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Organic & Biomolecular Chemistry Feb 2019The first construction of the challenging β-(1 → 5)-linked GalNAc-Kdo skeleton is described for the synthesis of the disaccharide antigen of the capsular...
The first construction of the challenging β-(1 → 5)-linked GalNAc-Kdo skeleton is described for the synthesis of the disaccharide antigen of the capsular polysaccharide of Kingella kingae KK01. TfOH-catalyzed glycosylation of N-Troc-protected d-galactosaminyl N-phenyl trifluoroacetimidate with a sterically hindered 5-hydroxyl group of the β-Kdo building block in toluene proceeded smoothly to provide the desired disaccharide in excellent yield with satisfactory β-selectivity. An optimal sequence for the deprotection of the disaccharide skeleton was found to access the disaccharide antigen of Kingella kingae KK01 for further immunological studies.
Topics: Acetylgalactosamine; Antigens, Bacterial; Bacterial Capsules; Catalysis; Chemistry Techniques, Synthetic; Disaccharides; Glycosylation; Kingella kingae; Polysaccharides, Bacterial; Sugar Acids
PubMed: 30346002
DOI: 10.1039/c8ob02340a -
Bioorganic & Medicinal Chemistry Letters Feb 2012The β-d-galactosyl-(1,3)-α-N-acetyl-d-galactosamine disaccharide is present in antifreeze glycoproteins (AFGPs). Analogs of this disaccharide including the β-linked...
The β-d-galactosyl-(1,3)-α-N-acetyl-d-galactosamine disaccharide is present in antifreeze glycoproteins (AFGPs). Analogs of this disaccharide including the β-linked (1,3)-, (1,4)-, and (1,6)-galactosyl-N-acetyl galactosamine and the β-(1,3)-galactosyl-galactoside were synthesized and evaluated for ice recrystallization inhibition (IRI) activity. The results from this study demonstrate that the β-linked-(1,4) disaccharide exhibits more potent IRI activity than the native β-linked-(1,3) disaccharide. The C2 N-acetyl group of the disaccharide does not affect IRI activity but in monosaccharides, the presence of the C2 N-acetyl group decreases IRI activity. The current study will facilitate the design of potent small-molecule ice recrystallization inhibitors.
Topics: Antifreeze Proteins; Crystallization; Disaccharides; Molecular Structure
PubMed: 22264482
DOI: 10.1016/j.bmcl.2011.12.097 -
Journal of the American Chemical Society Feb 2013In a recent study, the well-documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been...
In a recent study, the well-documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells but not the "normal" breast cell line MCF-10A. Furthermore, it was found that the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, did not target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study were the issues of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting and the possible cellular uptake of the disaccharide. In the present study, we conjugated BLM, deglycoBLM, and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreatic cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells and comparable to that of BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.
Topics: Bleomycin; Disaccharides; Female; Humans; MCF-7 Cells
PubMed: 23379863
DOI: 10.1021/ja311090e -
The Journal of Physical Chemistry. B Jun 2011Molecular level insight into water structure and structural dynamics near proteins, lipids, and nucleic acids is critical to the quantitative understanding of many...
Molecular level insight into water structure and structural dynamics near proteins, lipids, and nucleic acids is critical to the quantitative understanding of many biophysical processes. Unfortunately, understanding hydration and hydration dynamics around such large molecules is challenging because of the necessity of deconvoluting the effects of topography and chemical heterogeneity. Here we study, via classical all-atom simulation, the water structure and structural dynamics around two biologically relevant solutes large enough to have significant chemical and topological heterogeneity but small enough to be computationally tractable: the disaccharides kojibiose and trehalose. We find both molecules to be strongly amphiphilic (as quantified from normalized local density fluctuations) and to induce nonuniform local slowdown in water translational and rotational motions. Detailed analysis of the rotational slowdown shows that, while the rotational mechanism is similar to that previously identified in other aqueous systems by Laage, Hynes, and coworkers, two novel characteristics are observed: broadening of the transition state during hydrogen bond exchange (water rotation) and a subpopulation of water for which rotation is slowed because of hindered access of the new accepting water molecule to the transition state. Both characteristics are expected to be generic features of water rotation around larger biomolecules and, taken together, emphasize the difficulty in transferring insight into water rotation around small molecules to much larger amphiphilic solutes.
Topics: Disaccharides; Molecular Dynamics Simulation; Molecular Structure; Trehalose; Water
PubMed: 21561148
DOI: 10.1021/jp112178c -
Organic Letters Oct 2012A two-step strategy for disaccharide modulation using vancomycin as a model is reported. The strategy relies upon a glycosyltransferase-catalyzed 'reverse' reaction to...
A two-step strategy for disaccharide modulation using vancomycin as a model is reported. The strategy relies upon a glycosyltransferase-catalyzed 'reverse' reaction to enable the facile attachment of an alkoxyamine-bearing sugar to the vancomycin core. Neoglycosylation of the corresponding aglycon led to a novel set of vancomycin 1,6-disaccharide variants. While the in vitro antibacterial properties of corresponding vancomycin 1,6-disaccharide analogs were equipotent to the parent antibiotic, the chemoenzymatic method presented is expected to be broadly applicable.
Topics: Anti-Bacterial Agents; Biocatalysis; Biological Products; Disaccharides; Glycosylation; Glycosyltransferases; Molecular Structure; Vancomycin
PubMed: 22984807
DOI: 10.1021/ol3023374 -
Proceedings of the National Academy of... Apr 1995Inhibitors of glycosylation provide a tool for studying the biology of glycoconjugates. One class of inhibitors consists of glycosides that block glycoconjugate...
Inhibitors of glycosylation provide a tool for studying the biology of glycoconjugates. One class of inhibitors consists of glycosides that block glycoconjugate synthesis by acting as primers of free oligosaccharide chains. A typical primer contains one sugar linked to a hydrophobic aglycone. In this report, we describe a way to use disaccharides as primers. Chinese hamster ovary cells readily take up glycosides containing a pentose linked to naphthol, but they take up hexosides less efficiently and disaccharides not at all. Linking phenanthrol to a hexose improves its uptake dramatically but has no effect on disaccharides. To circumvent this problem, analogs of Xyl beta 1-->6Gal beta-O-2-naphthol were tested as primers of glycosaminoglycan chains. The unmodified disaccharide did not prime, but methylated derivatives had activity in the order Xyl beta 1-->6Gal(Me)3-beta-O-2-naphthol > Xyl beta 1-->6Gal (Me)2 beta-O-2-naphthol >> Xyl beta 1-->6Gal(Me)beta-O-2-naphthol. Acetylated Xyl beta 1-->6Gal beta-O-2-naphthol also primed glycosaminoglycans efficiently, suggesting that the terminal xylose residue was exposed by removing the acetyl groups. The general utility of using acetyl groups to create disaccharide primers was shown by the priming of oligosaccharides on peracetylated Gal beta 1-->4GlcNAc beta-O-naphthalenemethanol. This disaccharide inhibited sialyl Lewis X expression on HL-60 cells.
Topics: Animals; Biological Transport; CHO Cells; Carbohydrate Sequence; Cell Membrane Permeability; Cricetinae; Disaccharides; Glycoconjugates; Glycosaminoglycans; Glycosylation; Golgi Apparatus; Humans; Molecular Sequence Data; Oligosaccharides; Sialyl Lewis X Antigen; Structure-Activity Relationship
PubMed: 7724561
DOI: 10.1073/pnas.92.8.3323 -
Journal of Comparative Physiology. B,... May 2017In animals, the accepted model of carbohydrate digestion and absorption involves reduction of disaccharides into the monosaccharides glucose, fructose, and galactose...
In animals, the accepted model of carbohydrate digestion and absorption involves reduction of disaccharides into the monosaccharides glucose, fructose, and galactose followed by their individual transmembrane transport into cells. In 2011, a gene for a distinct disaccharide sucrose transporter (SCRT) was found in Drosophila melanogaster and characterized in a yeast expression system. The purpose of the present investigation was to functionally identify and characterize a putative disaccharide transporter analog in the hepatopancreas of the American lobster, Homarus americanus. Purified hepatopancreatic brush-border membrane vesicles (BBMV) were used in transport experiments using C-sucrose and a Millipore filter isolation technique. In the absence of sodium, an external pH of 4 significantly stimulated the uptake of C-sucrose compared to that occurring at pH 5, 6, or 7. At pH 7, increasing external concentrations of sodium increased C-sucrose uptake by BBMV in a hyperbolic fashion and this stimulation was significantly reduced when the pH was changed to 4, suggesting that both protons and sodium ions were each capable of driving the uptake of the sugar. In experiments with a variety of monosaccharides, disaccharides, and trisaccharides, used as potential inhibitors of C-sucrose uptake, only maltose and trehalose inhibited carrier-mediated C-sucrose transport. An additional experiment showed that 20 mM maltose was a competitive inhibitor of C-sucrose uptake. The use of a putative lobster SCRT by both maltose and trehalose is nutritionally appropriate for lobsters as they commonly digest glycogen and chitin, polymers of maltose and trehalose, respectively. These findings suggest there is a brush-border proton- or sodium-dependent, hepatopancreatic carrier process, shared by sucrose, maltose, and trehalose, that may function to absorb disaccharides that are produced from digestion of naturally occurring dietary constituents.
Topics: Animals; Biological Transport; Carbon Radioisotopes; Carrier Proteins; Disaccharides; Hepatopancreas; Hydrogen-Ion Concentration; Maltose; Microvilli; Nephropidae; Sodium; Sucrose; Trehalose
PubMed: 28180997
DOI: 10.1007/s00360-017-1058-9 -
Journal of Biochemistry Feb 1998Compositional analyses of heparin (Hep) and heparan sulfate (HS) have been undertaken with disaccharide units obtained by either enzymatic digestion with heparitinases...
Compositional analyses of heparin (Hep) and heparan sulfate (HS) have been undertaken with disaccharide units obtained by either enzymatic digestion with heparitinases or hydrazinolysis/deamination reaction of polysaccharides. Unsaturated disaccharide units generated by the enzymatic method are detectable on HPLC with a uv detector recording absorbance at 230 nm. On the other hand, disaccharide units generated by the chemical method possess a component of 2,5-anhydromannose (AnMan) bearing aldehyde groups in addition to intact iduronic acid (IdoA) or glucuronic acid (GlcA). The aldehyde groups of the disaccharide units are usually reduced with sodium borotritide, and detected by radiochromatography. Both of them, however, involve inevitable experimental problems, such as the use of costly enzymes and radioisotopes. In the present study, we have established a novel composition analysis system for Hep and HS essentially based on the chemical method. After hydrazinolysis/deamination treatment of Hep and HS, the aldehyde groups of AnMan in the disaccharide units generated were coupled with paranitrophenyl (PNP-) hydrazine instead of reduction with sodium borotritide, AnMan-CH=N-NH-PNP (AnMan-PNP) being formed. Then, the PNP-labeled disaccharides were pre-treated on a SepPak C-18 cartridge column, and subsequently separated and detected on ion-pairing reversed-phase HPLC with a detector recording absorbance at 390 nm. With the present system, the order of elution was GlcA-AnMan-PNP (GM), IdoA-AnMan-PNP (IM), IdoA(2S)-AnMan-PNP (ISM), IdoA-AnMan(6S)-PNP (IMS), and IdoA(2S)-AnMan(6S)-PNP (ISMS). As an application, the disaccharide compositions of heparin from bovine intestine and heparan sulfate from bovine kidney were analyzed by the present method, and the results were comparable to those obtained by a well-established enzymatic method. The present compositional analysis was demonstrated to be reliable and economical.
Topics: Acetylation; Animals; Cattle; Chromatography, High Pressure Liquid; Deamination; Disaccharides; Heparin; Heparitin Sulfate; Indicators and Reagents; Intestinal Mucosa; Intestines; Kidney; Nitrous Acid; Phenylhydrazines; Sulfates
PubMed: 9538198
DOI: 10.1093/oxfordjournals.jbchem.a021928 -
Chembiochem : a European Journal of... Sep 2004A highly convergent approach has been employed for the facile synthesis of a library of 24 disaccharides that are alpha(1-3), beta(1-3), alpha(1-4), or beta(1-4) linked...
A highly convergent approach has been employed for the facile synthesis of a library of 24 disaccharides that are alpha(1-3), beta(1-3), alpha(1-4), or beta(1-4) linked and contain 2-4 amino groups. Fourier-transformation ion cyclotron resonance mass spectrometry (FT-ICR MS) has been used to determine dissociation constant (Kd) values for the binding of the disaccharides to a prototypical fragment of 16S ribosomal RNA. Several derivatives bound with affinities similar to that of neamine. Structure-activity relationships have revealed the substitution pattern that is important for high-affinity binding. The compounds described here are unique lead compounds for the design of novel aminoglycoside antibiotics.
Topics: Aminoglycosides; Carbohydrate Sequence; Crystallography, X-Ray; Disaccharides; Framycetin; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Molecular Sequence Data; RNA; Structure-Activity Relationship
PubMed: 15368574
DOI: 10.1002/cbic.200400105 -
Carbohydrate Research Nov 1999The 'adiabatic' (phi, psi) potential-energy surface of the disaccharide alpha-D-galactopyranosyl-(1-->3)-beta-D-galactopyranose was obtained by several established...
The 'adiabatic' (phi, psi) potential-energy surface of the disaccharide alpha-D-galactopyranosyl-(1-->3)-beta-D-galactopyranose was obtained by several established methods, using the MM3 molecular mechanics force field. The constrained minimizations throughout the whole grid were carried out using sharply different dielectric constants. The attainment of the 'true' adiabatic map is very difficult due to the 'multiple minimum problem', originating in the large number of exocyclic pendant groups present in a disaccharide. However, these results suggest that at low dielectric constants, the usual approach starting with conformers carrying cooperative hydrogen bonds results in a good approximation to the true adiabatic map, while at high dielectric constants this approach fails due to the damping of electrostatic and hydrogen-bonding interactions.
Topics: Carbohydrate Conformation; Disaccharides; Hydrogen Bonding; Thermodynamics
PubMed: 10629950
DOI: 10.1016/s0008-6215(99)00207-4