronyltransferase-catalyzed coupling of the glucuronyl moiety of UDP-glucuronic acid with the phenolic hydroxyl of Sch 58235. It was shown that the product yield is limited by the hydrolysis of UDP-glucuronic acid by impurities present in the commercial microsomal preparation of the transferase. This detrimental effect of UDPGluA hydrolysis could be diminished by the presence of high concentration of glucuronlytransferase. Optimization of reaction conditions and purification procedure resulted in a process that proceeded with 95% conversion and 88% isolated product yield. The¹³C₆-glucuronide of Sch 58235 was prepared with the help of a cascade of eight enzymes operating concurrently in one pot.     

Discovery of neurosteroid glucuronides in mouse brain

Neurosteroid glucuronides were found for the first time in brain samples. The intact glucuronides were extracted from the cortex, hippocampus, hypothalamus, and mid-brain tissues of nicotine- and water-treated mice, and detected with capillary liquid chromatography-electrospray-tandem mass spectrometry (CapLC-ESI-MS/MS). The glucuronides of estradiol, cortisol, corticosterone, tetrahydrodeoxycorticosterone, pregnenolone, and isopregnanolone were identified by comparing retention times in selected reaction monitoring (SRM) chromatograms and the relative abundances of two SRM transitions of each neurosteroid glucuronide between the reference and authentic samples, thus providing reliable identification. In vitro experiments, carried out by using S9 fractions from mouse and rat brains, showed a formation of glucuronides with selected test compounds (corticosterone, pregnenolone, and dehydroepiandrosterone), suggesting that biosynthesis of neurosteroid glucuronides is possible in rodent brain.     

Convenient syntheses of metabolically important quercetin glucuronides and sulfates

Synthetic approaches to the major human plasma metabolites of quercetin, quercetin 3′-sulfate and the β-d-glucopyranosiduronic acid derivatives 3′-methylquercetin 3-glucuronide (isorhamnetin 3-glucuronide), quercetin 3-glucuronide and quercetin 3′-glucuronide are described. This is the first report of the chemical synthesis of quercetin 3′-glucuronide. All procedures start from the same precursor, 4′,7-di-O-benzylquercetin, and all are more convenient than existing methods.     

Glucuronidation of Two Novel Metabolites of Benproperine with Trichloroacetimidate Donor

IntroductionGlucuronides are well known as phaseⅡ metabo-lites of xenobiotics, usually of phenols, alcohols, andacids, as well as those of hydroxylamines and tertiaryamine[1]. There is a growing interest in identifyingsuch metabolites and in establishing…