- A glycal-based photoaffinity probe that enriches sialic acid binding proteins
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To identify sialic acid binding proteins from complex proteomes, three photocrosslinking affinity-based probes were constructed using Neu5Ac (5 and 6) and Neu5Ac2en (7) scaffolds. Kinetic inhibition assays and Western blotting revealed the Neu5Ac2en-based 7 to be an effective probe for the labeling of a purified gut microbial sialidase (BDI_2946) and a purified human sialic acid binding protein (hCD33). Additionally, LC–MS/MS affinity-based protein profiling verified the ability of 7 to enrich a low-abundance sialic acid binding protein (complement factor H) from human serum thus validating the utility of this probe in a complex context.
- Thuy-Boun, Peter S.,Wolan, Dennis W.
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p. 2609 - 2612
(2019/08/07)
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- SIALIDASE INHIBITORS AND PREPARATION THEREOF
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New 2-deoxy-2,3-dehydro-sialic acids and 2,7-anhydro-sialic acids, which are useful as sialidase inhibitors, and enzymatic methods for preparing them are disclosed. The methods include forming a reaction mixture comprising a glycoside acceptor, a sialic acid donor, and a sialyltransferase; maintaining the reaction mixture under conditions sufficient to form a sialoside; and contacting the sialoside with a Streptococcus pneumoniae sialidase to form the sialic acid product. Methods for the inhibition and sialidases and the treatment of cancer and infectious diseases are also disclosed.
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- Synthesis and chemical characterization of several perfluorinated sialic acid glycals and evaluation of their: In vitro antiviral activity against Newcastle disease virus
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Newcastle Disease Virus (NDV), belonging to the Paramyxoviridae family, causes a serious infectious disease in birds, resulting in severe losses in the poultry industry every year. Haemagglutinin neuraminidase glycoprotein (HN) has been recognized as a key protein in the viral infection mechanism, and its inhibition represents an attractive target for the development of new drugs based on sialic acid glycals, with the 2-deoxy-2,3-didehydro-d-N-acetylneuraminic acid (Neu5Ac2en) as their backbone. Herein we report the synthesis of several Neu5Ac2en glycals and of their perfluorinated C-5 modified derivatives, including their respective stereoisomers at C-4, together with evaluation of their in vitro antiviral activity. While all synthesized compounds were found to be active HN inhibitors in the micromolar range, we found that their potency was influenced by the chain-length of the C-5 perfluorinated acetamido functionality. Thus, the binding modes of the inhibitors were also investigated by performing a docking study. Moreover, the perfluorinated glycals were found to be more active than the corresponding normal C-5 acylic derivatives. Finally, cell-cell fusion assays on NDV infected cells revealed that the addition of a newly synthesized C-4α heptafluorobutyryl derivative almost completely inhibited NDV-induced syncytium formation.
- Rota,Papini,La Rocca,Montefiori,Cirillo,Piccoli,Scurati,Olsen,Allevi,Anastasia
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p. 1505 - 1513
(2017/07/25)
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- Three streptococcus pneumoniae sialidases: Three different products
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Streptococcus penumoniae is a major human pathogen responsible for respiratory tract infections, septicemia, and meningitis and continues to produce numerous cases of disease with relatively high mortalities. S. pneumoniae encodes up to three sialidases, NanA, NanB, and NanC, that have been implicated in pathogenesis and are potential drug targets. NanA has been shown to be a promiscuous sialidase, hydrolyzing the removal of Neu5Ac from a variety of glycoconjugates with retention of configuration at the anomeric center, as we confirm by NMR. NanB is an intramolecular trans-sialidase producing 2,7-anhydro-Neu5Ac selectively from α2,3-sialosides. Here, we show that the first product of NanC is 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en) that can be slowly hydrated by the enzyme to Neu5Ac. We propose that the three pneumococcal sialidases share a common catalytic mechanism up to the final product formation step, and speculate on the roles of the enzymes in the lifecycle of the bacterium.
- Xu, Guogang,Kiefel, Milton J.,Wilson, Jennifer C.,Andrew, Peter W.,Oggioni, Marco R.,Taylor, Garry L.
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supporting information; experimental part
p. 1718 - 1721
(2011/04/17)
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- INHIBITORS OF SIALIDASE OR SIALIDASE-LIKE ENZYMES
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The present invention describes compounds of Formula I or a pharmaceutically acceptable salts or derivatives thereof. Compositions comprising compounds of Formula I are also described. The present invention further relates to a method of producing non-2-enonate compounds.
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Page/Page column 31-32
(2010/11/18)
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- 2-Deoxy-2,3-didehydro-N-acetylneuraminic acid analogs structurally modified by thiocarbamoylalkyl groups at the C-4 position: Synthesis and biological evaluation as inhibitors of human parainfluenza virus type 1
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4-O-Thiocarbamoylmethyl-Neu5Ac2en 3 has strong inhibitory activity toward human parainfluenza virus type 1 (hPIV-1) sialidase compared with the parent Neu5Ac2en 2. We synthesized analogs having thiocarbamoylethyl- 4 and thiocarbamoylpropyl group 5 at the C-4 position of 2. The inhibition degrees of 4 and 5 were weaker than that of thiocarbamoylmethyl analog 3, indicating a remarkable effect of the carbon chain length in thiocarbamoylalkyl groups at the C-4 position on inhibitory activities against hPIV-1 sialidase.
- Ikeda, Kiyoshi,Sato, Kazuki,Nishino, Reiko,Aoyama, Shinya,Suzuki, Takashi,Sato, Masayuki
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p. 6783 - 6788
(2008/12/22)
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- Preparation of a fluorous protecting group and its application to the chemoenzymatic synthesis of sialidase inhibitor
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2-(Perfluorohexyl)ethoxymethyl chloride was prepared as a novel fluorous protecting reagent. Neu5Ac aldolase-catalyzed chemoenzymatic transformation of N-acetyl-d-mannosamine to Neu5Ac derivatives was achieved successfully by using the fluorous reagent not only for hydroxy group protection but also for fluorous tagging. This chemoenzymatic method was applied to the synthesis of 2-deoxy-2,3-didehydrosialic acid 1 known as a potent sialidase inhibitor. The Royal Society of Chemistry 2006.
- Ikeda, Kiyoshi,Mori, Hitomi,Sato, Masayuki
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p. 3093 - 3094
(2008/09/20)
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- Unexpected stability of aryl β-N-acetylneuraminides in neutral solution: Biological implications for sialyl transfer reactions
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A reagent panel comprised of seven aryl β-D-N-acetylneuraminides was synthesized and then used to probe the mechanisms of nonenzymatic hydrolysis. These reactions proceeded via four independent pathways: (1) acid-catalyzed hydrolysis of the neutral molecule; (2) acid-catalyzed hydrolysis of the anionic form, or its kinetic equivalent spontaneous hydrolysis of the neutral form; (3) spontaneous hydrolysis of the anionic form; and (4) a base-promoted pathway. The pH-independent spontaneous hydrolysis of 4-nitrophenyl α-D-N- acetylneuraminide (5) occurs at a rate that is over 100 times faster than that of the corresponding reaction of 4-nitrophenyl β-D-N-acetylneuraminide (4a). Spontaneous hydrolyses of four aryl β-D-N-acetylneuraminides displayed a βIg value of -1.24 ± 0.16 (pH = 8.1, T = 100 °C), and at a pH value of 1.0 (50 °C), all seven panel members gave a βIg value of 0.14 ± 0.08. The aqueous ethanolyses of 4a and 5 gave similar products and displayed sensitivity parameters (m) in a standard Winstein-Grunwald analysis of -0.04 ± 0.01 and ± 0.23 ± 0.02, respectively. These results, plus the activation parameters calculated for the spontaneous hydrolyses of the anionic forms of 5 (ΔH? = 116 ± 2 kJ mol-1 and ΔS? = 27 ± 4 J mol-1 K-1) and 4a (ΔH? = 138 ± 3 kJ mol-1 and ΔS? = 59 ± 8 J mol -1 K-1), are inconsistent with anomeric carboxylate assistance occurring during the hydrolysis reactions, and the likely cause for the enhanced reactivity of 5 in comparison to that of 4a is an increase in ground-state steric strain.
- Dookhun, Veedeeta,Bennet, Andrew J.
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p. 7458 - 7465
(2007/10/03)
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- The design, synthesis and biological evaluation of neuraminic acid-based probes of Vibrio cholerae sialidase
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A molecular modelling study using the program GRID has been used to investigate the structural requirements of a potential inhibitor binding to Vibrio cholerae sialidase. A number of favourable interactions were predicted between the sialidase and Neu2en derivatives containing hydroxyl- or halogen-substituted acyl groups on the C-5 amine. As a result of this study, a detailed analysis of the interactions of C-5-substituted Neu2en derivatives with the active site of V. cholerae sialidase was undertaken using a conformational searching routine based on molecular dynamics. Based on the results of these molecular design studies several N-acyl-Neu2en-based probes were prepared and evaluated for sialidase inhibition. As envisaged, and pleasingly, the designed compounds were found to be accommodated by the enzyme's active site architecture, and to be strong inhibitors of V. cholerae sialidase. Copyright (C) 2000 Elsevier Science Ltd.
- Wilson, Jennifer C.,Thomson, Robin J.,Dyason, Jeffrey C.,Florio, Pas,Quelch, Kaylene J.,Abo, Samia,Von Itzstein, Mark
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- AN EFFICIENT APPROACH TO STEREOSELECTIVE GLYCOSYLATION OF N-ACETYLNEURAMINIC ACID: USE OF PHENYLSELENYL GROUP AS A STEREOCONTROLLING AUXILIARY
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α-Selective glycosylation of N-acetylneuraminic acid was achieved by use of the fluoride 3 which carries 3β-phenylselenyl substituent.
- Ito, Yukishige,Ogawa, Tomoya
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p. 6221 - 6224
(2007/10/02)
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- Reinvestigation of the synthesis of 4-methylcoumarin-7-yl 5-acetamido-3,5-dideoxy-alpha-D-glycero-D-galacto-2-nonulopyranosidonic acid, a fluorogenic substrate for neuraminidase.
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A crystalline tetrabutylammonium salt of 7-hydroxy-4-methylcoumarin was prepared and shown to contain two coumarin residues for each ammonium group. Condensation of this salt with the glycosyl chloride of methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-beta-D-glycero-D-galacto-2-nonulopyranosonate in dry acetonitrile at room temperature gave the corresponding alpha-glycoside in higher yield and purity than previously reported methods. Removal of the acetyl and methyl ester blocking-groups gave the free glycoside, which was shown to have the alpha configuration by n.m.r. spectroscopy. In contrast, the reaction of the free coumarin derivative with the chloro sugar in refluxing, dry toluene in the presence of cadmium carbonate as acid acceptor gave none of the above glycoside, but gave the corresponding glycal in good yield.
- Baggett,Marsden
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