- Extended scaffold glucuronides: En route to the universal synthesis of O -aryl glucuronide prodrugs
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We demonstrate that an extended scaffold based on a self-immolative linker (SIL) enables the universal production of O-aryl glucuronide prodrugs: high yield glucuronidation is performed on a precursor substrate (SIL) and the subsequent drug conjugation proceeds via less challenging chemical reactions.
- Walther, Raoul,Jarlstad Olesen, Morten T.,Zelikin, Alexander N.
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p. 6970 - 6974
(2019/08/01)
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- Preparation method of substituted benzyl or substituted phenyl beta-D-hexuronic acid glucoside
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The invention relates to the technical field of pharmaceutical and chemical industries, and discloses a preparation method of substituted benzyl or substituted phenyl beta-D-hexuronic acid glucoside.The preparation method comprises the steps of taking hexuronic acid as a raw material, and performing acetylation, selective acyl removal, methyl esterification, bromization, aethrization and alkalinealcoholysis to form substituted benzyl or substituted phenyl beta-hexuronic acid glucoside with a structural formula as follows as shown in the description, wherein n is equal to 0-1; and R is o-, m-or para-hydrogen, nitryl, methoxy or halogen. The method is mild in reaction condition, simple in step and suitable for large-scale preparation, and a reaction reagent is easy to obtain.
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- Mechanistic insights from substrate preference in unsaturated glucuronyl hydrolase
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Natural and synthetic unsaturated glucuronides were tested as substrates for Clostridium perfringens unsaturated glucuronyl hydrolase to probe its mechanism and to guide inhibitor design. Of the natural substrates, a chondroitin disaccharide substrate with sulfation of the primary alcohol on carbon 6 of its N-acetylgalactosamine moiety was found to have the highest turnover number of any substrate reported for an unsaturated glucuronyl hydrolase, with kcat=112 s-1. Synthetic aryl glycoside substrates with electron-withdrawing aglycone substituents were cleaved more slowly than those with electron-donating substituents. Similarly, an unsaturated glucuronyl fluoride was found to be a particularly poor substrate, with k cat/Km=44 nM-1 s-1 - a very unusual result for a glycoside-cleaving enzyme. These results are consistent with a transition state with positive charge at carbon 5 and the endocyclic oxygen, as anticipated in the hydration mechanism proposed. However, several analogues designed to take advantage of strong enzyme binding to such a transition state showed little to no inhibition. This result suggests that further work is required to understand the true nature of the transition state stabilised by this enzyme. Copyright
- Jongkees, Seino A. K.,Yoo, Hayoung,Withers, Stephen G.
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p. 124 - 134
(2014/01/06)
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- Glycoside cleavage by a new mechanism in unsaturated glucuronyl hydrolases
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Unsaturated glucuronyl hydrolases (UGLs) from GH family 88 of the CAZy classification system cleave a terminal unsaturated sugar from the oligosaccharide products released by extracellular bacterial polysaccharide lyases. This pathway, which is involved in extracellular bacterial infection, has no equivalent in mammals. A novel mechanism for UGL has previously been proposed in which the enzyme catalyzes hydration of a vinyl ether group in the substrate, with subsequent rearrangements resulting in glycosidic bond cleavage. However, clear evidence for this mechanism has been lacking. In this study, analysis of the products of UGL-catalyzed reactions in water, deuterium oxide, and dilute methanol in water, in conjunction with the demonstration that UGL rapidly cleaves thioglycosides and glycosides of inverted anomeric configuration (substrates that are resistant to hydrolysis by classical glycosidases), provides strong support for this new mechanism. A hydration-initiated process is further supported by the observed UGL-catalyzed hydration of a C-glycoside substrate analogue. Finally, the observation of a small β-secondary kinetic isotope effect suggests a transition state with oxocarbenium ion character, in which the hydrogen at carbon 4 adopts an axial geometry. Taken together, these observations validate the novel vinyl ether hydration mechanism and are inconsistent with either inverting or retaining direct hydrolase mechanisms at carbon 1.
- Jongkees, Seino A. K.,Withers, Stephen G.
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p. 19334 - 19337
(2012/01/31)
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- Synthesis of the glucuronide metabolite of ABT-751
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A linear synthesis of the glucuronide metabolite of ABT-751 was replaced with a convergent synthesis that features direct glycosidic coupling between the aglycone and a trichloroacetimidate glucuronyl donor. Structural elucidation of a unique and unexpect
- Engstrom, Kenneth M.,Henry, Rodger F.,Marsden, Ian
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p. 1359 - 1362
(2007/10/03)
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- Towards the synthesis of aryl glucuronides as potential heparanase probes. An interesting outcome in the glycosidation of glucuronic acid with 4-hydroxycinnamic acid
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This work describes our preliminary efforts towards the development of aryl glucuronides as potential probes for heparanase. During the course of these initial investigations, attempted glycosidation of methyl 2,3,4-tri-O-acetyl- α-d-glucopyranosyluronate trichloroacetimidate with 4-hydroxycinnamic acid gave a complex mixture of four different components. These were identified as the 1-cinnamyl glucuronate ester 13, the cinnamyl linked disaccharide 14, the glucuronate trichloroacetamide 15, and the glucuronyl α-fluoride 16. This paper rationalises the formation of each of these products, and reports our efforts in trying to optimise the formation of the α-fluoride 16.
- Pearson, Andrew G.,Kiefel, Milton J.,Ferro, Vito,Von Itzstein, Mark
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p. 2077 - 2085
(2007/10/03)
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- A novel synthesis of β-phenylglucuronides using the Mitsunobu reaction; an application of phenolic chromium tricarbonyl complexes
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Methyl 2,3,4-tri-O-acetyl-D-glucopyranuronate reacts with phenols under Mitsunobu conditions to give β-phenylglucuronides.Improved yields are obtained with p-methyl and p-methoxyphenol by prior complexation to the chromium tricarbonyl residue, which serve
- Badman, Geoffrey T.,Green, Darren V.S.,Voyle, Martyn
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p. 117 - 121
(2007/10/02)
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- A Novel Method for Stereoselective Glucuronidation
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A variety of hydroxylic aglycones can be glucuronidated directly with methyl 2,3,4-tri-O-acetylglucopyranuronate (4a), activated with trimethylsilyl trifluoromethanesulfonate (Me3Si-OTf).This reaction provides mostly β, and sometimes α, glucopyranosiduronic acid derivatives (referred to as glucuronides) rapidly and at low temperatures.The epimeric ratio depends on the relative aglycone nucleophilicity vs. its tendency to form a stabilized carbocation by the formal loss of -OH.Glucuronides of various aromatic and aliphatic aglycones as well as those of a number of cyanohydrins were prepared.The characteristic features of the 1H NMR spectra of α and β derivatives which are presented are useful in the assignment of product stereochemistry and determination of epimeric ratios in those reactions where mixtures are obtained.
- Fischer, Bilha,Nudelman, Abraham,Ruse, Margareta,Herzig, Jacob,Gottlieb, Hugo E.,Keinan, Ehud
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p. 4988 - 4993
(2007/10/02)
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