- Synthesis of Oligomers Derived from Amide-Linked Neuraminic Acid Analogues
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N-Fluoren-9-ylmethoxycarbonyl-protected sugar amino acids derived from α-O-methoxy- and 2,3-dehydroneuraminic acids have been prepared. Incorporation of these monomer units into solid-phase synthesis led to the efficient synthesis of two series of oligomers varying from one to eight units in length. The (1-5)-linked amides of 2,3-dehydroneuraminic acid were further subjected to hydrogenation giving a third series of oligomers with a β-hydrido substituent at the anomeric carbon.
- Gregar, Travis Q.,Gervay-Hague, Jacquelyn
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- Sialated diazeniumdiolate: A new sialidase-activated nitric oxide donor
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(Chemical Equation Presented) A new sialated diazeniumdiolate has been synthesized, and the glycosylation product was exclusively an α anomer. This new nitric oxide donor exhibited significantly improved stability as compared to its parent diazeniumdiolate salts, and it could be efficiently hydrolyzed by neuraminidase to release nitric oxide with a Km of 0.14 mM. The sialic acid-NO conjugate would be a valuable prodrug that targets NO to influenza viruses.
- Cai,Lu, Dongning,Landerholm, Megan,Wang, Peng George
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- Characterization of a high-affinity sialic acid-specific CBM40 from Clostridium perfringens and engineering of a divalent form
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CBMs(carbohydrate-binding modules) are a class of polypeptides usually associated with carbohydrate-active enzymatic sites. We have characterized a new member of the CBM40 family, coded from a section of the gene NanI from Clostridium perfringens. Glycan arrays revealed its preference towards α(2,3)-linked sialosides, which was confirmed and quantified by calorimetric studies. The CBM40 binds to α(2,3)-sialyl-lactose with a Kd of -30 μM, the highest affinity value for this class of proteins. Inspired by lectins' structure and their arrangement as multimeric proteins, we have engineered a dimeric form of the CBM, and using SPR (surface plasmon resonance) we have observed 6-11- fold binding increases due to the avidity affect. The structures of the CBM, resolved by X-ray crystallography, in complex with α(2,3)- or α(2,6)-sialyl-lactose explain its binding specificity and unusually strong binding.
- Ribeiro, Joao P.,Pau, William,Pifferi, Carlo,Renaudet, Olivier,Varrot, Annabelle,Mahal, Lara K.,Imberty, Anne
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- Synthesis and Biological Evaluation of Several Dephosphonated Analogues of CMP-Neu5Ac as Inhibitors of GM3-Synthase
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Previous studies demonstrated that reducing the GM3 content in myoblasts increased the cell resistance to hypoxic stress, suggesting that a pharmacological inhibition of the GM3 synthesis could be instrumental for the development of new treatments for ischemic diseases. Herein, the synthesis of several dephosphonated CMP-Neu5Ac congeners and their anti-GM3-synthase activity is reported. Biological activity testes revealed that some inhibitors almost completely blocked the GM3-synthase activity in vitro and reduced the GM3 content in living embryonic kidney 293A cells, eventually activating the epidermal growth factor receptor (EGFR) signaling cascade.
- Rota, Paola,Cirillo, Federica,Piccoli, Marco,Gregorio, Antonio,Tettamanti, Guido,Allevi, Pietro,Anastasia, Luigi
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- Investigation of protecting group for sialic acid carboxy moiety toward sialylglycopeptide synthesis by the TFA-labile protection strategy
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The sialylation using sialyl donor with 2,6-dimethylbenzyl (DMBn) ester at C-1 carboxy group rapidly proceeded with good α-selectivity to yield sialyl-N-acetylgalactosaminylated 9-fluorenylmethoxycarbonyl (Fmoc) serine unit. The unit was used for the solid-phase peptide synthesis (SPPS) of the sialyl glycopeptide. The DMBn group was removed during the final deprotection by the trifluoroacetic acid (TFA) treatment keeping the sialyl bond intact and the desired sialyl glycopeptide was successfully obtained. This protecting group strategy provided easier access to sialyl glycoamino acids for sialyl glycopeptides synthesis.
- Ito, Shun,Asahina, Yuya,Hojo, Hironobu
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- Donor-Reactivity-Controlled Sialylation Reactions
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Although tremendous efforts have been made for the efficient preparation of sialosides, controlling the stereochemical outcome of sialylation reaction still remains one of the most challenging tasks due to the unique chemical structure of sialic acid. We developed a new strategy to statistically analyze the stereoselectivity of sialylation reactions on six types of p-tolyl thiosialosides in NIS/TfOH system using Relative Reactivity Value (RRV) as the indicator. Analysis of the reaction mechanism showed the formation of the relatively stable glycosyl bromide and glycosyl chloride intermediates from halide- and triflate-containing promotors in the absence of an acceptor. We found that the α/β-stereoselectivity, yields, and intermediate changes were associated with their donor reactivity. These findings enable to tailor the most suitable building blocks for stereo-controlled sialylation reactions.
- Asressu, Kesatebrhan Haile,Chang, Chun-Wei,Lam, Sarah,Wang, Cheng-Chung
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supporting information
p. 4525 - 4530
(2021/08/09)
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- One pot synthesis of thio -glycosides via aziridine opening reactions
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A one-pot aziridine opening reaction by glycosyl thiols generated in situ from the corresponding anomeric thio-acetates affords thio-glycosides with a pseudo-disaccharide structure and an N-linked tether. The scope of the one-pot aziridine opening reaction was explored on a series of mono- and disaccharides, creating a class of pseudo-glycosidic compounds with potential for further functionalization. Unexpected anomerization of glycosyl thiols was observed under the reaction conditions and the influence of temperature, base and solvent on the isomerization was investigated. Single isomers were obtained in good to acceptable yields for mannose, rhamnose and sialic acid derivatives. The class of thio-glycomimetics synthesized can potentially be recognized by various lectins, while presenting hydrolytic and enzymatic stability. The nitrogen functionality incorporated in the glycomimetics can be exploited for further functionalization, including tethering to linkers, scaffolds or peptide residues.
- Hribernik, Nives,Tamburrini, Alice,Falletta, Ermelinda,Bernardi, Anna
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supporting information
p. 233 - 247
(2021/01/14)
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- MATERIALS AND METHODS FOR THE PREPARATION OF BACTERIAL CAPSULAR POLYSACCHARIDES
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Methods for preparing saccharide products such as bacterial capsular polysaccharides are provided. The methods include: forming a reaction mixture containing one or more bacterial capsular polysaccharide synthases, a sugar acceptor, and one or more sugar
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Paragraph 0009; 0097-0098
(2020/08/22)
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- Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases
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Sialidases (SAs) hydrolyze sialyl residues from glycoconjugates of the eukaryotic cell surface and are virulence factors expressed by pathogenic bacteria, viruses, and parasites. The catalytic domains of SAs are often flanked with carbohydrate-binding module(s) previously shown to bind sialosides and to enhance enzymatic catalytic efficiency. Herein, non-hydrolyzable multivalent thiosialosides were designed as probes and inhibitors of V. cholerae, T. cruzi, and S. pneumoniae (NanA) sialidases. NanA was truncated from the catalytic and lectinic domains (NanA-L and NanA-C) to probe their respective roles upon interacting with sialylated surfaces and the synthetically designed di- and polymeric thiosialosides. The NanA-L domain was shown to fully drive NanA binding, improving affinity for the thiosialylated surface and compounds by more than two orders of magnitude. Importantly, each thiosialoside grafted onto the polymer was also shown to reduce NanA and NanA-C catalytic activity with efficiency that was 3000-fold higher than that of the monovalent thiosialoside reference. These results extend the concept of multivalency for designing potent bacterial and parasitic sialidase inhibitors.
- Brissonnet, Yoan,Assailly, Coralie,Saumonneau, Amélie,Bouckaert, Julie,Maillasson, Mike,Petitot, Clémence,Roubinet, Benoit,Didak, Blanka,Landemarre, Ludovic,Bridot, Clarisse,Blossey, Ralf,Deniaud, David,Yan, Xibo,Bernard, Julien,Tellier, Charles,Grandjean, Cyrille,Daligault, Franck,Gouin, Sébastien G.
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supporting information
p. 2358 - 2365
(2019/01/16)
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- Regio/Stereoselective Glycosylation of Diol and Polyol Acceptors in Efficient Synthesis of Neu5Ac-α-2,3-LacNPhth Trisaccharide
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A concise approach to a Neu5Ac-α-2,3-LacNPhth trisaccharide derivative was developed. First, the regio/stereoselective glycosylation between glycoside donors and glucoNPhth diol acceptors was investigated. It was found that the regioselectivity depends not only on the steric hindrance of the C2-NPhth group and the C6-OH protecting group of the glucosamine acceptors, but also on the leaving group and protecting group of the glycoside donors. Under optimized conditions, LacNPhth derivatives were synthesized in up to 92 % yield through a regio/stereoselective glycosylation between peracetylated-α-galactopyranosyl trichloroacetimidate and p-methoxyphenyl 6-O-tert-butyldiphenylsilyl-2-deoxy-2-phthalimido-β-d-glucopyranoside, avoiding the formation of glycosylated orthoesters and anomeric aglycon transfer. Then, the LacNPhth derivative was deacylated and then protected on the primary position by TBDPS to form a LacNPhth polyol acceptor. Finally, the Neu5Ac-α-2,3-LacNPhth derivative was synthesized in 48 % yield through the regio/stereoselective glycosylation between the LacNPhth polyol acceptor and a sialyl phosphite donor. Starting from d-glucosamine hydrochloride, the target Neu5Ac-α-2,3-LacNPhth derivative was synthesized in a total yield of 18.5 % over only 10 steps.
- Zhang, Ying,Zhao, Fu-Long,Luo, Tao,Pei, Zhichao,Dong, Hai
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supporting information
p. 223 - 234
(2018/12/05)
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- Differential recognition of diet-derived Neu5Gc-Neoantigens on glycan microarrays by carbohydrate-specific pooled human IgG and IgA antibodies
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Sialic acids (Sias) cover vertebrate cell surface glycans. N-Acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc) are common Sia in mammals. Humans cannot synthesize Neu5Gc but accumulate it on cells through red-meat rich diets, generating numerous immunogenic Neu5Gc-neoantigens. Consequently, humans have diverse anti-Neu5Gc antibodies affecting xenotransplantation, cancer, atherosclerosis, and infertility. Anti-Neu5Gc antibodies circulate as IgG, IgM, and IgA isotypes; however, repertoires of the different isotypes in a large population have not been studied yet. Here, we used glycan microarrays to investigate anti-Neu5Gc IgGs and IgAs in intravenous immunoglobulin (IVIG) or pooled human IgA, respectively. Binding patterns on microarrays fabricated with Neu5Gc- and Neu5Ac-glycans, together with inhibition assays, revealed that different IVIG preparations have highly specific anti-Neu5Gc IgG reactivity with closely related repertoires, while IgAs show cross-reactivity against several Neu5Ac-glycans. Such different anti-Neu5Gc IgG/IgA repertoires in individuals could possibly mediate distinctive effects on human diseases.
- Leviatan Ben-Arye, Shani,Schneider, Christoph,Yu, Hai,Bashir, Salam,Chen, Xi,Von Gunten, Stephan,Padler-Karavani, Vered
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p. 1565 - 1574
(2019/05/22)
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- 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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supporting information
p. 2609 - 2612
(2019/08/07)
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- Synthesis of neuraminidase-resistant sialoside-modified three-way junction DNA and its binding ability to various influenza viruses
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Natural sialic acid-modified compounds are capable of targeting influenza virus hemagglutinin (HA). However, these compounds have limited inhibitory effect because natural O-glycoside bond in these compounds are prone to be cleaved by neuraminidase (NA) on the surface of viruses. In this study, we synthesized NA-resistant sialoside that included unnatural S-glycoside bonds and modified this sialoside on a three-way junction (3WJ) DNA to display complementary distribution to its binding sites on a HA trimer. This S-glycoside-containing sialoside-modified 3WJ DNA showed certain NA resistance and maintained high binding affinity. Importantly, our observations showed that substituting natural O-glycoside with unnatural S-glycoside did not affect the binding affinity of the sialoside-modified 3WJ DNA for viruses. Thus, this study is an important step forward in the development of NA-resistant sialoside derivatives for more effective detection and inhibition of infection by a broad spectrum of viruses.
- Yamabe, Miyuki,Fujita, Akira,Kaihatsu, Kunihiro,Ebara, Yasuhito
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- Synthesis of highly controlled carbohydrate-polymer based hybrid structures by combining heparin fragments and sialic acid derivatives, and solid phase polymer synthesis
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Heparin is a polymeric carbohydrate with a variety of biomedical applications that is particularly challenging from a synthetic point of view. Here, we present the synthesis of carbohydrate-polymer based hybrid structures by combining defined heparin fragments with monodisperse, sequence-controlled glycooligo(amidoamines) suitable as glycan mimetic model compounds of heparin as demonstrated by STD-NMR binding studies with viral capsids.
- Baier, Mischa,Ruppertz, Jana L.,Pfleiderer, Moritz M.,Blaum, B?rbel S.,Hartmann, Laura
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supporting information
p. 10487 - 10490
(2018/09/21)
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- Multivalent neuraminidase hydrolysis resistant triazole-sialoside protein conjugates as influenza-adsorbents
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We report the synthesis of pseudo triazole-sialoside protein conjugates of various valency that are resistant to neuraminidase for the adsorption of influenza viruses. The glycotriazole monomer bearing an amine-functionalized linker was synthesized by click chemistry and grafted to the lysine residues of bovine serum albumin (BSA) or human serum albumin (HSA) via diethyl squarate and adipate-based strategy. The binding of hemagglutinin (HA) and neuraminidase (NA) on the virion surface by the synthetic neoglycoproteins were evaluated by hemagglutination and neuraminidase inhibition assay, respectively. The results demonstrated that these synthetic glycoproteins have significantly higher affinity with NA than HA. The interactions between these neoglycoproteins and intact influenza viruses were further investigated by Dynamic Light Scattering (DLS) technique. The pronounced agglutination indicated that these glycoconjugates can be used as adsorbents to prevent virus from invading host cells as well as the release of newly synthesized viral particles, which are crucial in the life cycle of the influenza virus. With the high binding affinity to intact influenza viruses, these neoglycoproteins can also be used as probe to elucidate the molecular mechanism of the sialic acid-influenza recognition and biosensors for influenza detection.
- Meng, Xin,Yang, Meibing,Li, Yang,Li, Xiaobin,Jia, Tianwei,He, Haojie,Yu, Qun,Guo, Na,He, Yun,Yu, Peng,Yang, Yang
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- NOVEL NEISSERIA MENINGITIDIS SEROGROUP Y OLIGOMER AND PROCESS FOR SYNTHESIZING THEREOF
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The present invention relates to novel oligomers of Neisseria meningitidis serogroup Y capsular polysaccharide repeating unit (Men-Y oligomers) and process for synthesizing novel Men- Y oligomers. In particular, the present invention relates to the chemic
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Page/Page column 12; 15
(2017/02/24)
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- Synthesis and in vitro anti-influenza virus evaluation of novel sialic acid (C-5 and C-9)-pentacyclic triterpene derivatives
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The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-pentacyclic triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with pentacyclic triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-pentacyclic triterpene conjugates. Their structures were confirmed by ESI-HRMS,1H-NMR, and13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 μM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 μM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 μM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 μM, ~20–30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold.
- Han, Xu,Si, Long-Long,Shi, Yong-Ying,Fan, Zi-Bo,Wang, Shou-Xin,Tian, Zhen-Yu,Li, Man,Sun, Jia-Qi,Jiao, Ping-Xuan,Ran, Fu-Xiang,Zhang, Yong-Min,Zhou, De-Min,Xiao, Su-Long
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- Synthesis of a New Series of Sialylated Homo- and Heterovalent Glycoclusters by using Orthogonal Ligations
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The synthesis of heteroglycoclusters (hGCs) is being subjected to rising interest, owing to their potential applications in glycobiology. In this paper, we report an efficient and straightforward convergent protocol based on orthogonal chemoselective ligations to prepare structurally well-defined cyclopeptide-based homo- and heterovalent glycoconjugates displaying 5-N-acetyl-neuraminic acid (Neu5Ac), galactose (Gal), and/or N-acetyl glucosamine (GlcNAc). We first used copper-catalyzed azide–alkyne cycloaddition and/or thiol-ene coupling to conjugate propargylated α-sialic acid 3, β-GlcNAc thiol 5, and β-Gal thiol 6 onto cyclopeptide scaffolds 7–9 to prepare tetravalent homoglycoclusters (10–12) and hGCs (13–14) with 2:2 combinations of sugars. In addition, we have demonstrated that 1,2-diethoxycyclobutene-3,4-dione can be used as a bivalent linker to prepare various octavalent hGCs (16, 19, and 20) in a controlled manner from these tetravalent structures.
- Daskhan, Gour Chand,Pifferi, Carlo,Renaudet, Olivier
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p. 477 - 484
(2016/10/21)
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- Stereocontrolled Synthesis of Phenolic α-d-Glycopyranosides
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Adopting the ‘remote activation concept’ toward stereocontrolled glycoside synthesis with minimal use of protection groups, a general synthesis of phenolic 1,2-cis glycopyranosides is reported, as exemplified by aryl α-d-galacto-, α-d-gluco- and 2-azido α-d-glucopyranosides among others using glycosyl donors bearing an anomeric (3-bromo-2-pyridyloxy) group and catalyzed by methyl triflate.
- St-Pierre, Gabrielle,Dafik, Laila,Klegraf, Ellen,Hanessian, Stephen
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supporting information
p. 3575 - 3588
(2016/10/17)
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- Design, synthesis and biological activity evaluation of novel conjugated sialic acid and pentacyclic triterpene derivatives as anti-influenza entry inhibitors
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Influenza virus is a major human pathogen that causes annual epidemics and occasional pandemics. Recently, plant-derived pentacyclic triterpenes have been shown to act as highly potent anti-viral agents by efficiently preventing the attachment of the virion to the host cells. In this report, we conjugated sialic acid with oleanolic acid (OA), a natural product with broad antiviral entry activity, as well as three other analogs echinocystic acid (EA), ursolic acid (UA) and betulinic acid (BA). A total of 24 conjugated sialic acid and pentacyclic triterpene derivatives with different linkers were synthesized and evaluated for antiviral activity against influenza A/WSN/33 (H1N1) virus in MDCK cell culture. The most potent compound had an IC50 of 41.2 μM. Time-of-addition, hemagglutination inhibition (HI), surface plasmon resonance (SPR) and molecular docking assays demonstrated that compound 20a acted as an influenza virus entry inhibitor by preventing the binding of influenza virus hemagglutinin (HA) protein to host cells.
- Han, Xu,Shi, Yongying,Si, Longlong,Fan, Zibo,Wang, Han,Xu, Renyang,Jiao, Pingxuan,Meng, Kun,Tian, Zhenyu,Zhou, Xiaoshu,Jin, Hongwei,Wu, Xinyu,Chen, Hong,Zhang, Yongmin,Zhang, Lihe,Xiao, Sulong,Zhou, Demin
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p. 1932 - 1945
(2016/10/22)
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- Total synthesis of trifluorobutyryl-modified, protected sialyl Lewis X by a convergent [2+2] approach
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Structural and quantitative changes in the expression of sialic acid residues on the surface of eukaryotic cells profoundly influence a broad range of biological processes including inflammation, antigen recognition, microbial attachment and tumour metastasis. Uptake and incorporation of sialic acid analogues in mammalian cells enable structure-function studies and perturbation of specific recognition events. Our group has recently shown that a trifluorobutyryl-modified sialic acid metabolite diminishes the adhesion of mammalian cells to E and P-Selectin, presumably by leading to the expression of fluorinated sLex epitopes on cell surfaces, and interfering with the sLex-selectin interactions that are well known in mediating tumour cell migration (J. Med. Chem. 2010, 53, 4277). For studies directed towards understanding the molecular basis of this reduced adhesion, chemical synthesis of trifluorobutyrylated sialyl Lewis X (C4F3-sLex) was crucial. We have developed a highly efficient [2+2] approach for the assembly of C4F3-sLex on a preparative scale that contains versatile protective groups allowing the glycan to be surface immobilized or solubilized as needed for biophysical studies to investigate selectin interactions. This strategy can, in principle, be used for preparation of other N-modified sLex analogues.
- Ak?ay, Gizem,Ramphal, John Y.,D'Alarcao, Marc,Kumar, Krishna
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p. 109 - 114
(2015/02/02)
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- Tuning mechanism-based inactivators of neuraminidases: Mechanistic and structural insights
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3-Fluorosialosyl fluorides are inhibitors of sialidases that function by the formation of a long-lived covalent active-site adduct and have potential as therapeutics if made specific for the pathogen sialidase. Surprisingly, human Neu2 and the Trypanosoma cruzi trans-sialidase are inactivated more rapidly by the reagent with an equatorial fluorine at C3 than by its axial epimer, with reactivation following the same pattern. To explore a possible stereoelectronic basis for this, rate constants for spontaneous hydrolysis of the full series of four 3-fluorosialosyl fluorides were measured, and ground-state energies for each computed. The alpha (equatorial) anomeric fluorides hydrolyze more rapidly than their beta anomers, consistent with their higher ground-state energies. However ground-state energies do not explain the relative spontaneous reactivities of the 3-fluoro-epimers. The three-dimensional structures of the two 3-fluoro-sialosyl enzyme intermediates of human Neu2 were solved, revealing key stabilizing interactions between Arg21 and the equatorial, but not the axial, fluorine. Because of changes in geometry these interactions will increase at the transition state, likely explaining the difference in reaction rates. Understanding reactivity and selectivity: The mechanistic basis for the surprisingly different rates of inactivation and reactivation of human and Trypanosoma cruzi sialidases by the two 3-fluoro epimers of 2,3-difluorosialic acid was probed through spontaneous hydrolysis kinetics, computational analysis, and X-ray crystallography.
- Buchini, Sabrina,Gallat, Francois-Xavier,Greig, Ian R.,Kim, Jin-Hyo,Wakatsuki, Soichi,Chavas, Leonard M. G.,Withers, Stephen G.
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p. 3382 - 3386
(2014/04/03)
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- Chemical Synthesis and Enzymatic Testing of CMP-Sialic Acid Derivatives
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The cycloSal approach has been used in the past for the synthesis of a range of phosphorylated bioconjugates. In those reports, cycloSal nucleotides were allowed to react with different phosphate nucleophiles. With glycopyranosyl phosphates as nucleophile
- Wolf, Saskia,Warnecke, Svenja,Ehrit, Joerg,Freiberger, Friedrich,Gerardy-Schahn, Rita,Meier, Chris
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p. 2605 - 2615
(2013/01/16)
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- Synthesis and inhibitory activity of sialic acid derivatives targeted at viral sialate-O-acetylesterases
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A series of sialosides modified at the 4- and 9-hydroxy group were synthesised and tested for inhibition of the viral haemagglutinin-esterase activity from various Orthomyxoviruses and Coronaviruses. While no inhibition of the sialate-4-O-acetylesterases
- Stanley, Mathew,Mayr, Juliane,Huber, Wolfgang,Vlasak, Reinhard,Streicher, Hansj?rg
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scheme or table
p. 2852 - 2860
(2011/07/08)
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- N,N-Diacetylsialyl chloride-a novel readily accessible sialyl donor in reactions with neutral and charged nucleophiles in the absence of a promoter
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N,N-Diacetylneuraminic acid glycosyl chloride was prepared for the first time and made to react with various nucleophiles to give the corresponding α-glycosyl phosphate, β-glycosyl dibenzyl phosphate, α-glycosyl azide, α-phenyl thioglycoside and α-glycosyl xanthate in 65-82% yields and high stereoselectivity while its reactions with simple alcohols were not stereoselective. The new sialyl donor made possible the first stereoselective synthesis of sialic acid glycosyl phosphate with α-configuration and highly efficient synthesis of β-configured sialic acid glycosyl dibenzyl phosphate.
- Orlova, Anna V.,Shpirt, Anna M.,Kulikova, Nadezhda Y.,Kononov, Leonid O.
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scheme or table
p. 721 - 730
(2010/06/14)
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- A fragment-based in situ combinatorial approach to identify high-affinity ligands for unknown binding sites
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[Figure Presented] In the lead: The title method for the identification of ligands is particularly useful for binding sites where little or no structural information is available. In a fragment-based approach, a suitable pair of first- and second-site ligands is identiled by NMR experiments. By applying a receptor-mediated in situ combinatorial approach, the two ligands are then linked to generate a new high-affinity lead structure (see picture).
- Shelke, Sachin V.,Cutting, Brian,Jiang, Xiaohua,Koliwer-Brandl, Hendrik,Strasser, Daniel S.,Schwardt, Oliver,Kelm, Soerge,Ernst, Beat
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supporting information; experimental part
p. 5721 - 5725
(2010/11/02)
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- Synthesis of poly(aspartimide)-based bio-glycoconjugates
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The purpose of this programme was to synthesize and analyze new bioconjugates of interest for the potential inhibition of the influenza virus, using poly(aspartimide) as a polymer support. The macromolecular targets were obtained by attaching various sial
- Carlescu, Irina,Osborn, Helen M.I.,Desbrieres, Jacques,Scutaru, Dan,Popa, Marcel
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- Preparation of aminoethyl glycosides for glycoconjugation
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The synthesis of a number of aminoethyl glycosides of cell-surface carbohydrates, which are important intermediates for glycoarray synthesis, is described. A set of protocols was developed which provide these intermediates, in a short number of steps, from commercially available starting materials.
- Sardzik, Robert,Noble, Gavin T.,Weissenborn, Martin J.,Martin, Andrew,Webb, Simon J.,Flitsch, Sabine L.
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supporting information; experimental part
p. 699 - 703
(2011/01/03)
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- Anomeric samarium(III) intermediates of N-acetylneuraminic acid from anomeric 2-pyridylsulfides
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Treatment of the anomeric 2-thiopyridyl derivative of N-acetylneuraminic acid (sialic acid or Neu5Ac) with samarium diiodide in the presence of aldehydes or ketones provides the corresponding C-sialylated derivatives in excellent yields. The efficiency of
- Malapelle, Adeline,Abdallah, Zouleika,Doisneau, Gilles,Beau, Jean-Marie
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scheme or table
p. 1417 - 1424
(2010/10/03)
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- Systematic syntheses of influenza neuraminidase inhibitors: A series of carbosilane dendrimers uniformly functionalized with thioglycoside-type sialic acid moieties
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In order to develop novel influenza sialidase inhibitors, we constructed a library of glycoclusters composed of twelve types of sialylated dendrimers with thioglycosidic linkage that are resistant to hydrolysis by the sialidases. These sialodendrimers were synthesized by condensation reaction between a thiosialoside modified on the aglycon terminal end by a thioacetyl group and twelve types of carbosilane dendrimers having brominated terminal ends under deacetylation conditions, and temporal re-protection was performed for purification. Removal of all protection of the glycodendrimers was accomplished by transesterification and subsequent saponification to provide corresponding water-soluble glycodendrimers in good yields. For investigation of the structure-activity relationship, dendrimer scaffolds having differences in number of the sugar moieties, such as 3-, 4-, 6- and 12-functionalized dendrimers, and in linkage patterns, such as normal aliphatic linkage, ether- and amide-linkages. Biological evaluations of these glycodendrimers showed that all of the ether- and amide-elongated compounds had inhibitory potencies for the influenza sialidases in the mM range, while compounds having normal aliphatic linkage did not have any activities except for a 12-functionalized compound.
- Sakamoto, Jun-Ichi,Koyama, Tetsuo,Miyamoto, Daisei,Yingsakmongkon, Sangchai,Hidari, Kazuya I.P.J.,Jampangern, Wipawee,Suzuki, Takashi,Suzuki, Yasuo,Esumi, Yasuaki,Nakamura, Takemichi,Hatano, Ken,Terunuma, Daiyo,Matsuoka, Koji
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scheme or table
p. 5451 - 5464
(2009/12/09)
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- Synthesis and evaluation of influenza virus sialidase inhibitory activity of hinokiflavone-sialic acid conjugates
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The known biflavonoid, hinokiflavone (1) was isolated from the leaves of Metasequoia glyptostroboides Hu et Cheng and displayed influenza A and B virus sialidase inhibitory activity. The unnatural glycoconjugate, hinokiflavone-sialic acid (8) was synthesi
- Miki, Kazuhiko,Nagai, Takayuki,Nakamura, Takayuki,Tuji, Mitsuru,Koyama, Kiyotaka,Kinoshita, Kaoru,Furuhata, Kimio,Yamada, Haruki,Takahashi, Kunio
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p. 879 - 885
(2008/09/21)
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- Neuramindase Inhibitor
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There are provided a novel compound having irreversible inhibitory activity against neuraminidase, a therapeutic agent and a detection agent for a disease involving neuraminidase. A compound represented by the following formula (I) and a salt thereof, a production method thereof, and an application method thereof, wherein: A1 represents an aryl group optionally having a substituent group or a heteroaryl group optionally having a substituent group;A2 represents —CX2R6 or —CHXR6 wherein X represents —F, —Cl, —Br, or —I;R1 represents a hydrogen atom or an alkyl group optionally having a substituent group;R2, R3, R4, and R5 represent each independently —OC(═O)R6, —OR6, —N(R6)2, —N3, —NHC(═NH)NHR6, —NHCOR6, —OSO3R6, —OPO3(R6)2, F, Cl, Br, or I; andR6 represents each independently a hydrogen atom, an alkyl group optionally having a substituent group, an aryl group optionally having a substituent group, or an optionally substituted heteroaryl group.
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Page/Page column 11
(2008/12/05)
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- A new generation of specific Trypanosoma cruzi trans-sialidase inhibitors
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(Chemical Equation Presented) A substitution for inhibition: The incorporation of anaryl substituent at C9 of 3-fluorosialyl fluorides provides specificity and dramatically slows the reactivation of the glycosylphosphatidylinositol-anchored surface protein Trypanosoma cruzi trans-sialidase (TcTS) by transglycosylation (see picture). X-ray crystallographic analysis of the trapped intermediate has provided a structural rationale for this behavior.
- Buchini, Sabrina,Buschiazzo, Alejandro,Withers, Stephen G.
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p. 2700 - 2703
(2008/12/23)
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- Synthesis and evaluation of 4-O-alkylated 2-deoxy-2,3-didehydro-N-acetylneuraminic acid derivatives as inhibitors of human parainfluenza virus type-3 sialidase activity
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The X-ray crystal structure of the paramyxoviral surface glycoprotein haemagglutinin-neuraminidase (HN) from Newcastle Disease virus was used as a template to design inhibitors of the HN from human parainfluenza virus type-3 (hPIV-3). 4-O-Alkylated derivatives of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en), accessed from 8,9-O-isopropylidenated-Neu5Ac2en1Me, were found to inhibit the sialidase (neuraminidase) activity of hPIV-3 (strain C243) in the range of 3-30 μM. This is comparable or improved activity compared to the parent 4-hydroxy compound.
- Tindal, David J.,Dyason, Jeffrey C.,Thomson, Robin J.,Suzuki, Takashi,Ueyama, Hiroo,Kuwahara, Yohta,Maki, Naoyoshi,Suzuki, Yasuo,Von Itzstein, Mark
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p. 1655 - 1658
(2007/10/03)
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- Anti-influenza virus activity of biflavonoids
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Ginkgetin was found to inhibit the influenza virus sialidase. Ginkgetin-sialic acid conjugates showed a significant survival effect in the influenza-virus-infected mice.
- Miki, Kazuhiko,Nagai, Takayuki,Suzuki, Kazushige,Tsujimura, Ryo,Koyama, Kiyotaka,Kinoshita, Kaoru,Furuhata, Kimio,Yamada, Haruki,Takahashi, Kunio
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p. 772 - 775
(2007/10/03)
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- An expeditious synthesis of N-acetylneuraminic acid α-C-glycosyl derivatives ("α-C-glycosides") from the anomeric acetates
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The reductive metallation of the readily available peracetylated derivatives of methyl N-acetylneuraminate 3a and 3b by samarium diiodide without any additive generates the corresponding anomeric samarium(III) organometallics. These intermediates react ef
- Malapelle, Adeline,Coslovi, Anna,Doisneau, Gilles,Beau, Jean-Marie
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p. 3145 - 3157
(2008/02/09)
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- Anomeric acetates of N-acetylneuraminic acid are useful C-sialyl donors in samarium-mediated reformatsky coupling reactions
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(Chemical Equation Presented) Teaching an old molecule new tricks: A new solution for an expeditious C-sialylation from N-acetylneuraminic acid involves the use of the peracetylated derivative 1, a very common starting material prepared 40 years ago in He
- Malapelle, Adeline,Abdallah, Zouleika,Doisneau, Gilles,Beau, Jean-Marie
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p. 6016 - 6020
(2007/10/03)
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- Conversion of N-acetylneuraminic acid glycosyl chloride into dibenzyl glycosyl phosphate: O-glycosylation in the absence of a promoter
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Readily accessible N-acetylneuraminic acid (Neu5Ac) glycosyl chloride, which was regarded to be a poor glycosyl donor, was shown to react with dibenzyl phosphoric acid salts in the absence of glycosylation promoters to give the corresponding β-Neu5Ac dibenzyl glycosyl phosphate in high yield.
- Shpirt,Kononov,Torgov,Shibaev
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p. 717 - 719
(2007/10/03)
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- Syntheses of alkenylated carbohydrate derivatives toward the preparation of monolayers on silicon surfaces
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This note describes the synthesis of different alkenylated carbohydrate derivatives suitable for direct attachment to hydrogen-terminated silicon surfaces. The derivatives were alkenylated at the C-1 position, while the remaining hydroxyl groups were protected. The development of such new carbohydrate-based sensing elements opens the access to new classes of biosensors.
- De Smet, Louis C.P.M.,Pukin, Aliaksei V.,Stork, Gerrit A.,De Vos, C.H. Ric,Visser, Gerben M.,Zuilhof, Han,Sudh?lter, Ernst J.R.
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p. 2599 - 2605
(2007/10/03)
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- Synthesis of O-Glycolyl-Linked Neuraminic Acids through a Spirocyclic Intermediate
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(Equation Presented) The neuraminic acid derivative 5 is readily converted in several steps to the neuraminic acid dimer 12, linked through the hydroxyl of a 5-N-glycolyl group in an α-2,5 glycosidic linkage. The sequence is shown to proceed through a spi
- McAuliffe, Joseph C.,Rabuka, David,Hindsgaul, Ole
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p. 3067 - 3069
(2007/10/03)
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- Hydrolase and sialyltransferase activities of Trypanosoma cruzi trans-sialidase towards NeuAc-α-2,3-Gal-β-O-PNP
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NeuAc-α-2,3-Gal-β-O-PNP has been synthesised and its ability to act as a substrate for the hydrolase and transferase activities of Trypanosoma cruzi trans-sialidase have been investigated. The turn-over of this compound shows marked differences from the behaviour of NeuAc-MU. In addition, distinct differences in the action of T. cruzi trans-sialidase and Clostridium perfringens neuraminidase on NeuAc-α-2,3-Gal-β-O-PNP were apparent.
- Harrison, Jennifer A.,Kartha,Turnbull,Scheuerl, Shona L.,Naismith, James H.,Schenkman, Sergio,Field, Robert A.
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p. 141 - 144
(2007/10/03)
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- Phenylboronic acid as a labile protective agent: the selective derivatisation of 1,2,3-triols
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The ability of phenylboronic acid to act as a labile protective agent for open-chain 1,2,3-triols is demonstrated in the highly selective terminal derivatisation of D-mannitol and an antiviral sialic acid derivative. Protection, derivatisation and deprotection are carried out in a single pot, yielding analytically pure products in moderate yield, without the need for chromatography or formal recrystallisation steps. In both classes of compound, the selectivity of protection is found to be complementary to existing methods, providing access to relatively uncommon 1,6-diesters and the 1,6-bis(benzyl ether) of D-mannitol, and 9-o-acylsialic acid derivatives.
- Bhaskar, Vijaya K.,Duggan, Peter J.,Humphrey, David G.,Krippner, Guy Y.,McCarl, Victoria,Offermann, Daniel A.
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p. 1098 - 1102
(2007/10/03)
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- Syntheses of C-3-modified sialylglycosides as selective inhibitors of influenza hemagglutinin and neuraminidase
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In an effort to develop new structures as inhibitors of both influenza virus proteins hemagglutinin and neuraminidase, a series of sialic acid derivatives, including those with one of the hydrogen atoms at the C-3 position replaced by either OH or F, were synthesized. The sialic acid derivative with a 3-eq-OH group was first synthesized by means of a new process and used as the key intermediate for further derivatization at the C- 3 position. The stability of these compounds under acid- and sialidase- catalyzed hydrolysis conditions was studied, and the results showed that these compounds exhibit stronger resistance towards both conditions than their parent p-nitrophenyl α-sialoside. Further inhibition assay indicated that the 3-ax-OH or F derivatives 4, 5, and 24, the 4-epimer of 4, are effective specific inhibitors of the sialidases from Clostridium perfringens, among other bacterial sialidases tested. The 3-eq-OH derivative 3, however, showed little inhibition. The same tendency was observed for the inhibition of human influenza sialidases N1 and N2. Compounds 3-5 and sialic acid were then converted into the distealoylphosphatidylethanolamine conjugates. Of these liposome-like compounds, the ones from 4 and 5 showed potent and selective inhibitory activities against the hemagglutinin H3 subtype, but displayed resistance to the influenza virus neuraminidases N1 and N2.
- Sun, Xue-Long,Kanie, Yoshimi,Guo, Chao-Tan,Kanie, Osamu,Suzuki, Yasuo,Wong, Chi-Huey
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p. 2643 - 2653
(2007/10/03)
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- Glycosylation chemistry promoted by iodine monobromide: Efficient synthesis of glycosyl bromides from thioglycosides, and O-glycosides from 'disarmed' thioglycosides and glycosyl bromides
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Iodine monobromide has been found to be an efficient reagent for the conversion of both 'armed' and 'disarmed' thioglycosides (-SMe, -SPr(i), - SPh) into glycosyl bromides. This reagent is compatible with most common protecting groups, and O-glycosidic linkages. The additional potency of I- Br, compared to iodine, as an iodonium ion source also permits the glycosylation of sugar alcohols by 'disarmed' glycosyl bromides and thioglycosides.
- Kartha, K. P. Ravindranathan,Field, Robert A.
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p. 8233 - 8236
(2007/10/03)
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- Thioglycosides of N-acetyl- and N-glycolylneuraminic acids as glycosyl donors. Synthesis of 3-aminopropylglycosides
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Protected derivatives of ethylthioglycosides of N-acetyl- and N-glycolylneuraminic acids were shown to be efficient glycosyl donors in the reaction with 3-trifluoroacetamidopropanol promoted with a N-iodosuccinimide-trifluoromethanesulfonic acid (or its trimethylsilyl ester) pair. This reaction led to high yields of the corresponding anomeric glycosides; however, its α-stereoselectivity was only moderate: α: β ratio ranged from 1 : 1 to 2 : 1. An analog of the Neu5Gc-donor with the O9 and O4 acetyl groups substituted by acetoxyacetyl groups manifested a high tendency to the predominant formation of the α-anomer. Separation of the anomers and their deprotection prepared the corresponding aminopropylglycosides for further condensation with a polymer carrier.
- Simeoni,Tuzikov,Byramova,Bovin
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p. 126 - 132
(2007/10/03)
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- Synthesis and enzymatic and NMR studies of novel sialoside probes: Unprecedented, selective neuraminidase hydrolysis of and inhibition by C-6-(methyl)-Gal sialosides
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We report here the synthesis of sialoside analogs, namely, αDNeuAc(2-6)(6-Me,R)βDGal-OR1 (R isomer, tg rotamer analog) and αDNeuAc(2-6)(6-Me,S)βDGal-OR1 (S isomer, gt rotamer analog, R1 = CH2CH2SiMe3 or H) and the corresponding sulfur linked thiosialosides useful for the determination of carbohydrate structural requirements in neuraminidase hydrolysis and for the design of neuraminidase inhibitors. The purpose of methyl substitution at C-6 of the galactose in these analogs is (a) to render the rotation around C6-C5 bond of the galactose more rigid, (b) to maintain the C-6-O-6 arm of the galactose predominantly in 'tg' or 'gt' rotamer orientation, and (c) to evaluate the importance of these two rotamer orientations in neuraminidase catalyzed hydrolysis. Compared to the natural disaccharide αDNeuAc(2-6)βDGal-OR, the gt rotamer analogs are very poorly hydrolyzed by neuraminidases from the influenza A virus, Arthrobacter ureafaciens(A.U.), Vibria cholerae (V.C.), and Clostridium perfringens (C.P.) In contrast, the tg rotamer analogs are hydrolyzed by all four neuraminidases at comparable rates relative to the natural disaccharide. Detailed enzyme kinetic analysis indicates that the gt rotamer analogs bind less efficiently to the neuraminidases and have 4- to 18-fold smaller V(max), as compared to the tg rotamer analogs. Evaluation of the sulfur analogs as neuraminidase inhibitors indicates that only a 'tg rotamer' thiosialoside analog is a good competitive inhibitor of the four neuraminidases. The inhibition constant K(i) ranges from 0.3 to 1 mM. Neither the natural thiosialoside analog nor the gt thiosialoside analogs are effective inhibitors (K(i) > 5 mM). Detailed NMR investigations of these sialosides show that in tg rotamer analogs there is a preferential anti orientation of the sialoside aglycon as compared to the natural or the 'gt sialosides'. Computer assisted docking of these analogs into the binding pocket of the influenza A neuraminidase-sialic acid crystal structure shows that the tg rotamer analog fits favorably into the neuraminidase binding pocket, whereas the natural isomer in the gt rotamer orientation or the gt rotamer analog encounters severe repulsive interactions with the arginine residues at the catalytic site. The perturbation of these important arginine residues appear to be responsible for the lack of neuraminidase catalyzed hydrolysis or inhibition by the gt rotamer analogs. These findings may have important implications in the rational design of neuraminidase inhibitors.
- Sabesan, Subramaniam,Neira, Susana,Davidson, Fred,Duus, Jens ?.,Bock, Klaus
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p. 1616 - 1634
(2007/10/02)
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- Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza A virus: Multivalency and steric stabilization of particulate biological systems
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An α-sialoside linked to acrylamide by a short connector (5-acetamido-2- O-(N-acryloyl-8-amino-5-oxaoctyl)-2,6-anhydro-3,5-dideoxy-D-glycero-D- galacto-α-nonulopyranosonoic acid, 1) was prepared. Compound 1 formed high molecular weight copolymers with acr
- Lees,Spaltenstein,Kingery-Wood,Whitesides
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p. 3419 - 3433
(2007/10/02)
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- Structural Transformations of N-Acetylneuraminic Acid, XXV: Synthesis of Methyl-2-α-glycosides of 4-Epi-, 7-Epi-, 8-Epi-, and 7,8-Bis-epi-N-acetylneuraminic Acid
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The α-methylketoside of N-acetylneuraminic acid methylester (4) is transformed via the deacetylated compound 5 into the 9,8-O-isopropylidenderivative 6 which could be oxidized regioselectively by RuO4 to the corresponding 4-oxo-sialic acid analogue 7.Reduction with the borane-ammonia complex produces a 1:1 mixture of 6 and the desired α-methylketoside of 9,8-O-isopropyliden-4-epi-N-acetyl-neuraminic acid methylester (8).Removing of the isopropylidene group gives the α-methylketoside of 4-epi-N-acetylneuraminic acid methylester (9), which was further transformed to the ammonium salt of 4-epi-N-acetylneuraminic acid α-methylketoside (10).On the other hand compound 5 was turned into the 4,8,9-tri-O-t-butyldimethylsilylderivative 11a from which the corresponding 7-oxo-compound 12 by oxidation with RuO4 derives.The reduction of 12 with BH3-NH3 yielded a 1:1 mixtures of the starting material 11a and the desired 7-epi-derivative 13a which gives either via the purified peracetylated α-methylketoside of 7-epi-N-acetylneuraminic acid methylester (14) or a direct saponification the sodium salt of 7-epi-N-acetylneuraminic acid-α-methylketoside (15).Applying the Koenigs-Knorr procedure to the peracetylated 8-epi-N-acetylneuraminic acid methylester (16) gives rise to the formation of a 1:1 mixture of the corresponding α- and β-methylketosides 17 and 18 besides traces of the corresponding 2,3-dideoxy-2,3-didehydro-sialic acid derivative 19.After chromatographic separation of 17 further saponification leads to the sodium salt of 8-epi-N-acetylneuraminic acid-α-methylketoside (20).In an analogous procedure the sodium salt of 7,8-di-epi-N-acetylneuraminic acid-α-methylketoside (25) was prepared starting from the peracetylated 7,8-di-epi-N-acetylneuraminic acid methylester (21), whereby a mixture of the α- and β-methylketosides 22 and 23 was formed in a ratio 95:5 besides traces of the peracetylated 2,3-dideoxy-2,3-didehydro-sialic acid methylester (24).Keywords.Sialic acid analogoues; Methyl-α-ketosides of sialic aicd analogues.
- Bandgar, B. P.,Zbiral, E.
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p. 1075 - 1088
(2007/10/02)
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- Synthesis of C-Glycosides of N-Acetylneuraminic Acid and Other Derivatives
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Reaction of the β-pyranosyl chloride 1 of N-acetylneuraminic acid with allyl(tributyl)stannane under radical-induced conditions affords a mixture of the allyl C-glycosides 2/3.After deprotection, the pure allyl α-C-glycoside 5 and the analogous β isomer 7 can be isolated.The allyl C-glycosides 2 and 3 are converted into the corresponding epoxypropyl C-glycosides 9 and 11 by epoxidation of the allylic group.Further modified allyl C-glycosides are prepared from the C-3-hydroxylated N-acetylneuraminic acid, which are available as pure α- and β-glycosides 19 and 21 after deprotection.At C-3 modified compounds are also synthesized which have allyl and azido residues at C-3.All compounds are interesting as potential inhibitors of sialidases, CMP sialate syntheses, and viral infection.
- Paulsen, Hans,Matschulat, Peter
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p. 487 - 495
(2007/10/02)
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