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Biochemistry Nov 1995The selectins are a family of three adhesion molecules (L-, P-, and E-) that direct the interaction of circulating leukocytes with endothelial cells during the first...
The selectins are a family of three adhesion molecules (L-, P-, and E-) that direct the interaction of circulating leukocytes with endothelial cells during the first step in recruitment to tissue sites. Their involvement in inflammatory disease makes the selectins attractive targets for anti-inflammatory therapy. The sialyl Lewis x tetrasaccharide binds weakly to all three selectins and has demonstrated anti-inflammatory activity in vivo. However, the synthetic difficulties inherent to sialylated and fucosylated oligosaccharides motivate the search for alternative antagonists. Here we demonstrate that information gained from the biochemical analysis of a physiological selectin ligand can provide new leads for small molecule design. Previous structural analysis of the oligosaccharide chains on GlyCAM-1, an endothelial-derived ligand for L-selectin, revealed two novel structures: 6'-sulfo sialyl Lewis x and 6-sulfo sialyl Lewis x. The sulfate esters on these structures are thought to be essential for high-affinity binding to L-selectin. By incorporating sulfate esters on the analogous positions of the disaccharide lactose, we generated a simple small molecule (lactose 6',6-disulfate) with greater inhibitory potency for L-selectin than sialyl Lewis x.
Topics: Carbohydrate Sequence; Disaccharides; L-Selectin; Ligands; Molecular Sequence Data; Molecular Structure; Mucins; Sulfates
PubMed: 7578028
DOI: 10.1021/bi00044a001 -
The Journal of Organic Chemistry Jul 2017Koenigs-Knorr glycosylation of acceptors with more than one free hydroxyl group by 2,3,5,6-tetrabenzoyl galactofuranosyl bromide was performed using diphenylborinic acid...
Koenigs-Knorr glycosylation of acceptors with more than one free hydroxyl group by 2,3,5,6-tetrabenzoyl galactofuranosyl bromide was performed using diphenylborinic acid 2-aminoethyl ester (DPBA) as inducer of regioselectivity. High regioselectivity for the glycosylation on the equatorial hydroxyl group of the acceptor was obtained thanks to the transient formation of a borinate adduct of the corresponding 1,2-cis diol. Nevertheless formation of orthoester byproducts hampered the efficiency of the method. Interestingly electron-withdrawing groups on O-6 or on C-1 of the acceptor displaced the reaction in favor of the desired galactofuranosyl containing disaccharide. The best yield was obtained for the furanosylation of p-nitrophenyl 6-O-acetyl mannopyranoside. Precursors of other disaccharides, found in the glycocalix of some pathogens, were synthesized according to the same protocol with yields ranging from 45 to 86%. This is a good alternative for the synthesis of biologically relevant glycoconjugates.
Topics: Bacteria; Disaccharides; Fungi; Furans; Galactosides; Glycosylation; Molecular Structure; Quantum Theory; Stereoisomerism; Trypanosomatina
PubMed: 28631470
DOI: 10.1021/acs.joc.7b00565 -
Pulmonary Pharmacology & Therapeutics Jun 2014The tetrasaccharide sequence of heparin oligosaccharides is the minimum chain length possessing anti-allergic activity, as the disaccharide fraction is inactive. Since... (Comparative Study)
Comparative Study
The tetrasaccharide sequence of heparin oligosaccharides is the minimum chain length possessing anti-allergic activity, as the disaccharide fraction is inactive. Since sulfation pattern can modify the biological actions of heparin, we hypothesized that "supersulfation" of the inactive heparin disaccharide could confer anti-allergic activity to this molecule. To test this, we produced a supersulfated heparin disaccharide (Hep-SSD) and evaluated its anti-allergic activity in sheep with documented antigen-induced early and late airway responses (EAR and LAR) and airway hyperresponsiveness (AHR). Porcine intestinal heparin was depolymerized with nitrous acid, the disaccharide fraction separated by size exclusion chromatography, and then treated with pyridine-sulfur trioxide complex to yield Hep-SSD. Its chemical structure [IdoU2',3',4'S (1→4) AMan1,3,6S] was confirmed by HPLC, Mass Spectrometry and NMR analysis. Inhaled doses of 5 mg, 10 mg and 20 mg Hep-SSD produced inhibition of EAR (8%, 35% and 35%), LAR (50%, 80%, and 77%) and AHR (67%, 100% and 75%), respectively. A single oral dose of 2 mg/kg Hep-SSD given 90 min before challenge significantly inhibited EAR, LAR and AHR, but 1 mg/kg was ineffective. Multi dose oral treatment with Hep-SSD had a cumulative effect, as a once daily dose of 2 mg/kg for 3 days (last dose, 16 h before antigen) inhibited EAR, LAR and AHR by 30%, 75% and 74%, respectively. Finally, the oral activity of Hep-SSD could be enhanced 4 fold by formulating it with Carbopol(®)934P, in an enteric coated capsule. These data demonstrate that "supersulfation" can confer biological activity to the inactive heparin disaccharide. Both inhaled and oral Hep-SSD demonstrate significant anti-allergic activity and, therefore, may have therapeutic potential.
Topics: Acrylates; Administration, Inhalation; Administration, Oral; Animals; Antigens; Bronchial Hyperreactivity; Chromatography, Gel; Chromatography, High Pressure Liquid; Disaccharides; Dose-Response Relationship, Drug; Heparin; Magnetic Resonance Spectroscopy; Mass Spectrometry; Sheep; Sulfates; Swine; Time Factors
PubMed: 24355631
DOI: 10.1016/j.pupt.2013.12.001 -
Journal of Bacteriology Dec 1958
Topics: Bacteria; Carbohydrate Metabolism; Cellvibrio; Disaccharides; Glucose
PubMed: 13610794
DOI: 10.1128/jb.76.6.565-570.1958 -
Carbohydrate Research Nov 2002The potential energy surfaces of several alpha-(1-->3)- and beta-(1-->4)-linked disaccharides were obtained and plotted in terms of energy versus psi glycosidic angle....
The potential energy surfaces of several alpha-(1-->3)- and beta-(1-->4)-linked disaccharides were obtained and plotted in terms of energy versus psi glycosidic angle. These plots were compared to those obtained previously in the way of the usual 3D contour maps, which relate the energy with the two glycosidic angles (phi and psi). Given the usually small variations of the phi angle in the low-energy regions (at least using MM3), both kinds of graphs lead to similar conclusions concerning flexibility measurements by two different methods and assessment of the effects of sulfation and/or hydroxyl group orientation. Only second-order effects were found with some sulfated disaccharides, not changing the general conclusions. The computational efforts required to produce those plots are smaller, and the plots are easier to interpret. Besides, the conversion of a 3D map into a 2D plot leaves the possibility of constructing 3D maps of carbohydrates including a second variable different to phi, e.g., the second psi angle of a trisaccharide or the omega angle of a 6-linked disaccharide.
Topics: Carbohydrate Conformation; Computer Simulation; Disaccharides; Pliability
PubMed: 12431887
DOI: 10.1016/s0008-6215(02)00257-4 -
Biochemical and Biophysical Research... May 2015Glycosaminoglycans reportedly play important roles in prion formation, but because of their structural complexity, the chemical structures affecting prion formation have...
Glycosaminoglycans reportedly play important roles in prion formation, but because of their structural complexity, the chemical structures affecting prion formation have not been fully evaluated. Here, we compared two types of low molecular weight heparins and found that heparinase I-sensitive structures influenced anti-prion activity in prion-infected cells. Surface plasmon resonance analyses showed significant binding of a representative heparinase I substrate disaccharide unit, GlcNS6S-IdoA2S, to recombinant prion protein (PrP) fragments, such as full-length PrP23-231 and N-terminal domain PrP23-89, but not to PrP89-230. This binding was competitively inhibited by heparin or pentosan polysulfate, but not by Cu(2+). These PrP binding profiles of the disaccharide unit are consistent with those previously reported for heparin. However, synthetic compounds comprising disaccharide unit alone or its multimers exhibited no anti-prion activity in prion-infected cells. Consequently, the findings suggest that the heparin disaccharide unit that binds to the N-terminal region of PrP is a key structure, but it is insufficient for exerting anti-prion activity.
Topics: Animals; Cell Line, Tumor; Disaccharides; Heparin; Heparin Lyase; Mice; Prions
PubMed: 25839661
DOI: 10.1016/j.bbrc.2015.03.139 -
Carbohydrate Research Jan 2014A simple strategy for the synthesis of a β-GlcNAc-(1→4)-MurNAc (NAG-NAM) moiety, crucial for the preparation of synthetic components of a bacterial peptidoglycan, was...
A simple strategy for the synthesis of a β-GlcNAc-(1→4)-MurNAc (NAG-NAM) moiety, crucial for the preparation of synthetic components of a bacterial peptidoglycan, was achieved. This strategy relies on the use of three O-protecting groups, 4,6-O-benzilidene acetal, benzyl, and acetyl group, which allows further regioselective manipulation at O-3, O-4 positions, and on the insertion of the peptide chain at the lactate moiety in an advanced and versatile intermediate. Overall, a simple route to achieve the biological relevant NAG-NAM is presented, which may serve as a conceptual framework in the designing of synthetic strategies of different natural and non-natural polysaccharides.
Topics: Carbohydrate Conformation; Disaccharides
PubMed: 24374641
DOI: 10.1016/j.carres.2013.12.007 -
Chemical Communications (Cambridge,... Jun 2007A new carbohydrate receptor possesses a C3-symmetric polar cavity capable of encapsulating disaccharides; binding to beta-maltosyl is preferred, complementing previous...
A new carbohydrate receptor possesses a C3-symmetric polar cavity capable of encapsulating disaccharides; binding to beta-maltosyl is preferred, complementing previous systems which have favoured "all-equatorial" substrates.
Topics: Circular Dichroism; Disaccharides; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Receptors, Cell Surface; Spectrophotometry, Ultraviolet
PubMed: 17844756
DOI: 10.1039/b618776e -
Carbohydrate Research Sep 2007The synthesis of a C-disaccharide that is designed as a mimetic for the repeating unit disaccharide of hyaluronic acid is described. The target compound was obtained via...
The synthesis of a C-disaccharide that is designed as a mimetic for the repeating unit disaccharide of hyaluronic acid is described. The target compound was obtained via the SmI2-promoted coupling reaction of the sulfone, 2-acetamido-4,6-O-benzylidene-3-O-tert-butyldimethylsilyl-1,2-dideoxy-1-pyridinylsulfonyl-beta-D-glucopyranose (6), and the aldehyde, p-methoxyphenyl 2,3-di-O-benzyl-4-deoxy-4-C-formyl-6-O-p-methoxybenzyl-beta-D-glucopyranoside (14).
Topics: Carbohydrate Conformation; Carbohydrate Sequence; Disaccharides; Glycosylation; Hyaluronic Acid; Indicators and Reagents; Models, Molecular; Molecular Sequence Data; Sulfones
PubMed: 17572398
DOI: 10.1016/j.carres.2007.05.031 -
Molecular Nutrition & Food Research Apr 2020This review represents a focus on the structure and properties of the common nutritional disaccharides (lactose, maltose, and sucrose) in health and disease. The aim is... (Review)
Review
SCOPE
This review represents a focus on the structure and properties of the common nutritional disaccharides (lactose, maltose, and sucrose) in health and disease. The aim is to provide a comprehensive reference source related to the role of disaccharides in human nutrition.
METHODS AND RESULTS
Key reference sources are searched, including Web of Science, PubMed, Science Direct, and Wiley Online, and key reference works are selected to support the factual basis of the text where interpretations and relevance of the works are discussed in the review. There are key nutritional health benefits of receiving dietary energy in the form of sugars, but equally life-threatening issues exist associated with constant/excess consumption. These issues are discussed together with genetic disorders, which impact upon health associated with consumption of the disaccharides (e.g., specific disaccharide intolerance due to deficiency of relevant digestive enzymes).
CONCLUSIONS
As the three common dietary disaccharides (lactose, maltose, and sucrose) are consumed on a very regular basis in the human diet, it is critical to understand insofar as possible their role in health and disease. This review provides an insight into the structure and properties of these molecules in health and disease.
Topics: Attention Deficit Disorder with Hyperactivity; Cardiovascular Diseases; Diabetes Mellitus; Disaccharides; Glycation End Products, Advanced; Glycemic Index; Humans; Lactose; Lipids; Maltose; Non-alcoholic Fatty Liver Disease; Obesity; Sucrose
PubMed: 32045507
DOI: 10.1002/mnfr.201901082