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PubMedDate not supplied

Glycosaminoglycan-mimetic biomaterials. 3. Glycopolymers prepared from alkene-derivatized mono- and disaccharide-based glycomonomers.

Mono- and disaccharide-containing glycopolymers were synthesized by two different free-radical processes, and their ability to act as heparan sulfate glycomimetics in promoting the binding of Fibroblast Growth Factor-2 (FGF-2) to its receptor (FGFR-1) was evaluated using an in vitro cell-based assay. Cyanoxyl (*OC triple bond N)-mediated polymerization of acrylamide with alkene-derivatized mono- and disaccharides including sulfated or nonsulfated N-acetyl-D-glucosamine is described. The results of this approach are compared to those obtained via the classical ammonium peroxodisulfate (APS)/N,N,N',N'-tetramethylethylenediamine (TMEDA) initiating system and confirm the capacity of cyanoxyl-mediated polymerization to generate a variety of glycopolymers with high saccharide contents and low polydispersity indexes. In vitro assays demonstrate that specific glycopolymers can potentiate FGF-2/FGFR-1 binding interactions.

Alkenes↗
PubMed1989

Glycolipid membrane surface structure: orientation, conformation, and motion of a disaccharide headgroup.

The orientation of the disaccharide headgroup of a lactose-containing lipid, 3-O-(4-O-beta-D-galactopyranosyl-beta-D-glucopyranosyl)-1,2-di-O-tetrade cyl-sn- glycerol (DTLL), relative to the surface of bilayer membranes has been determined via 2H NMR. The lactosyl headgroup is extended away from the membrane surface into the aqueous phase. The headgroup motion has axial symmetry as evidenced by the spectral line shape and order parameter tensor. 2H NMR of oriented multibilayers of DTLL confirms that the director of motional averaging is the bilayer normal. The two sugar residues have segmental order parameters S (glucose, 0.53; galactose, 0.51) which indicate that the headgroup fluctuates about the bilayer normal as a rigid unit. 2H spin-lattice relaxation times T1z for deuterons on each of the two sugar rings are similar, indicating further that there is no substantial motion about the disaccharide linkage within the headgroup. The magnitude of the relaxation times (4 ms) suggests that the rigid body motions of the headgroup are approaching the Larmor frequency; however, they increase with increasing temperature, indicating that the motions are rapid enough to be in the fast motional regime (omega o2 tau c2 less than 1). The conformation about the galactose-glucose intersaccharide linkage, calculated from the 2H NMR data, is shown to differ substantially from those found in X-ray diffraction studies of crystalline lactose and high-resolution NMR studies of methyl lactoside in nonviscous solution. The orientations of the hydroxymethyl groups in the headgroup have been calculated from the 2H NMR data. For the galactosyl residue the data are consistent with the presence of more than one rotamer about the C5"-C6" bond which are in fast exchange on the 2H NMR time scale. The hydroxymethyl group of the glucose residue exists in two rotameric forms about the C5'-C6' bond which have relative populations of ca. 2:1 and which are in slow exchange on the 2H NMR time scale (10(-5) s). The two rotamers differ from those deduced from X-ray crystallography of crystalline lactose and 13C NMR studies of methyl lactoside in solution.

Carbohydrate Conformation↗
PubMed2003

Anomeric configuration, glycosidic linkage, and the solution conformational entropy of O-linked disaccharides.

Oligosaccharides perform a large number of biological roles, as dictated by their chemical structure and spatial arrangement. While conformational entropies are usually determined in vacuo by computer modeling, molecular recognition processes normally take place in solution. Here I show results of experiments using size-exclusion chromatography (SEC), an entropically driven solution technique. These clearly differentiate the individual contributions of the alpha and beta anomeric configurations and of the (1 --> 4) and (1 --> 6) glycosidic linkages to the solution conformational entropy of O-linked disaccharides. I also distinguish between the members of the epimeric disaccharide pair isomaltose-melibiose and trace the difference to that between their constituent monosaccharides, alpha-glucose and alpha-galactose.

Carbohydrate Conformation↗
PubMed2004

Glycosidic torsional motions in a bicelle-associated disaccharide from residual dipolar couplings.

An analysis of torsional motions about glycosidic bonds in a disaccharide is undertaken using residual dipolar coupling measurements and selective immobilization of the reducing end sugar to provide a suitable motional reference. The immobilization is accomplished by using the short chain of an alkyl glycoside to anchor the disaccharide to a bilayer medium aligned in magnetic field. Motions about the beta-(1-4) linkage of the n-butyl-4-O-beta-d-galactopyranosyl-alpha-d-mannopyranoside are shown to be substantial (+/-40 degrees ) and in good agreement with predictions of a fully solvated molecular dynamics simulation.

Carbohydrate Conformation↗
PubMed2003

Isolation, structure, synthesis, and bioactivity of a novel putative insulin mediator. A galactosamine chiro-inositol pseudo-disaccharide Mn2+ chelate with insulin-like activity.

We isolated from beef liver a putative insulin mediator termed INS-2, 1. Its structure was determined to be a novel inositol glycan pseudo-disaccharide Mn(2+) chelate containing D-chiro-inositol 2a (as pinitol) and galactosamine. Purification methods were scaled up from those previously reported to isolate an inositol glycan with similar composition from rat liver.(1) Structure of the beef liver glycan was determined by degradative chemistry and 2D NMR spectroscopy and confirmed by chemical synthesis. Its structure is 4-O-(2-amino-2-deoxy-beta-D-galactopyranosyl)-3-O-methyl-D-chiro-inositol 1 (INS-2, Figure 1). Its role as an insulin mimetic was demonstrated by its action in vivo to decrease elevated blood glucose injected to low-dose streptozotocin diabetic rats in a stereospecific and dose-dependent manner. The pseudo-disaccharide also stimulated [(14)C]glucose incorporation into [(14)C]glycogen in a dose-dependent manner in H4IIE hepatoma cells in the presence of insulin, thus enhancing insulin action. Only when chelated to Mn(2+) did it activate pyruvate dehydrogenase phosphatase in vitro in a dose-dependent manner. To our knowledge, this is the first example of a beta-1,4-linked inositol glycan consisting of D-chiro-inositol and galactosamine isolated from animal tissues with insulin mimetic actions.

Animals↗
PubMed2005

Syntheses and biological activities of disaccharide daunorubicins.

Carbohydrate moiety is found in many anticancer nature products. To explore the carbohydrate moiety of daunorubicin in enhancing anticancer efficacy, several daunorubicin derivatives bearing disaccharide (1-8) have been synthesized. Their cytotoxicities were tested in leukemia K562 and colon cancer SW620 cells. Topoisomerase II (topo II) poisoning was performed with the in vivo complex of topoisomerase bioassay. In both cell lines, compounds with various terminal 2,6-dideoxy sugars (compounds 1, 3, 5, and 8) showed 30- to 60-fold higher anticancer activity than compounds with 2-deoxy- or 6-deoxy sugar (compounds 6 and 7). Compounds with an alpha-linkage between two sugar units (compound 3) showed 35-fold higher anticancer activity than compounds with a beta-linkage (compound 4). In addition, the anticancer activities of these compounds correlated with their ability to target topo II mediated genomic DNA damage in vivo. Compounds 1 and 3 with 2,6-dideoxy sugars produced more covalent topo-DNA complex than compounds with 2-deoxy sugar (6) and 6-deoxy sugar (7). Compounds with an alpha-configuration of terminal 2,6-dideoxy sugar (compounds 1 and 3) showed higher topo II poisoning than their counterparts with the beta-configuration (compounds 2 and 4). These results indicate that sugar moieties in daunorubicin play a significant role in its anticancer activity and topo II inhibition. The second sugar of disaccharide daunorubicin should possess 2,6-dideoxy with alpha-linkage to the first sugar to exhibit better anticancer activity.

Antineoplastic Agents↗
PubMed2006

Syntheses and biological activities of 3'-azido disaccharide analogues of daunorubicin against drug-resistant leukemia.

Anthracyclines, such as daunorubicin (DNR) and doxorubicin (Dox), are widely used for cancer therapy but are limited by drug resistance and cardiotoxicity. To overcome drug resistance, we synthesized a novel class of disaccharide analogues of DNR against drug-resistant leukemia. In these disaccharide analogues (1-6) the first (inner) sugar in the carbohydrate chain is a 3-azido-2,3,6-trideoxy-L-lyxo-alpha-hexopyranose; the second (outer) sugars that are linked via alpha(1-->4) to the first sugar are a series of uncommon sugars. Their cytotoxicities were examined in drug-sensitive leukemia cells K562 and doxorubicin-resistant K562/Dox cells by MTS assay. In drug-sensitive cells, compounds 1-6 were found to be active against leukemia K562 cells with IC50 in the nanomolar range (200-1100 nM), while compounds 2-5 with 2,6-dideoxy sugars showed better activity than compounds 1 and 6 with 2,3,6-trideoxy sugars. In doxorubicin-resistant K562/Dox cells, compounds 1, 3, and 5 exhibited much better activities (with IC50 between 0.29 and 2.0 microM) than DNR (with IC50 > 5 microM). Compound 3 emerged as the most active compound, showing at least 17-fold higher activity against drug-resistant cells than parent compound DNR. The IC50 values of compound 3 in both drug-sensitive and drug-resistant cells are identical, which indicates that compound 3 completely overcomes drug resistance. Structure-activity relationship (SAR) studies showed that the substitution and orientation of the 3-OH group in the second sugar significantly influence its activity against drug-resistant leukemia. These results suggest that sugar modifications of anthracyclines change their activity and overcome drug resistance.

Antineoplastic Agents↗
PubMed2001

De novo synthesis of a methylene-bridged Neu5Ac-alpha-(2,3)-gal C-disaccharide.

A general strategy toward the synthesis of C-ketosides of N-acetylneuraminic acid (Neu5Ac) has been developed and successfully applied to the synthesis of methylene-bridged Neu5Ac-alpha-(2,3)-Gal C-disaccharide 2. The key strategic element of this novel approach is a stereoselective, 6-exo-trig selective, electrophilic cyclization of the appropriate open chain precursor 4 by means of phenylselenyl triflate. The open chain precursor was formed by the addition of lithiated iodide 18 accessible from D-galactose to open chain aldehyde 5a obtained from D-glucono-delta-lactone by chain elongation. Subsequent C1-incorporation using Tebbe-reagent, formation of a cyclic carbonate, and deprotection of the two isopropylidene ketals afforded tetrol 4 which, upon treatment with phenylselenyl triflate, was stereoselectively cyclized in a 6-exo-trig selective manner. A selena-Pummerer rearrangement, oxidation, and esterification readily led to methyl ester 37 which, after deacetylation, could be regioselectively tetrabenzoylated with benzoyl cyanide. Triflate activation of the axial hydroxyl group in 40 and nucleophilic displacement by azide ion with inversion of configuration afforded azide 41, which was reduced with hydrogen and Pearlman's catalyst. Concomitant removal of the benzyl ethers and subsequent saponification of all ester moieties successfully completed the de novo synthesis of the desired methylene bridged Neu5Ac-alpha-(2,3)-Gal C-disaccharide 2.

Alkenes↗
PubMed2002

New synthesis of pyrrolidine homoazasugars via aminohomologation of furanoses and their use for the stereoselective synthesis of aza-C-disaccharides.

The introduction of a formyl group at the anomeric center of 2,3,5-tri-O-benzyl furanoses and substitution of the ring oxygen with a basic nitrogen atom (aminohomologation) was carried out via stereoselective addition of 2-lithiothiazole to N-benzyl, N-furanosylhydroxylamines (masked N-benzyl sugar nitrones), followed by reductive dehydroxylation of the resulting open-chain adducts, and then ring closure via intramolecular displacement of the free hydroxy group by the amino group and unmasking of the formyl group from the thiazole ring. The resulting formyl aza-C-glycosides were transformed into 2,5-dideoxy-2,5-imino-hexitols (pyrrolidine homoazasugars) by reduction of the formyl to the hydroxymethyl group and removal of the O- and N-benzyl groups by hydrogenolysis. This reaction sequence was applied to four furanoses (D-arabino, D-ribo, D-lyxo, L-xylo) to give the hydroxy- and amino-free homoazasugars, including the natural product 2,5-dideoxy-2,5-imino-D-mannitol, in 17% overall yields (six steps). The formyl aza-C-glycosides proved to be valuable intermediates for the synthesis of more complex derivatives. In fact, these sugar aldehydes were employed in Wittig-type coupling reactions with galactose and ribose phosphoranes to give bis-glycosylated alkenes, which upon reduction of the double bond were transformed into methylene isosteres of (1-->6)- and (1-->5)-linked disaccharides in which one of the two sugar moieties was an azasugar (aza-(1-->x)-C-disaccharides).

Azacitidine↗
PubMed2003

Synthesis of the C-linked disaccharide alpha-D-Man-(1-->4)-D-Man employing a SmI(2)-mediated C-glycosylation step: en route to cyclic C-oligosaccharides.

Investigations are reported on the assembly of the C-linked disaccharide alpha-D-Man-(1-->4)-D-Man, representing the first steps in our projected synthesis of a cyclic C-oligomer containing repeating units of this C-dimer. The key step in this synthesis uses a SmI(2)-mediated coupling of 2,3,4,6-tetra-O-benzyl-alpha-D-mannopyranosyl 2'-pyridyl sulfone with a C4-formyl branched mannopyranoside unit, affording the C-disaccharide derivative with complete stereocontrol at the two new stereogenic centers. Subsequently, a modified tin hydride based deoxygenation produced the target carbohydrate analogue. The synthesis of the C4-formyl monosaccharide makes use of a stereoselective radical-based allylation followed by double bond migration and ozonolysis.

Catalysis↗
PubMed2003

Synthesis and partial biological evaluation of a small library of differentially-linked beta-C-disaccharides.

The synthesis of a small library of differentially-linked beta-C-disaccharides has been carried out through the use of a radical allylation-RCM strategy. Acids 6 were prepared by Keck allylation of a suitable carbohydrate-based radical precursor, followed by oxidative cleavage of the formed alkene. Dehydrative coupling of these acids with the known olefin alcohol 5 then gave the precursor esters 7 in excellent yield. Methylenation of the esters 7 was followed by RCM and in situ hydroboration-oxidation of the formed glycals to furnish the protected beta-C-disaccharides 10 in good overall yield. Five examples were then deprotected and screened for their efficacy as enzyme inhibitors of beta-glycosidase and against several solid-tumor cell lines for in vitro differential cytotoxicity.

Combinatorial Chemistry Techniques↗
PubMed2000

Stereoselective synthesis of the alpha-glycoside of a KDO "C"-disaccharide.

The reaction of tert-butyl (4,5,7, 8-tetra-O-acetyl-3-deoxy-alpha-D-manno-2-octulopyranosyl chloride)onate donor 7 with the 6-formylgalactopyranoside acceptor 4 in the presence of SmI(2) provided only the KDO alpha-C-disaccharide 8. The bulky tert-butyl ester in the donor was used to reverse the stereochemical outcome of C-glycosylation, stereoselectively forming the alpha-"C"-disaccharide of KDO.

Carbohydrate Sequence↗
PubMed2004

Studies related to carba-pyranoses: a radical decarboxylation approach to monocarba-disaccharides.

(1--> 1), (1--> 3) and (1--> 4) acetal-linked monocarba-disaccharides have been synthesised from a series of glucosylated gamma- and delta-lactonic acids prepared from common intermediate, obtained from the Diels-Alder reaction of maleic anhydride and (E)-1-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyloxy)-3-(trimethylsiloxy)buta-1,3-diene 1. Thiohydroxamic ester 14, prepared from gamma-lactonic acid 9, gave, upon treatment with tert-butyl thiol and light, the lactone 15. Subsequent lithium aluminium hydride reduction and acetylation gave the (1--> 3) acetal-linked monocarbadisaccharides 1,6-di-O-acetyl-3-O-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyl)-2,4-dideoxy-5a-carba-beta-L-threo-hexopyranose 16. In a similar manner, protected monocarba-disaccharides 13, 19, 30, and 35 possessing L-ido, L-xylo, D-arabino and L-ido configurations of the carba-pyranose ring have been prepared. Treatment of thiohydroxamic esters 14 and 17 with either tert-butyl thiol or trityl thiol, dimethyl sulfide, oxygen and light gave alcohols 20 and 22. Subsequent lithium aluminium hydride reduction and aceytlation gave the monocarbadisaccharides 1,4,6-tri-O-acetyl-3-O-[2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyl]-2-deoxy-5a-carba-beta-L-arabino-hexopyranose 21 and 1,2,4,6-tetra-O-acetyl-3-O-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyl)-5a-carba-beta-L-glucopyranose 23 respectively.

Acetals↗
PubMed1968

Novel heparin degradation products. Isolation and characterization of novel disaccharides and oligosaccharides produced from heparin by bacterial degradation.

1. Heparin was degraded by enzymes of adapted Flavobacterium heparinum. Several degradation products were separated by combined Sephadex-gel filtration and paper chromatography, and chemically analysed. 2. These products were identified as glucosamine 2,6-disulphate, saturated disaccharides constituted of uronic acid and glucosamine and containing two and three sulphate residues, and tetra- and hexa-saccharides with the same basic disaccharide units. 3. The implications of these findings with respect to the present knowledge of heparin structure and its enzymic degradation are discussed.

Chromatography↗
PubMed1987

Conformational equilibria of alpha-L-iduronate residues in disaccharides derived from heparin.

The disaccharides IdoA(2SO3)-anManOH(6SO3) and IdoA-anManOH (where IdoA represents alpha-L-iduronate, anManOH represents 2,5-anhydro-D-mannitol and SO3 represents sulphate ester) were prepared from bovine lung heparin using HNO2 depolymerization, borohydride reduction and desulphation, and were examined by 400 MHz 1H-n.m.r. spectroscopy. Three-bond proton-proton coupling constants around the IdoA ring were determined under a range of experimental conditions. For unsulphated IdoA all four proton-proton coupling constants varied markedly as a function of temperature, pH and solvent, providing clear evidence for a rapid conformational equilibrium. These data were analysed in terms of the three most energetically stable IdoA conformers: 1C4, 4C1, and 2S0. Predicted coupling constants for these conformers were determined using a modified Karplus-type relationship. For unsulphated IdoA in dimethyl sulphoxide the equilibrium was provoked strongly in favour of a slightly distorted 4C1 'chair' IdoA conformer for which coupling constants have not previously been reported. For sulphated IdoA in aqueous conditions and at low pH the equilibrium is strongly in favour of the alternative 1C4 chair conformer. Under many conditions, however, significant contributions from all three conformers occur for the non-reducing terminal IdoA in these disaccharides.

Carbohydrate Conformation↗
PubMed1981

Sulphamidase activity in leucocytes, cultured skin fibroblasts and amniotic cells: diagnosis of the Sanfilippo A syndrome with the use of radiolabelled disaccharide substrate.

1. Sulphamidase activity was assayed by incubation of the radiolabelled disaccharide O-(alpha-2-sulphamino-2-deoxy-D-glucopyranosyl)- (1 leads to 3)-L-[6-3H]idonic acid with homogenates of leucocytes and cultured skin fibroblasts and concentrates of urine derived from normal individuals, patients affected with sulphamidase deficiency disorder [mucopolysaccharidosis type IIIA (MPS IIIA): the Sanfilippo A syndrome], parents of such patients and patients affected with other mucopolysaccharidoses and lysosomal enzyme deficiencies. 2. The assay clearly distinguished affected homozygotes from normal controls, heterozygotes and other mucopolysaccharidoses types. 3. Sulphamidase displayed remarkable thermal stability; reaction rates were constant for at least 24 h at 60 degrees C for leucocyte and 20 h at 37 degrees C for cultured fibroblast preparations. Apparent Km values for fibroblast sulphamidase were 71 mumol/l at 37 degrees C and 100 mumol/l at 50 degrees C; the corresponding Vmax, values were 21 and 72 pmol min-1 mg-1 of protein respectively. An incubation temperature of 60 degrees C was used for the routine assay of sulphamidase activity in leucocytes, urine and amniotic supernatant preparations. The specific activities of fibroblast and amniotic cell sulphamidase, assessed at incubation temperatures of 37 degrees C, were more than 10-fold the leucocyte enzyme activity at 60 degrees C. 4. We recommend the use of radiolabelled disaccharide substrate for the assay of sulphamidase in leucocytes, skin fibroblasts and urine, for the routine enzymic detection of the sulphamidase deficiency disorder of the Sanfilippo A syndrome.

Amnion↗
PubMed2007

Exploring conformational energy landscape of glassy disaccharides by cross polarization magic angle spinning 13C NMR and numerical simulations. I. Methodological aspects.

This article demonstrates the ability of chemical shift surfaces to provide information on distributions of various conformations of disaccharides in the glassy, solid state. The validity of the general method leading to a simulation of inhomogeneous (13)C chemical shift distributions is discussed in detail. In particular, a proper consideration of extrema and saddle points of the chemical shift map correctly accounts for the observed discontinuities in the experimental cross polarization magic angle spinning spectra. Provided that these basic requirements are met, density functional theory/gauge-independent atomic orbital chemical shift maps calculated on relaxed conformations lead to a very satisfactory description of the experimental line shapes. Using amorphous trehalose as a model disaccharide, the simulation unambiguously defines the range of most populated conformations in the glass.

Carbon Radioisotopes↗
PubMed1997

Wild-type Escherichia coli grows on the chitin disaccharide, N,N'-diacetylchitobiose, by expressing the cel operon.

We report here that wild-type Escherichia coli can grow on the chitin disaccharide, N,N'-diacetylchitobiose (GlcNAc)2, as the sole source of carbon. Transposon mutants were isolated that were unable to ferment (GlcNAc)2 but grew normally on the monosaccharide GlcNAc. One such mutant was used to screen a wild-type E. coli genomic cosmid library for restoration of (GlcNAc)2 fermentation. A partial sequence analysis of the isolated fragment mapped the clone to the (previously sequenced) E. coli genome between 39.0 and 39.2 min. The nucleotide ORFs at this region had been previously assigned to code for a "cryptic" cellobiose utilization (cel) operon. We report here, however, that functional analysis of the operon, including growth and chemotaxis, reveal that it encodes a set of proteins that are not cryptic, but are induced by (GlcNAc)2 and catabolize the disaccharide. We therefore propose to rename the cel operon as the chb (N,N'-diacetylchitobiose) operon, with the letter designation of the genes of the operon to be reassigned consistent with the nomenclature based on functional characterization of the gene products as follows: celA to chbB, celB to chbC, celC to chbA, celD to chbR, and celF to chbF. Furthermore, sequencing evidence indicates that the operon contains an additional gene of unknown function to be designated as chbG. Thus, the overall gene sequence is to be named chbBCARFG.

Cellulase↗