- SYNTHESES OF 2-O-GLYCOSYL DERIVATIVES OF N-ACETYL-D-NEURAMINIC ACID
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Syntheses of N-acetyl-D-neuraminic acid derivatives are reported.Methyl 4,7,8,9-tetra-O-acetyl-N-acetyl-2-chloro-2-deoxy-β-D-neuraminate (3) was prepared directly from methyl N-acetyl-β-D-neuraminate (2) in good yield.Koenigs-Knorr reaction of 3 with an excess of methanol gave the methyl α-glycoside of methyl N-acetyl-D-neuraminate (4). 2,3-O-Isopropylidene-D-ribono-1,4-lactone, 2,3-O-isopropylideneuridine, and 5-fluor-2,3-O-isopropylideneuridine reacted with 3 to give anomeric mixtures of methyl N-acetyl-D-neuraminate derivatives.The stereochemistry of these compounds was confirmed from n.m.r. and c.d. spectra, and measurements of the rate of hydrolysis of the glycosidic bond.
- Ogura, Haruo,Furuhata, Kimio,Itoh, Masayoshi,Shitori, Yoshiyasu
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- Quantitative Standards of 4-O-Acetyl- and 9-O-Acetyl-N-Acetylneuraminic Acid for the Analysis of Plasma and Serum
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N-Acetylneuraminic acid (sialic acid, Neu5Ac) is one of a large, diverse family of nine-carbon monosaccharides that play roles in many biological functions such as immune response. Neu5Ac has previously been identified as a potential biomarker for the presence and pathogenesis of cardiovascular disease (CVD), diabetes and cancer. More recent research has highlighted acetylated sialic acid derivatives, specifically Neu5,9Ac2, as biomarkers for oral and breast cancers, but advances in analysis have been hampered due to a lack of commercially available quantitative standards. We report here the synthesis of 9-O- and 4-O-acetylated sialic acids (Neu5,9Ac2 and Neu4,5Ac2) with optimisation of previously reported synthetic routes. Neu5,9Ac2 was synthesised in 1 step in 68 % yield. Neu4,5Ac2 was synthesised in 4 steps in 39 % overall yield. Synthesis was followed by analysis of these standards via quantitative NMR (qNMR) spectroscopy. Their utilisation for the identification and quantification of specific acetylated sialic acid derivatives in biological samples is also demonstrated.
- Cheeseman, Jack,Badia, Concepcion,Thomson, Rebecca I.,Kuhnle, Gunter,Gardner, Richard A.,Spencer, Daniel I. R.,Osborn, Helen M. I.
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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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- Revealing Functional Significance of Interleukin-2 Glycoproteoforms Enabled by Expressed Serine Ligation
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Naturally occurring interleukin-2 (IL-2) is a pleiotropic glycoprotein that regulates immune responses by controlling the differentiation and homeostasis of T cells. Non-glycosylated IL-2 has been used in clinical settings for three decades. However, the function of the O-glycan of native IL-2 remains elusive. Herein, to stress this issue, we report a highly efficient semi-synthesis of homogeneous glycosylated IL-2 with various glycoproteoforms on a multi-milligram scale. The glycopeptide fragment was prepared by chemical synthesis and then merged with recombinant fragment via a serine ligation to generate the desired glycoprotein in a single operation. Biological evaluation of the homogenous glycoprotein library reveals that the activity of IL-2 in activating individual T cell subset is glycan dependent, thus highlighting the possibility of further improving current clinical medicine.
- Cao, Qi,Li, Bin,Liu, Jiazhi,Liu, Lizhen,Liu, Xinnan,Shao, Hong,Tao, Houchao,Wang, Can,Wang, Ping,Xue, Dongxiang,Ye, Farong,Yu, Biao,Zhao, Hongbo,Zhao, Jie
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supporting information
(2022/01/31)
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- Synthesis of an STnThr analogue, structurally based on a TnThr antigen mimetic
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The monosaccharide Tn and the disaccharide STn are tumor antigens with similar structures and common biosynthetic pathways. Both are always over-expressed simultaneously on tumor cell surfaces. We report herein the efficient synthesis of the STnThr antigen analogue 2, featuring the immunogenic TnThr mimetic 1 aglycon. Analogously to the native STn, 2 is recognized by the influenza N1 neuraminidase. A model of the N1·2 complex showed the sialyl moiety of 2 well nested in the active site pocket, with docking unaffected by the rigid aglycon. The analogue 2 is, therefore, in association with mimetic 1, a good determinant for the design of new multiantigen cancer vaccines.
- Papi, Francesco,Paris, Arnaud,Lafite, Pierre,Daniellou, Richard,Nativi, Cristina
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supporting information
p. 7366 - 7372
(2020/10/13)
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- Addition of Sialic Acid to Insulin Confers Superior Physical Properties and Bioequivalence
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Native insulin is susceptible to biophysical aggregation and fibril formation, promoted by manual agitation and elevated temperatures. The safety of the drug and its application to alternative forms of administration could be enhanced through the identification of chemical modifications that strengthen its physical stability without compromising its biological properties. Complex polysialic acids (PSAs) exist naturally and provide a means to enhance the physical properties of peptide therapeutics. A set of insulin analogues site-specifically derivatized with sialic acid were prepared in an overall yield of 50-60%. Addition of a single or multiple sialic acids conferred remarkable enhancement to the biophysical stability of human insulin while maintaining its potency. The time to the onset of fibrillation was extended by more than 10-fold relative to that of the native hormone. These results demonstrate that simplified sialic acid conjugates represent a viable alternative to complex natural PSAs in increasing the stability of therapeutic peptides.
- Kabotso, Daniel E. K.,Kabotso, Daniel E. K.,Smiley, David,Mayer, John P.,Gelfanov, Vasily M.,Perez-Tilve, Diego,Dimarchi, Richard D.,Pohl, Nicola L. B.,Liu, Fa
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p. 6134 - 6143
(2020/07/10)
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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
(2020/08/22)
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- Cooperative Multipoint Recognition of Sialic Acid by Benzoboroxole-Based Receptors Bearing Cationic Hydrogen-Bond Donors
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Sialic acid recognition remains an interesting and challenging target in molecular receptor design. Herein, we report a series of benzoboroxole-based receptors in which cationic hydrogen-bond donors have been introduced and shown to promote multipoint sialic acid recognition. One striking feature revealed by these receptors is that the carboxylate sialic acid residue is the primary binding determinant for recognition by benzoboroxole, in which the presence of charge-reinforced hydrogen bonds results in enhanced selectivity for sialic acid over other carbohydrates and a 4.5-fold increase in affinity. These findings open up wide possibilities for benzoboroxole-based receptors use in life science research, biotechnology, and diagnostics.
- Di Pasquale, Alice,Tommasone, Stefano,Xu, Lili,Ma, Jing,Mendes, Paula M.
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p. 8330 - 8338
(2020/07/17)
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- SMALL MOLECULE LIGAND-TARGETED DRUG CONJUGATES FOR ANTI-INFLUENZA CHEMOTHERAPY AND IMMUNOTHERAPY
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Disclosed herein is a small molecule targeted drug conjugate for anti-influenza chemotherapy and immunotherapy. The disclosed drug conjugate may form an adaptor to recruit additional CAR T cells or other immune cells for precise elimination of influenza virus-infected cells in a subject. Concurrently administered antibodies or pre-existing immunity in influenza-virus infected subject works well with the targeted conjugate to eliminate virus infected cells, saving valuable time for rescuing late stage patients.
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Page/Page column 20
(2020/02/16)
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- NEW POTENT SIALYLTRANSFERASE INHIBITORS
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The present invention relates to anew class of sialyltransferase inhibitors. The class features a carbamate or similar moiety on the amine of a neuraminic acid derivative. Such inhibitors are suitable for use as a medicament, for example for treating, preventing, or delaying bacterial infection, viral infection, cancer, a disorder of sialic acid metabolism, or an autoimmune disease.
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Page/Page column 24; 27
(2019/08/12)
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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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- Glycopeptide nanofiber platform for Aβ-sialic acid interaction analysis and highly sensitive detection of Aβ
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The variation of amyloid β peptide (Aβ) concentration and Aβ aggregation are closely associated with the etiology of Alzheimer’s diseases (AD). The interaction of Aβ with the monosialoganglioside-rich neuronal cell membrane has been suggested to influence Aβ aggregation. Therefore, studies on the mechanism of Aβ and sialic acids (SA) interaction would greatly contribute to better understanding the pathogenesis of AD. Herein, we report a novel approach for Aβ?SA interaction analysis and highly sensitive Aβ detection by mimicing the cell surface presentation of SA clusters through engineering of SA-modified peptide nanofiber (SANF). The SANF displayed well-ordered 1D nanostructure with high density of SA on surface. Using FAM-labeled Aβ fragments of Aβ1?16, Aβ16?23, and Aβ24?40, the interaction between Aβ and SA was evaluated by the fluorescence titration experiments. It was found that the order of the SA-binding affinity was Aβ1?16 > Aβ24?40 > Aβ16?23. Importantly, the presence of full-length Aβ1?40 monomer triggered a significant fluorescence enhancement due to the multivalent binding of Aβ1?40 to the nanofiber. This fluorescent turn-on response showed high selectivity and sensitivity for Aβ1?40 detection and the method was further used for Aβ aggregation process monitoring and inhibitor screening. The results suggest the proposed strategy is promising to serve as a tool for mechanism study and the early diagnosis of Alzheimer’s disease.
- Lei, Li,Geng, Rui,Xu, Zhiai,Dang, Yijing,Hu, Xianli,Li, Lingling,Geng, Ping,Tian, Yang,Zhang, Wen
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p. 8129 - 8136
(2019/08/26)
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- Sialic acid lipid derivative and preparation method and application thereof
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The invention belongs to the technical field of medicines, and provides a sialic acid lipid derivative which can be used for modifying a particle preparation and a preparation method and application thereof. The structural general formula of the sialic acid lipid derivative is as shown in the specification, wherein R1 is an H atom or C1-C6 alkyl; R2 is H, (CH2) m or C2-C6 alkenyl, and m =1-17; when X is an H atom or an O atom, R3 is (CH2) n or cholesteryl, and n = 1-17; when X is a carbonyl group, R3 is a C12-C24 alkoxy group, a C12-C24 alkyl substituted amino group or cholesteryl; and R4 is -OH, -NHCOCH3 or -NHCOCH2OH. The sialic acid lipid derivative disclosed by the invention can be used for modifying a particle preparation and realizing different treatment or diagnosis purposes according to the properties of the medicine. Especially in the anti-tumor aspect, the sialic acid lipid derivative can endow a particle preparation with excellent tumor targeting ability to improve the tumorinhibition effect.
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Paragraph 0103-0108
(2019/12/29)
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- Stereoselective Total Syntheses of (+)-Castanospermine and Neu5Ac Methyl Ester
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Concise and stereocontrolled total syntheses of (+)-castanospermine and N-acetylneuraminic acid methyl ester were achieved from diastereomerically enriched anti,syn,syn-1,3-oxazine and anti,syn,anti-1,3-oxazine, respectively. The key step in this strategy was the stereoselective BF3·OEt2-mediated allylation.
- Myeong, In-Soo,Lee, Yong-Taek,Kang, Jihun,Ham, Won-Hun
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p. 4211 - 4220
(2019/04/30)
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- Heteromultivalent Glycooligomers as Mimetics of Blood Group Antigens
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Precision glycomacromolecules have proven to be important tools for the investigation of multivalent carbohydrate–lectin interactions by presenting multiple glycan epitopes on a highly-defined synthetic scaffold. Herein, we present a new strategy for the versatile assembly of heteromultivalent glycomacromolecules that contain different carbohydrate motifs in proximity within the side chains. A new building block suitable for the solid-phase polymer synthesis of precision glycomacromolecules was developed with a branching point in the side chain that bears a free alkyne and a TIPS-protected alkyne moiety, which enables the subsequent attachment of different carbohydrate motifs by on-resin copper-mediated azide–alkyne cycloaddition reactions. Applying this synthetic strategy, heteromultivalent glycooligomers presenting fragments of histo-blood group antigens and human milk oligosaccharides were synthesized and tested for their binding behavior towards bacterial lectin LecB.
- Bücher, Katharina S.,Konietzny, Patrick B.,Snyder, Nicole L.,Hartmann, Laura
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supporting information
p. 3301 - 3309
(2019/02/14)
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- Selective Inhibition of Sialic Acid-Based Molecular Mimicry in Haemophilus influenzae Abrogates Serum Resistance
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Pathogens such as non-typeable Haemophilus influenzae (NTHi) evade the immune system by presenting host-derived sialic acids. NTHi cannot synthesize sialic acids and therefore needs to utilize sialic acids originating from host tissue. Here we report sialic acid-based probes to visualize and inhibit the transfer of host sialic acids to NTHi. Inhibition of sialic acid utilization by NTHi enhanced serum-mediated killing. Furthermore, in an in vitro model of the human respiratory tract, we demonstrate efficient inhibition of sialic acid transfer from primary human bronchial epithelial cells to NTHi using bioorthogonal chemistry. Molecular mimicry of non-typeable Haemophilus influenzae (NTHi) with host sialic acid sugars mediates resistance to serum killing and increases virulence. Heise et al. have developed sialic acid derivatives that allow either visualization or inhibition of host sialic acid transfer to NTHi, the latter enhancing serum-mediated killing.
- Heise, Torben,Langereis, Jeroen D.,Rossing, Emiel,de Jonge, Marien I.,Adema, Gosse J.,Büll, Christian,Boltje, Thomas J.
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p. 1279 - 8,1285
(2018/06/14)
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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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- Amino-sialic acid sugar-based CD169 affinitive anti-tumor compound and preparation method thereof
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The invention discloses an amino-sialic acid sugar-based CD169 affinitive anti-tumor compound and a preparation method thereof. The amino-sialic acid sugar-based CD169 affinitive anti-tumor compound is a 9-site substituted derivative of N-acetylneuraminic
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Paragraph 0039
(2018/07/30)
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- Syntheses and anti-cancer activity of CO-releasing molecules with targeting galactose receptors
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CO-releasing molecules (CORMs) containing cobalt have many bioactivities, but most of them do not dissolve in water and have no selectivity to tissue and organs. On the basis of the specific recognition of galactose or sialic acid by a receptor, a series of CORMs based on carbohydrates were synthesized and evaluated. The test results show that all the complexes displayed anticancer activity. Among them, the effects of the complexes of galactose (1), GalNAc (8) and sialic acid (10) were very distinct. Complex 1 displayed higher activity against HeLa, HePG2, MCF-7 and HT-29 cell proliferation than cis-platin (DDP), and its selectivity was far much better than DDP compared with normal cell W138. Furthermore, the uptakes of complexes 1, 8 and 10 by HePG2, HT-29, A549 and RAW264.7 cell lines were studied. The uptake ratio of each cell line for complex 1 was different, and the order of uptake ratio in the four cell lines was HePG2 > HT-29 > RAW264.7 > A549. The HePG2 cells absorbed complex 1 beyond 60% after incubation for 8 h, while A549 absorbed only 27.8%. For complex 8, the uptake trend was similar to that of complex 1 with it being absorbed by all the four cancer cells, but the uptake rate was lower. However, differently, complex 10 was absorbed heavily by macrophage RAW264.7, followed by HePG2; after 8 h incubation, the uptake ratio of RAW264.7 was over 50%. In addition, the mechanism of action was explored, and the results showed that the complexes inhibited cell cycle arrest at the G2/M phase; complex 1 up-regulated the expression levels of caspase-3 and Bax, and down-regulated the Bcl-2 expression, giving rise to HePG2 cell apoptosis.
- Li, Jili,Zhang, Jinlong,Zhang, Qiuping,Bai, Zhongjie,Zhao, Quanyi,He, Dian,Wang, Zhen,Chen, Yonglin,Liu, Bin
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p. 8115 - 8129
(2018/11/23)
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- Concise synthesis of 2,7-anhydrosialic acid derivatives and its application
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In N-acetylneuraminic acid, apart from O9 and O8, a possible glycosylation site is the O4 position. For example, gangliosides HLG-2 and HPG-7 are considered to be potential lead compounds for carbohydrate-based drug development to treat neural disorders. However, the construction of their α(1 → 4) fucosyl sialic acid and α(2 → 4) linkages between sialic acids is difficult because of the regioselectivity problem. Herein, N-acetyl-2,7-anhydroneuraminic acid was synthesized in three steps from Neu5Ac methyl ester through per-O-trimethylsilylation, heating-assisted intramolecular anomeric protection (iMAP) and desilylation. The iMAP simultaneously circumvents both the 2- and 7-OH protection. Upon protecting the 8- and 9-OH groups as a benzylidene acetal, only 4-OH is free for glycosylation. These 2,7-anhydro-8,9-O-benzylidenesialic acid derivatives were examined as acceptor for an α-selective fucosylation to construct the glycosidic linkage of fucosyl α(1 → 4) 2,7-anhydroneuraminic acid.
- Asressu, Kesatebrhan Haile,Wang, Cheng-Chung
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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; 14
(2017/02/24)
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- Synthesis of sialic acid derivatives based on chiral substrate-controlled stereoselective aldol reactions using pyruvic acid oxabicyclo[2.2.2]octyl orthoester
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The synthesis of sialic acids and their analogs was accomplished based on substrate-controlled asymmetric aldol reactions between sterically complicated aldehydes easily prepared from commercially available carbohydrates and a novel pyruvic acid oxabicyclo[2.2.2]octyl orthoester. Systematic aldol reaction studies using chiral aldehydes revealed that α,β,γ-benzyloxy-substituted aldehydes with an α,β-anti relative configuration preferentially provided the Felkin products with the 4,5-anti configuration with high diastereoselectivity. The relative β,γ-configuration in α,β,γ-benzyloxy-substituted aldehydes with an α,β-syn arrangement exerted a secondary effect on the diastereoselectivity of the stereogenic center formed in aldol reactions, and α,β-syn-β,γ-anti benzyloxyaldehyde exhibited superior diastereoselectivity to α,β-syn-β,γ-syn benzyloxyaldehyde to yield the Felkin products.
- Norimura, Yusuke,Yamamoto, Daisuke,Makino, Kazuishi
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p. 640 - 648
(2017/01/25)
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- Synthesis of novel pentacyclic triterpene-Neu5Ac2en derivatives and investigation of their: In vitro anti-influenza entry activity
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Sialic acid derivatives, analogs, and their conjugates are important pharmacophores. Modification of the C-4 hydroxyl group of sialic acid can lead to derivatives, such as zanamivir, with potent anti-influenza activities. Herein, we described the synthesis of C-4-modified sialic acid derivatives via conjugation with naturally derived pentacyclic triterpenes, which are active ingredients of traditional Chinese medicine, and the evaluation of their in vitro anti-influenza virus activity in MDCK cells. Interestingly, a set of configurational isomers was obtained during the de-O-acetylation reaction of two pentacyclic triterpene-sialic acid conjugates under Zemplén conditions, and a mechanism was proposed. Owing to the attachment of the Neu5Ac2en moiety, all synthesized conjugates displayed lower hydrophobicity than their parent compounds. In comparison with ursane- and lupane-type triterpenes, oleanane-type triterpene-functionalized Neu5Ac2en conjugates were most promising. The insertion of a (1,2,3-triazol-4-yl)-methyl between the amide bond and Neu5Ac2en caused a substantial decrease in activity. Compound 15a exhibited the highest inhibitory activity (IC50 = 8.3 μM) and selectivity index (SI = 22.7). Further studies involving hemagglutination inhibition and neuraminidase inhibition suggested that compound 15a inhibited virus-induced hemagglutination with no effect on the enzymatic activity of neuraminidase, indicating that the antiviral activity appeared to be mediated via interaction with hemagglutinin at the initial stage of viral infection.
- Shi, Yongying,Si, Longlong,Han, Xu,Fan, Zibo,Wang, Shouxin,Li, Man,Sun, Jiaqi,Zhang, Yongmin,Zhou, Demin,Xiao, Sulong
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p. 1531 - 1541
(2017/07/25)
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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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- A fluorescein-labelled sialic acid reagent and its preparation method and application
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The invention relates to a fluorescein-labelled sialic acid reagent, a preparation method and an application, which belongs to the sialic acid reagent. A molecular formula of the fluorescein-labelled sialic acid reagent is C32H31N3O13S. According to the invention, N-N dimethyl formamide and potash are added in 9th position amino sialic acid and fluorescein isothiocyanate, after the reaction, the fluorescein-labelled sialic acid reagent is prepared; a molecular formula of the 9th position amino sialic acid is C11H20N2O8, and a molecular formula of fluorescein isothiocyanate is C21H11NO5S. The fluorescein-labelled sialic acid reagent can be used in preparation of a diagnosis agent before a tumour operation and a tracer in the tumour operarion. The specialty of the fluorescein-labelled sialic acid reagent is high, and the fluorescein-labelled sialic acid reagent specially enters into the tumour tissue, so that the fluorescein-labelled sialic acid reagent has low background signals, the fluorescein-labelled sialic acid reagent is successfully used in tumour small focuses so as to provide good auxiliary effect for tumor resection.
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Paragraph 0030; 0037
(2017/01/23)
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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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- FATTY ACID ANTIVIRAL CONJUGATES AND THEIR USES
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The invention relates to fatty acid antiviral conjugates; compositions comprising an effective amount of a fatty acid antiviral conjugate; and methods for treating or preventing a viral infection comprising the administration of an effective amount of a fatty acid antiviral conjugate.
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Paragraph 0755; 0756; 0757
(2016/06/01)
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- Neuraminidase inhibitor and preparation method and in the preparation of anti-influenza virus application of the medicament (by machine translation)
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The invention discloses neuraminidase inhibitor and preparation method and in the preparation of anti-influenza virus application of the medicament. In the general formula (I) - (III) shown in any one of the compound or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic, tautomeric, or prodrug thereof, . Pharmaceutical composition, which comprises at least one of the following: the above-mentioned compound, its pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, its amine, the tautomers, prodrugs thereof. Compound or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic, tautomeric, or prodrug thereof in the preparation of anti-influenza virus application of the medicament. Through measuring the compound of the invention with a certain inhibition of influenza virus activity, is expected to be used in preparation of anti-influenza virus drugs. (by machine translation)
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Paragraph 0061; 0062
(2016/10/27)
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- Glycoprotein labeling with click chemistry (GLCC) and carbohydrate detection
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Molecular labeling and detection techniques are essential to research in life science. Here, a method for glycoprotein labeling/carbohydrate detection through glycan replacement, termed glycoprotein labeling with click chemistry (GLCC), is described. In this method, a glycoprotein is first treated with specific glycosidases to remove certain sugar residues, a procedure that creates acceptor sites for a specific glycosyltransferase. A 'clickable' monosaccharide is then installed onto these sites by the glycosyltransferase. This modified glycoprotein is then conjugated to a reporter molecule using a click chemistry reaction. For glycoproteins that already contain vacant glycosylation sites, deglycosylation is not needed before the labeling step. As a demonstration, labeling on fetal bovine fetuin, mouse immunoglobulin IgG and bacterial expressed human TNFα and TNFβ are shown. Compared to traditional ways of protein labeling, labeling at glycosylation sites with GLCC is considerably more specific and less likely to have adverse effects, and, when utilized as a method for carbohydrate detection, this method is also highly specific and sensitive.
- Wu, Zhengliang L.,Huang, Xinyi,Burton, Andrew J.,Swift, Karl A.D.
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- One-pot SSA-catalyzed β-elimination: An efficient and inexpensive protocol for easy access to the glycal of sialic acid
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Neu5Ac2en1Me per-OAc, the fully protected glycal of sialic acid, is a key intermediate in the discovery of therapeutics and diagnostics, including anti-influenza drugs and proteolysis resistant peptidomimetic foldamers. The synthesis of this sialic acid derivative, however, still relies on standard sugar chemistry that utilizes multi-step methodologies. Herein we report a facile and highly efficient microwave-assisted preparation of Neu5Ac1Me using silica sulfuric acid (SSA) as solid-supported acid catalyst that is one- to two-orders of magnitude faster than standard procedures. We also describe the microwave-assisted and SSA-catalyzed one-pot, rapid, solvent free reaction that combines both peracetylation and β-elimination reactions in one step to generate the glycal from Neu5Ac1Me. We coined the term One-pot SSA-catalyzed Technology for β-Elimination Protocol (OneSTEP) to describe this least laborious, most efficient, and practical preparation to date of Neu5Ac2en1Me per-OAc in terms of yield, time, reagent cost, and waste generation.
- Paragas, Erickson M.,Monreal, I. Abrrey,Vasil, Chris M.,Saludes, Jonel P.
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supporting information
p. 77 - 80
(2015/02/02)
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- Prodrugs of neuraminidase inhibitors
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A new class of neuramidase inhibitor prodrugs is provided characterized by a prodrug moiety of a carboxyl group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide or a carbonyl ethoxy tripeptide, a guanidine group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide, a carbonyl ethoxy tripeptide; a primary alcohol modified to form an esterified single amino acid, dipeptide or tripeptide of zanavimir of the unaltered therapeutic agent. Exemplary therapeutic agents so modified to form prodrugs include zanavimir, oseltamivir and peramivir. The prodrug has increased oral bioavailability relative to the unaltered neuraminidase inhibitor and is effective in the inhibition of viral infections involving neuraminidase in the viral reproductive cycle.
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Page/Page column 11; 12
(2015/12/01)
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- METHOD FOR PRODUCING NEURAMINIC ACID DERIVATIVE
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The present invention provides methods for manufacturing neuraminic acid derivatives. [Means for solution] Methods for manufacturing compounds represented by the formula (I) : [wherein R1 represents a C1-C19 alkyl group], or a pharmacologically acceptable salt thereof, using N-acetylneuraminic acid dihydrate as a starting raw material are provided.
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Paragraph 0134
(2014/10/29)
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- A facile microwave-assisted protocol for rapid synthesis of N-acetylneuraminic acid congeners
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We developed a simple, rapid and efficient microwave irradiation-assisted protocol that is 1- to 2-orders of magnitude faster than conventional techniques, providing an expedient access to the sialic acid congeners Neu5Ac1Me (1), Neu5Acβ1,2Me2 (2), Neu5Ac1Me O-peracetate (3) and 4,5-oxazoline of Neu5Ac2en1Me O-peracetate (4).
- Saludes, Jonel P.,Sahoo, Dhananjaya,Monreal, I. Abrrey
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supporting information
p. 507 - 510
(2014/02/14)
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- FATTY ACID ANTIVIRAL CONJUGATES AND THEIR USES
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The invention relates to fatty acid antiviral conjugates; compositions comprising an effective amount of a fatty acid antiviral conjugate; and methods for treating or preventing a viral infection comprising the administration of an effective amount of a fatty acid antiviral conjugate.
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Paragraph 0878; 0879; 0880
(2014/09/30)
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- A DNA-templated synthesis of encoded small molecules by DNA self-assembly
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We report a novel method for the synthesis of DNA-encoded libraries without the need for discrete DNA template. Reactant DNAs self-assemble to enable chemical reactions and photo-cleavage transfers the product to the DNA terminus, making it suitable for the subsequent affinity-based selection and hit deconvolution. This journal is the Partner Organisations 2014.
- Cao, Cheng,Zhao, Peng,Li, Ze,Chen, Zitian,Huang, Yanyi,Bai, Yu,Li, Xiaoyu
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supporting information
p. 10997 - 10999
(2014/11/07)
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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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supporting information
p. 3382 - 3386
(2014/04/03)
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- CONJUGATES OF A GLYCOPROTEIN OR A GLYCAN WITH A TOXIC PAYLOAD
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The invention relates to a glycoprotein-toxic pay- load molecule conjugate, a toxic payload molecule- glycan conjugate, and a pharmaceutical composi- tion.The invention further relates to a method for preparing the glycoprotein-toxic payload mole- cule conjugate, the method for modulating growth of a cell population and a method of treating tu- mour cells.
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Page/Page column 93; 110
(2014/11/13)
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- An efficient synthesis of C3 C-alkylated Neu5Ac2en derivatives
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C3-modified Neu5Ac2en derivatives can be used to study the flexible 150-loop region of influenza virus sialidases and also provide a new template for the development of next-generation sialidase inhibitors. This Letter describes an efficient synthetic route towards the large scale synthesis of C3 C-alkylated Neu5Ac2en derivatives. The key intermediate, a 3-eq-allyl-Neu5Ac derivative, is formed by stereoselective addition of the allyl group in an equatorial configuration at C3, regardless of the stereochemistry of the bromohydrin precursor.
- Rudrawar, Santosh,Pascolutti, Mauro,Bhatt, Beenu,Thomson, Robin J.,Von Itzstein, Mark
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supporting information
p. 1198 - 1201
(2013/03/14)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF METABOLIC CONDITIONS AND MUSCULAR DISORDERS
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The disclosures herein provide compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. These salts may be formulated as pharmaceutical compositions. The pharmaceutical compositions of compound of formula I may be formulated for peroral, topical, enteral, transmucosal administration, sustained release, delayed release, transdermal or injection. Such compositions may be used to treatment of human inclusion body myopathy, lysosomal storage diseases and other glycobiology related neuromuscular disorders or its associated complications.
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-
Paragraph 00190-00192
(2013/03/26)
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- FATTY ACID ANTIVIRAL CONJUGATES AND THEIR USES
-
The invention relates to fatty acid antiviral conjugates; compositions comprising an effective amount of a fatty acid antiviral conjugate; and methods for treating or preventing a a viral infection comprising the administration of an effective amount of a fatty acid antiviral conjugate.
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Paragraph 00176
(2013/07/05)
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- The total synthesis of a ganglioside Hp-s1 analogue possessing neuritogenic activity by chemoselective activation glycosylation
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The total synthesis of ganglioside 2, an analogue of the ganglioside Hp-s1 (1) which displays neuritogenic activity toward the rat pheochromocytoma cell line PC-12 cell in the presence of nerve growth factor (NGF) with an effect (34.0%) greater than that
- Tsai, Yow-Fu,Shih, Cheng-Hua,Su, Yu-Ting,Yao, Chun-Hsu,Lian, Jang-Feng,Liao, Chun-Chen,Hsia, Ching-Wu,Shui, Hao-Ai,Rani, Rashmi
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supporting information; experimental part
p. 931 - 934
(2012/04/04)
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- Rapid and clean microwave-assisted synthesis of N-acetylneuraminic acid methyl ester and its β-methyl glycoside
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The effect of microwave irradiation on the synthesis of N-acetylneuraminic acid methyl ester and its β-methyl glycoside is investigated. On a 1 g scale, a high yield (94%) of the methyl ester was obtained after 15 min at 80 °C. Acceleration of the glycosidation reaction was achieved, with the β-methyl glycoside isolated in good yield following optimisation of reaction conditions to 15 min at 12°C.
- Chopra, Pradeep,Thomson, Robin J.,Grice, I. Darren,Von Itzstein, Mark
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p. 6254 - 6256,3
(2012/12/11)
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- Rapid and clean microwave-assisted synthesis of N-acetylneuraminic acid methyl ester and its β-methyl glycoside
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The effect of microwave irradiation on the synthesis of N-acetylneuraminic acid methyl ester and its β-methyl glycoside is investigated. On a 1 g scale, a high yield (94%) of the methyl ester was obtained after 15 min at 80 °C. Acceleration of the glycosidation reaction was achieved, with the β-methyl glycoside isolated in good yield following optimisation of reaction conditions to 15 min at 12°C.
- Chopra, Pradeep,Thomson, Robin J.,Grice, I. Darren,Von Itzstein, Mark
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p. 6254 - 6256
(2013/01/15)
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- Exploring the effect of sialic acid orientation on ligand-receptor interactions
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Here, we present the synthesis of two sialo-micelles to validate the significance of sialic acid orientation during specific carbohydrate-protein and carbohydrate-carbohydrate interactions. Our data clearly suggest that orientation of carboxylic acid and
- Yadav, Rohan,Kikkeri, Raghavendra
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scheme or table
p. 7265 - 7267
(2012/08/28)
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- An efficient approach for total synthesis of aminopropyl functionalized ganglioside GM1b
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A highly efficient protocol for the synthesis of aminopropyl functionalized ganglioside GM1b has been described. The full protected ganglioside GM1b was obtained in 71% yield within 5 h. The key feature of the synthetic approach was the use of sialic acid
- Sun, Bin,Jiang, Heyan
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supporting information
p. 5711 - 5715
(2012/11/13)
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- Synthesis of the complete series of mono acetates of N-acetyl-d-neuraminic acid
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The short syntheses of each of the mono-acetates of N-acetyl-d-neuraminic acid are reported. These are important molecules for studying the mechanism and function of enzymes which utilise Neu5Ac as a substrate. However, until now these molecules were not
- Clarke, Paul A.,Mistry, Nimesh,Thomas, Gavin H.
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supporting information; experimental part
p. 529 - 535
(2012/01/15)
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- NOVEL GLYCOSYL PHOSPHITES
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The present invention relates to providing compounds of general formula (1) wherein A is glycosyl residue of a mono-, di- or oligosaccharide in protected form and R is selected from optionally substituted aryl or optionally substituted heteroaryl, methods
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Page/Page column 14
(2012/09/11)
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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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- Syntheses of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid analogues modified by N-sulfonylamidino groups at the C-4 position and biological evaluation as inhibitors of human parainfluenza virus type 1
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Eleven novel sialidase inhibitors 9 and 10 with an N-sulfonylamidino group at the C-4 position of Neu5Ac2en 1 against human parainfluenza virus type 1 (hPIV-1) were synthesized using copper-catalyzed three-component coupling reactions, and their inhibitory activities against hPIV-1 sialidase were studied.
- Nishino, Reiko,Ikeda, Kiyoshi,Hayakawa, Takuya,Takahashi, Tadanobu,Suzuki, Takashi,Sato, Masayuki
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scheme or table
p. 2418 - 2427
(2011/05/12)
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- Positive and negative electrospray ionisation travelling wave ion mobility mass spectrometry and low-energy collision-induced dissociation of sialic acid derivatives
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Mono- or oligosaccharide-containing samples, whether they are derived from biological sources or products of chemical synthesis, are often mixtures of spatial or constitutional isomers. The possibility of characterising or performing quality control on su
- Winkler, Wolfgang,Huber, Wolfgang,Vlasak, Reinhard,Allmaier, Guenter
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experimental part
p. 3235 - 3244
(2012/05/07)
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