Some recent applications of carbohydrates and their derivatives in the pharmaceutical industry

Boeckel, C. A. A. Van

doi:10.1002/recl.19861050202

Cited by 18 publications

(3 citation statements)

References 208 publications

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“…The surface in Figure 6a resembles the El ( 'Cq) surface for l a in Figure 5a, whereas the surface in 6b predicts a stable minimum due to a dative bond between the same sulfate and the metal ion. 49 The minimum in Figure 6b is similar to Figure 5b but only 18 states are included compared to 133 in Figure 6a. A bond length of 2.51 A is predicted between a sulfate oxygen and the Zn (11) ion (see Figure 7b).…”

Section: Evaluation Of Pe Surfaces For Predicting Interglycosidic-senmentioning

confidence: 78%

Heavy metal binding to heparin disaccharides. II. First evidence for zinc chelation

Whitfield

Sarkar

1992

Biopolymers

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To map out the heavy metal binding sites of iduronic acid containing oligosaccharides isolated from human kidneys, we studied Zn(II) binding by nuclear magnetic resonance (NMR) and molecular modeling to two disaccharides isolated after nitrous acid depolymerization of heparin and two synthetic disaccharides representative of the heparin structure, namely, IdopA2S (alpha 1,4)AnManOH, 1 alpha, IdopA2S (alpha 1,4)AnManOH6S, 1b, IdopA2S-(alpha 1,4)GlcNS alpha Me, 2a, and IdopA2S (alpha 1,4)GlcNS6S alpha Me, 2b (see previous article in this series). A conformational analysis of the metal free and metal bound solutions was made by comparing calculated [(NOE)]s, [T1]s, and [J]s to experimental values. The 1C4, 4C1, and 2S0 conformations of the L-idopyranosiduronate ring and the 4E and 4T3 of the anhydro-D-mannitol ring are evaluated as are rotations about the C5-C6 hydroxymethylene of the AnManOH(6S) or GlcNS (6S) residues. The NOE between IdopA2S H1 and H3 and the known NOE between H2 and H5, as well as the T1 of IdopA2S H3, are introduced as NMR observables sensitive to the IdopA2S ring conformation. Similarly, a NOE between IdopA2S H5 and AnManOH(6S) or GlcNS(6S) H3 was observed that directly restricts the allowed interglycosidic conformational space. For all disaccharides, the Zn(II) bound spectral data are consistent with models in which these motions are partially "frozen" such that the 1C4 conformation of the IdopA2S is stabilized along with the 4T3 conformation of the AnManOH(6S) ring. The interglycosidic conformation is also stabilized in one of two minima. Electrostatic potential energy calculations gave the best overall agreement with experiment and suggest metal binding conformations with the carboxylate and ring oxygen of the IdopA2S residues (1C4 conformation) and either O3 of the GlcNS(6S) residues or the sulfate oxygens of the 6-sulphate for 2b providing additional chelating sites. These chelation models concur with the observation of marked 13C and 1H NMR chemical shifts for the IdopA2S resonances and of GlcNS H3 for 2 alpha and GlcNS6S C6 for 2b. This study of model compounds implicates the IdopA2S(alpha 1,4)GlcNS6S group as part of the heavy metal binding site in biologically important acidic oligosaccharides such as heparin.

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Section: Evaluation Of Pe Surfaces For Predicting Interglycosidic-senmentioning

confidence: 78%

Heavy metal binding to heparin disaccharides. II. First evidence for zinc chelation

Whitfield

Sarkar

1992

Biopolymers

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“…such as cell adhesion4 and cell-virus interaction5 and have been shown to occur at an elevated level in certain types of cancer cells. 6 Fluorescence labeling has proven to be a useful tool in studies directed toward the elucidation of complex recognition phenomena in which sialic acids are involved. For example, fluorescent gangliosides have been used in monitoring the molecular organisation of glycolipids in membranes7 and a sensitive fluorescence polarization assay for the binding of ligands to the viral surface protein hemagglutinin has been developed.8 9The standard procedure7,9 for introducing a fluorescence probe into sialosides involves mild periodate oxidation of these compounds resulting in cleavage of the C(7)-C (8) bond of NeuSAc and subsequent derivatisation of the newly formed aldehydo group at C (7) with a fluorescence marker.…”

mentioning

confidence: 99%

“…Our approach, however, was to attach a fluorescent reporter group at an intact sialic acid which could then be be used as a building block in chemoenzymatic oligosaccharide synthesis.10 The design of sialic acid 5 was based on the following considerations: The position of the attachment of the fluorophore was chosen to be the C(9) of NeuSAc, because previous work11 has shown that CMP-NeuAc synthetase, the enzyme needed for activation prior to transfer, and a (2,6) sialyl transferases tolerate modifications at this position. The dansyl group was used because its fluorescence intensity depends on the polarity of the environment which is of interest with regard to future fluorescence assays for the binding of sialic acid containing ligands to their receptors.…”

mentioning

confidence: 99%

Combined Use of Subtilisin and N-Acetylneuraminic Acid Aldolase for the Synthesis of a Fluorescent Sialic Acid

Fitz¹,

Wong²

1994

J. Org. Chem.

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Enzyme in der organischen Synthese: das Problem der molekularen Erkennung von Kohlenhydraten (Teil 1)

et al. 1995

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Die auf Zelloberflächen anzutreffenden Saccharide sind Informationsträger auf molekularer Ebene. Obwohl sich Säugetiere normalerweise auf die Verwendung von nur sieben oder acht Monosaccharidbausteinen beschränken, ist wegen der Multifunktionalität dieser Monomere der Aufbau einer schier unbegrenzten Zahl komplexer Strukturen möglich. So können beispielsweise mehrere Millionen topologisch unterschiedlicher Tetrasaccharide aus diesen wenigen Monosacchariden entstehen, wenn man die Art der Verzweigung, die Konfiguration des glycosidischen C‐Atoms und Modifikationen der Hydroxy‐ und Aminogruppen in Betracht zieht. Oligosaccharide sind daher in der Lage, effizient die riesigen Datenmengen zu kodieren, die für biologische Erkennungsprozesse, von interzellulärer Kommunikation über Signalübertragung, Zelladhäsion, Infektion und Zelldifferenzierung bis hin zu Zellentwicklung und Metastase, benötigt werden. Trotz dieser zentralen Bedeutung ist die Entwicklung von pharmazeutischen Anwendungen dieser Substanzklasse verglichen mit der anderer Biomoleküle sehr langsam. Ein Grund dafür ist, daß Techniken zur Untersuchung komplexer Kohlenhydrate fehlen. So können Oligosaccharide weder für die Sequenzanalyse amplifiziert werden, noch gibt es eine Methode für ihre automatisierte Synthese. Darüber hinaus tragen die möglicherweise geringe Bioverfügbarkeit von Oligosacchariden und Schwierigkeiten bei ihrer Produktion in technischem Maßstab zweifellos nicht dazu bei, die Entwicklung zu beschleunigen. Die hier beschriebenen enzymatischen und chemoenzymatischen Methoden, besonders die unter Verwendung von Aldolasen und Glycosyl‐Transferasen, erscheinen geeignet für die Synthese von Mono‐ und Oligosacchariden sowie verwandten Verbindungen. Es steht zu erwarten, daß weitere Fortschritte in der Glycobiologie neue Methoden eröffnen werden, mit denen die molekulare Erkennung bei Kohlenhydraten untersucht und bioaktive Saccharide und Saccharidmimetica zur gezielten Beeinflussung eben jener Erkennungsprozesse synthetisiert werden können.

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Some recent applications of carbohydrates and their derivatives in the pharmaceutical industry

Cited by 18 publications

References 208 publications

Heavy metal binding to heparin disaccharides. II. First evidence for zinc chelation

Heavy metal binding to heparin disaccharides. II. First evidence for zinc chelation

Combined Use of Subtilisin and N-Acetylneuraminic Acid Aldolase for the Synthesis of a Fluorescent Sialic Acid

Enzyme in der organischen Synthese: das Problem der molekularen Erkennung von Kohlenhydraten (Teil 1)

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