- 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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p. 4525 - 4530
(2021/08/09)
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- Synthesis of MUC1-derived glycopeptide bearing a novel triazole STn analog
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The synthesis of MUC1 glycopeptides bearing modified tumor-associated carbohydrate antigens (TACAs) represents an effective strategy to develop potential antitumor vaccines that trigger strong immune response. In this context, we present herein the multis
- Marchiori, Marcelo F.,Bortot, Leandro O.,Carvalho, Ivone,Campo, Vanessa L.
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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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- 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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- 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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p. 3301 - 3309
(2019/02/14)
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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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- Platform Synthetic Lectins for Divalent Carbohydrate Recognition in Water
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Biomimetic carbohydrate receptors (“synthetic lectins”) have potential as agents for biological research and medicine. However, although effective strategies are available for “all-equatorial” carbohydrates (glucose, etc.), the recognition of other types of saccharide under natural (aqueous) conditions is less well developed. Herein we report a new approach based on a pyrene platform with polar arches extending from aryl substituents. The receptors are compatible with axially substituted carbohydrates, and also feature two identical binding sites, thus mimicking the multivalency observed for natural lectins. A variant with negative charges forms 1:2 host/guest complexes with aminosugars, with K1>3000 m?1for axially substituted mannosamine, whereas a positively charged version binds the important α-sialyl unit with K1≈1300 m?1.
- Carter, Tom S.,Mooibroek, Tiddo J.,Stewart, Patrick F. N.,Crump, Matthew P.,Galan, M. Carmen,Davis, Anthony P.
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supporting information
p. 9311 - 9315
(2016/08/05)
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- NOVEL COMPOUND AND FLUORESCENT COMPOSITION COMPRISING SAID COMPOUND
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PROBLEM TO BE SOLVED: To provide a new fluorescent substance for virus detection, cell or cancer cell detection, tissue or brain tissue staining or bacterium detection, the substance having larger fluorescence intensity and better local staining propertie
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Paragraph 0031
(2017/04/11)
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- Comparative studies on the O-sialylation with four different α/β-oriented (N-acetyl)-5-N,4-O-carbonyl-protected p-toluenethiosialosides as donors
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Four types of 5-N,4-O-carbonyl-protected p-toluenethiosialosides were synthesized and their couplings with different acceptors were thoroughly investigated. The results indicate that the sialyl donor structure, the amount of glycosyl acceptor, and the detailed promotion conditions have great influence on the sialylation stereoselectivties and product yields. Under the (p-Tol)2SO/Tf2O activation conditions, the glycosylations with simple alcohols provided declined α-selectivities and higher yields with increasing the amounts of acceptors from 1.1 equiv to 2.0 equiv. However, the outcome of same sialylation was independent of the relative amounts of sugar alcohol acceptors. With NIS/TfOH as promoter, the α-selectivities of the sialylations were significantly improved compared with the cases activated by (p-Tol)2SO/Tf2O. In general, the difference in configuration of N-acetylated sialyl donors (D2 and D4) has little effect on the sialylation yield and stereoselectivity. In contrast, the N-deacetylated α/β sialyl donors (D1 and D3) show complex sialylation profiles with different acceptors.
- Zhang, Xiao-Tai,Gu, Zhen-Yuan,Xing, Guo-Wen
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- Fluorogenic sialic acid glycosides for quantification of sialidase activity upon unnatural substrates
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Herein we report the synthesis of N-acetyl neuraminic acid derivatives as 4-methylumbelliferyl glycosides and their use in fluorometrically quantifying human and bacterial sialidase activity and substrate specificities. We found that sialidases in the human promyelocytic leukemic cell line HL60 were able to cleave sialic acid substrates with fluorinated C-5 modifications, in some cases to a greater degree than the natural N-acetyl functionality. Human sialidases isoforms were also able to cleave unnatural substrates with bulky and hydrophobic C-5 modifications. In contrast, we found that a bacterial sialidase isolated from Clostridium perfringens to be less tolerant of sialic acid derivatization at this position, with virtually no cleavage of these glycosides observed. From our results, we conclude that human sialidase activity is a significant factor in sialic acid metabolic glycoengineering efforts utilizing unnatural sialic acid derivatives. Our fluorogenic probes have enabled further understanding of the activities and substrate specificities of human sialidases in a cellular context.
- Zamora, Cristina Y.,D'Alarcao, Marc,Kumar, Krishna
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p. 3406 - 3410
(2013/06/27)
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- Macrocyclic mechanism-based inhibitor for neuraminidases
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A macrocyclic mechanism-based inhibitor for neuraminidases (NAs) bearing a 2-difluoromethylphenyl aglycone and a linker between the aglycone and C-9 positions of sialic acid was synthesized and evaluated. The macrocyclic structure was designed to keep the aglycone moiety in the active site of the neuraminidase after cleavage of the glycoside bond. When Vibrio chorelae neuraminidase (VCNA) was treated with a similar acyclic derivative in the presence of detergent, the irreversible inhibition property was disabled. In contrast, this macrocyclic compound acted as an irreversible inhibitor for VCNA in the presence of detergent. Inhibition assay for various NAs using this macrocyclic compound revealed that the irreversible inhibition property depends on the kcat of the neuraminidase treated. NAs having small k cat values, such as Influenza viruses, Clostridium, Trypanosoma cruzi, and Human, were also inhibited irreversibly. However, Salmonella typhimurium NA, which has an extremely high kcat, was not affected irreversibly by the inhibitor. Interestingly, in contrast to common k cat inhibitors, the irreversibility of inhibition by this macrocyclic compound is inversely proportional to the kcat of the target neuraminidase. Copyright
- Kai, Hirokazu,Hinou, Hiroshi,Naruchi, Kentaro,Matsushita, Takahiko,Nishimura, Shin-Ichiro
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supporting information
p. 1364 - 1372
(2013/02/25)
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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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- 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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- Novel glycosylation reactions using glycosyl thioimidates of N-acetylneuraminic acid as sialyl donors
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Novel sialyl donors 4 bearing a thioimidolyl moiety as the leaving group were successfully prepared from the corresponding arylthio derivatives 3 and a peracetylated chloro derivative of Neu5Ac 2 in the presence of N,N-di-isopropylethylamine with moderate
- Ikeda, Kiyoshi,Aizawa, Misato,Sato, Kazuki,Sato, Masayuki
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p. 2618 - 2620
(2007/10/03)
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- Design of a mechanism-based probe for neuraminidase to capture influenza viruses
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(Chemical Equation Presented) Getting a grip on the flu: A mechanism-based probe, 1, for neuraminidase was developed. It is capable of forming a biotinylated adduct with neuraminidase (NA) from Arthrobacter ureafaciens. It also displays an inhibitory effe
- Lu, Chun-Ping,Ren, Chien-Tai,Lai, Yi-Ning,Wu, Shih-Hsiung,Wang, Wei-Man,Chen, Jean-Yin,Lo, Lee-Chiang
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p. 6888 - 6892
(2007/10/03)
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- Preparation of 4-pentenoic acid ester of Neu5Ac and 4-pentenyl glycoside of Neu5Ac and their application to glycosylation
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Novel sialosyl donors, 4-pentenoic acid ester of N-acetylneuraminic acids (Neu5Ac) (1a) and 4-pentenyl glycoside of Neu5Ac (1b) were successfully prepared from the corresponding per-O-acetylated 2-hydroxy and 2-chloro derivatives of Neu5Ac, respectively a
- Ikeda, Kiyoshi,Fukuyo, Jun,Sato, Kazuki,Sato, Masayuki
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p. 1490 - 1493
(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 novel mimetics of CMP-sialic acid as the inhibitors of sialyltransferases
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Novel mimetics of CMP-sialic acid were designed as the inhibitors of sialyltransferases. They were synthesized in a short step from a cytosine carrying β-hydroxy-α-L-amino acid based on the knowledge that nikkomycin, a peptidic derivative of an uracil carrying amino acid, shows a potent inhibitory activity toward N-acetyl-D-glucosaminyltransferases that employ UDP-N-acetyl-D-glucosamine as the donor substrate. The cytosine carrying β-hydroxyl-α-L-amino acid, a key intermediate in our synthetic strategy, was easily prepared by the L-threonine aldolase (LTA) catalyzed reaction.
- Tanaka, Toru,Ozawa, Machiko,Miura, Tsuyoshi,Inazu, Toshiyuki,Tsuji, Shuichi,Kajimoto, Tetsuya
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p. 1487 - 1490
(2007/10/03)
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- One-step stereocontrolled synthesis of α-anomeric carboxylic acid esters from unprotected glycosyl donors: A water-soluble aspirin pro-drug analogue
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The reaction of 2-(3-methoxypyridyl) β-D-gluco- and D-galactopyranosides with various carboxylic acids affords the corresponding α-1-esters in high yields. Aspirin can be solubilized in water as the α-D-galactopyranosyl ester.
- Hanessian, Stephen,Mascitti, Vincent,Lu, Pu-Ping,Ishida, Hideki
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p. 1959 - 1968
(2007/10/03)
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- Stereoselective synthesis of Neu5Acalpha(2-->5)Neu5Gc: the building block of oligo/poly(-->5-O(g)(lycolyl)Neu5Gcalpha2-->) chains in sea urchin egg cell surface glycoprotein.
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The synthesis of a sialic acid dimer derivative, Neu5Acalpha(2-->5)Neu5Gc, is described. The synthetic strategy is based on the use of allyl alcohol to achieve an exclusive alpha-sialylation product. The allyloxy group is also a latent glycolic acid that provides the subsequent coupling with neuraminate with minimal protection-deprotection manipulations.
- Fan, Gang-Ting,Lee, Chen-Chang,Lin, Chun-Cheng,Fang, Jim-Min
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p. 7565 - 7568
(2007/10/03)
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- Synthesis of CMP-sialic acid conjugates: Substrates for the enzymatic synthesis of natural and designed sialyl oligosaccharides
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The syntheses of several congeners of CMP-NeuAc are described. These compounds are substrates for enzymatic glycosylation.
- Chappell, Mark D.,Halcomb, Randall L.
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p. 11109 - 11120
(2007/10/03)
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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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- Structural Variations of N-Acetylneuraminic Acid, 18 Synthesis of the Side Chain Stereo and Deoxy Analogs of 5-Acetamido-2,6-anhydro-3,5-dideoxy-D-erythro-L-manno-nonoic Acid
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The synthesis of 5-acetamido-2,6-anhydro-3,5-dideoxy-D-erythro-L-manno-nonoic acid (3b, 7,8-epi2-2-d-2-Heq-Neu5Ac) and sodium 5-acetamido-2,6-anhydro-3,5-dideoxy-L-threo-L-manno-nonoate (6b, 8-epi-2-d-2-Heq-Neu5Ac) could b
- Bandgar, Babasaheb P.,Hartmann, Michael,Schmid, Walther,Zbiral, Erich
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p. 1185 - 1195
(2007/10/02)
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- PHASE-TRANSFER-CATALYZED SYNTHESIS OF ARYL α-KETOSIDES OF N-ACETYLNEURAMINIC ACID. A 2-METHYLFLUORAN-6-YL GLYCOSIDE OF N-ACETYLNEURAMINIC ACID, 2-METHYL-6-(5-ACETAMIDO-3,5-DIDEOXY-α-D-glycero-D-galacto-NONULOPYRANOSYLONIC ACID)XANTHENE-9-SPIRO-1'-ISOBENZOFURAN-3'-ONE, A NEW SUBSTRATE..
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Glycosidation of N-acetylneuraminic acid by phase-transfer catalysis in chloroform-aqueous alkali gave several known and some new aryl α-ketosides in a short reaction time and in good yields.The 4-methylumbelliferyl α-ketoside, the standard substrate for neuraminidase, was prepared in a yield of up to 70percent.New Neu5Ac ketosides were prepared with fluorescein and the fluorescein analog, 2-methyl-6-hydroxyfluoran (2-methyl-6-hydroxyxanthene-9-spiro-1'-isobenzofuran-3'-one) as aglycons, the latter being synthesized from 2-(2-hydroxy-5-methylbenzoyl) benzoic acid and 3-fluorophenol.The α configuration was ascertained by 400-MHz 1H-NMR spectroscopy and by cleavage of the ketosides with neuraminidases from Vibrio cholerae and Clostridium perfringens.The enzymic hydrolysis of the 2-methylfluoran-6-yl ketoside gave Km values of 82 μM (V. cholerae) and 96 μM (C. perfringens).
- Rothermel, Joerg,Faillard, Hans
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