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Inhibition of glycosyltransferases requires the design of neutral inhibitors to allow cell permeation in contrast to their natural dianionic substrates. O-GlcNAc transferase (OGT) is a key enzyme involved in dynamic glycosylation of cytosolic and nuclear proteins in competition with phosphorylation. Designing OGT inhibitors is of prime interest for the better understanding of its biological implications. Introduction of a pyridine moiety as a pyrophosphate surrogate was evaluated, which provided moderate in vitro inhibition of OGT. Docking studies highlighted some key features for the binding of the designed inhibitors to the catalytic site of OGT where the carbohydrate moiety did not occupy its natural position but rather turned away and pointed to the solvent outside the catalytic pocket. Further investigation with cellular assays did not provide inhibition of OGT. This lack of OGT inhibition was rationalized with a permeation assay which revealed the sequestration of the inhibitors at the membrane. This journal is the Partner Organisations 2014.

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O-Glycosidation of the totally O-unprotected aldoses (D-glucose, D-galactose and D-mannose) and D-fructose in THF or 1,4-dioxane using anhydrous FeCl3 as promoter afforded either aldofuranosides 1, 3, 4 in good overall yields or exclusively beta-D-fructopyranosides 7. Conversely alpha-D-aldopyranosides 2, 5 and 6 were obtained respectively from D-glucose, D-mannose and N-acetyl-D-glucosamine when the reactions were performed in the presence of BF3.OEt2 under ultrasonication.

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A novel self-terminated Prins strategy has been developed for the synthesis of 2-substituted tetrahydropyran-4-one derivatives through a condensation of 3-(phenylthio)but-3-en-1-ol with carbonyl compounds in the presence of 5 mol% of Sc(OTf)3 under mild conditions. A few products were subsequently transformed into the corresponding indoles by Fisher-indole synthesis.

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The development of sialidase inhibitors is an area of continuing interest due to their potential use as therapeutic agents to combat viral and bacterial infections. Herein, we report our studies involving the sialidase from the pathogen Vibrio cholerae, through the modelling, synthesis and biological evaluation of mimetics of 5-acetamido-2,6-anhydro-3,5-dideoxy-d-glycero-d- galacto-non-2-enonic acid (Neu5Ac2en, 1), a naturally occurring sialidase inhibitor. These mimetics are O- and S-glycosides of N-acetyl-d-glucosaminuronic acid in which the aglycone portion effectively replaces the C-6 glycerol side chain of Neu5Ac2en (1). The choice of aglycones was aided by use of the X-ray crystal structure of V. cholerae sialidase complexed with Neu5Ac2en (1). All Neu5Ac2en mimetics tested were found to inhibit V. cholerae sialidase as determined using a standard fluorometric assay.

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A method of inhibiting the growth of tumour cells is provided, comprising contacting the cells with an inhibitor of glucokinase. The glucokinase enzyme, normally only found in liver and pancreatic ”beta”-cells, is found to be active in tumour cells.

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The binding properties of the rat sublingual glycoprotein (RSL) and its asialo product with lectins were characterized by quantitative precipitin (QPA) and precipitin inhibition (QPIA) assays. Among twenty lectins tested for QPA, native RSL reacted well only with Artocarpus integrifolia (jacalin) but weakly or not at all with the other lectins. However, its asialo product (asialo-RSL) reacted strongly with many Gal and GalNAc specific lectins- it bound best to three of the GalNAcalpha1?Ser/Thr (II) and/or Galbeta1?4GlcNAc active lectins [jacalin, Wistaria floribunda and Ricinus communis agglutinins] and completely precipitated each of these three lectins. Asialo-RSL also reacted well with Abrus precatorius, Glycine max Bauhinia purpurea alba, and Maclura pomifera agglutinins and abrin-a, but not with Arachis hypogeae and Dolichos biflorus agglutinins. The interaction between asialo-RSL and lectins were inhibited by either Galbeta1?4GlcNAc, p-NO2-phenylalpha-GalNAc or both. The mapping of the precipitation and inhibition profiles leads to the conclusion that the asialo rat sublingual glycoprotein provides important ligands for II(Galbeta1?4GlcNAcbeta1?) and Tn(GalNAcalpha1 ?Ser/Thr) active lectins.

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A novel lectin was purified to homogeneity from winter buds of Lysichiton camtschatcensis (L.) Schott of the Araceae family. It was a tetramer composed of two non-covalently associated polypeptides with small subunits (11 kDa) and large subunits (12 kDa). Sequencing of both subunits yielded unique N-terminal sequences. A cDNA encoding the lectin was cloned. The isolated cDNA contained an open reading frame that encoded 267 amino acids. It encoded both subunits, indicating that the lectin is synthesized as a single precursor protein that is post-translationally processed into two different subunits with 45% sequence identity. Each subunit contained a mannose-binding motif known to be conserved in monocot mannose-binding lectins, but its activity was not inhibited by monosaccharides, including methyl alpha-mannoside. Asialofetuin and yeast invertase were potent inhibitors. Lectin activity was detected in the buds formed during the winter season but not in the expanded leaves.

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The lipid carrier specificity of the protein N-glycosylation enzyme C. jejuni PglB was tested using a logical, synthetic array of natural and unnatural C10, C20, C30, and C40 polyisoprenol sugar pyrophosphates, including those bearing repeating cis-prenyl units. Unusual, short, synthetically accessible C20 prenols (nerylnerol 1d and geranylnerol 1e) were shown to be effective lipid carriers for PglB sugar substrates. Kinetic analyses for PglB revealed clear KM-only modulation with lipid chain length, thereby implicating successful in vitro application at appropriate concentrations. This was confirmed by optimized, efficient in vitro synthesis allowing >90% of Asn-linked beta-N-GlcNAc-ylated peptide and proteins. This reveals a simple, flexible biocatalytic method for glycoconjugate synthesis using PglB N-glycosylation machinery and varied chemically synthesized glycosylation donor precursors.

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A simple, rapid and highly regioselective green protocol has been developed for the halogenation of aromatic systems with N-halosuccinimides using room temperature ionic liquids (ILs) as novel and recyclable reaction media to produce the corresponding halogenated aromatic compounds in high to quantitative yields. N-Halosuccinimides show enhanced reactivity in ionic liquids thereby reducing the reaction times dramatically and improving the yields substantially.

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The binding properties of the rat sublingual glycoprotein (RSL) and its asialo product with lectins were characterized by quantitative precipitin (QPA) and precipitin inhibition (QPIA) assays. Among twenty lectins tested for QPA, native RSL reacted well only with Artocarpus integrifolia (jacalin) but weakly or not at all with the other lectins. However, its asialo product (asialo-RSL) reacted strongly with many Gal and GalNAc specific lectins- it bound best to three of the GalNAcalpha1?Ser/Thr (II) and/or Galbeta1?4GlcNAc active lectins [jacalin, Wistaria floribunda and Ricinus communis agglutinins] and completely precipitated each of these three lectins. Asialo-RSL also reacted well with Abrus precatorius, Glycine max Bauhinia purpurea alba, and Maclura pomifera agglutinins and abrin-a, but not with Arachis hypogeae and Dolichos biflorus agglutinins. The interaction between asialo-RSL and lectins were inhibited by either Galbeta1?4GlcNAc, p-NO2-phenylalpha-GalNAc or both. The mapping of the precipitation and inhibition profiles leads to the conclusion that the asialo rat sublingual glycoprotein provides important ligands for II(Galbeta1?4GlcNAcbeta1?) and Tn(GalNAcalpha1 ?Ser/Thr) active lectins.

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Reference:
Tetrahydropyran – Wikipedia,
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