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PubMed1994

Synthesis of hyaluronic acid-related di-, tri-, and tetra-saccharides having an N-acetylglucosamine residue at the reducing end.

The synthesis is reported of 4-methoxyphenyl O-(beta-D-glucopyranosyluronic acid)-(1-->3)-2-acetamido-2-deoxy-beta-D-glucopyranoside (1), 4-methoxyphenyl O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-(1-->4)-O-(beta-D- glucopyranosyluronic acid)-(1-->3)-2-acetamido-2-deoxy-beta-D-glucopyranoside (5), and 4-methoxyphenyl O-(beta-D-glucopyranosyluronic acid)-(1-->3)-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-(1-->4)-O-(b eta-D- glucopyranosyluronic acid)-(1-->3)-2-acetamido-2-deoxy-beta-D-glucopyranoside (10), which are structural elements of the extracellular polysaccharide hyaluronic acid. 6-O-Levulinoyl-2,3,4-tri-O-p-toluoyl-alpha-D-glucopyranosyl trichloroacetimidate (3) was condensed with 4-methoxyphenyl 2-deoxy-4,6-O-isopropylidene-2-phthalimido-beta-D-glucopyranoside (4). De-isopropylidenation and acetylation of the obtained disaccharide derivative yielded 4-methoxyphenyl O-(6-O-levulinoyl-2,3,4-tri-O-p-toluoyl-beta-D-glucopyranosyl)-(1-->3)-4 ,6-di-O - acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranoside, and subsequent delevulinoylation, oxidation, complete deprotection, and N-acetylation gave 1. Coupling of 4-O-allyloxycarbonyl-6-O-levulinoyl-2,3-di-O-p-toluoyl-alpha-D-glu copyranosyl trichloroacetamidiate with 4 followed by de-isopropylidenation, acetylation, and deallyloxycarbonylation of the obtained disaccharide derivative gave 8. Condensation of 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl trichloroacetimidate with 8 afforded trisaccharide derivative 4-methoxyphenyl O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl)-(1--> 4)-O-(6 - O-levulinoyl-2,3-di-O-p-toluoyl-beta-D-glucopyranosyl)-(1-->3)-4,6-di-O- acetyl- 2-deoxy-2-phthalimido-beta-D-glucopyranoside, and subsequent delevulinoylation, oxidation, complete deprotection, and N-acetylation gave 5. 3-O-Allyloxycarbonyl-2-deoxy-4,6-O-isopropylidene-2-phthalimido-be ta-D- glucopyranosyl trichloroacetimidate was coupled with disaccharide acceptor 8, and deallyloxycarbonylation of the obtained trisaccharide derivative yielded 12. Condensation of 3 with 12 followed by de-isopropylidenation and acetylation of the obtained tetrasaccharide derivative gave 4-methoxyphenyl O-(6-O-levulinoyl-2,3,4-tri-O-p-toluoyl-beta-D-glucopyranosyl)-(1-->3)-O -(4,6- di-O-acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl)-(1-->4)-O-(6-O- levulinoyl-2,3-di-O-p-toluoyl-beta-D-glucopyranosyl)-(1-->3)-4,6-di-O-ac etyl-2- deoxy-2-phthalimido-beta-D-glucopyranoside, and delevulinoylation, oxidation, complete deprotection, and N-acetylation yielded 10.

Acetylglucosamine↗
PubMed2001

Synthesis of methyl alpha-D-glucopyranosyl-(1-->4)-alpha-D-galactopyranoside and methyl alpha-D-xylo-hex-4-ulopyranosyl-(1-->4)-alpha-D-galactopyranoside.

The syntheses of methyl alpha-D-glucopyranosyl-(1-->4)-alpha-D-galactopyranoside (1) and methyl alpha-D-xylo-hex-4-ulopyranosyl-(1-->4)-alpha-D-galactopyranoside (4) are reported. The keto-disaccharide 4 is of interest in our design, synthesis, and study of pectate lyase inhibitors. The key step in the syntheses was the high-yielding, stereospecific formation of methyl 4,6-O-benzylidene-2',3'-di-O-benzyl-alpha-D-glucopyranosyl-(1-->4)-2,3,6-tri-O-benzyl-alpha-D-galactopyranoside (15), which was accomplished by reacting 2,3-di-O-benzyl-4,6-O-benzylidene-D-glucopyranosyl trichloroacetimidate (10) with methyl 2,3,6-tri-O-benzyl-alpha-D-galactopyranoside (14) in the presence of a catalytic amount of tert-butyldimethylsilyl trifluoromethane sulfonate (TMSOTF). Compound 15 was either hydrogenolyzed to yield disaccharide 1 or treated with NaBH3CN-HCl in 1:1 tetrahydrofuran-ether to yield methyl 2,3,6-tri-O-benzyl-alpha-D-glucopyranosyl-(1-->4)-2,3,6-tri-O-benzyl-alpha-D-galactopyranoside (2). The free 4'-OH of compound 2 was oxidized to a carbonyl group by a Swern oxidation, and the protecting groups were removed by hydrogenolysis to yield keto-disaccharide 4. These synthetic pathways were simple, yet high yielding.

Disaccharides↗
PubMed2002

Potential energy surfaces of carrageenan models: carrabiose, beta-(1 --> 4)-linked D-galactobiose, and their sulfated derivatives.

The adiabatic conformational surfaces of several beta-linked disaccharides, which correspond to the repeating structures of carrageenans, were calculated using the MM3 force-field. The studies were carried out on the disaccharide beta-D-Galp-(1 --> 4)-alpha-D-Galp and eight sulfated derivatives, as well as on carrabiose (beta-D-Galp-(1 --> 4)-3,6-An-alpha-D-Galp) and five sulfated derivatives. The presence of 3,6-anhydrogalactose does not change the main features of the maps, although it increases the flexibility of the glycosidic linkage. Sulfation neither produces a striking effect on the map shape, nor a shift on the global minimum, which always remains with psi (theta(C-1'-O-4-C-4C-5)) in trans orientation, and phi (theta(O-5'-C-1'-O-4-C-4)) with a value close to -80 degrees. This effect differs from that occurring on the alpha linkage of equivalent disaccharides, for which the sulfation pattern on the beta-galactose unit shifts the global minima to different positions. A reduction in the flexibility (originated in a deepening of the global minimum well) is observed by sulfation on position 2 of the beta-D-galactose unit, and by sulfation of position 6 of the alpha-D-galactose unit (when the beta-D-galactose unit is 4-sulfated). Within the compounds containing 3,6-anhydrogalactose, the effect of sulfation is even less noticeable. The calculated low-energy regions on carrabiose derivatives agree with X-ray diffraction data on carrageenan fibers and on peracetylated carrabiose dimethyl acetal, and with NOE calculations carried out on kappa-carrabiose.

Carbohydrate Conformation↗
PubMed2003

Synthesis of S-linked thiooligosaccharide analogues of Nod factors: synthesis of new protected thiodisaccharide and thiotrisaccharide intermediates.

We are investigating the synthesis of thioanalogues of nodulation factors that will be resistant to degradation by chitinases. To study the influence of our protecting group strategy, the glycosylation of 1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-beta-D-glucopyranoside (7) with two trichloroacetimidate glycosyl donors carrying an azido group at C-2 and either benzyl or benzoyl protecting groups on O-3 and O-4 was first attempted under catalysis with BF(3).Et(2)O in toluene. While glycosylation with the benzoylated glycosyl donor gave only a poor yield (27%) of the disaccharide, a similar reaction with the benzylated donor gave the corresponding disaccharide in good yield (77%). Although both products were obtained as anomeric mixtures, the benzylated donor led to improved stereoselectivity in favor of the desired beta-anomer (alpha:beta 3:7). Based on these results, a novel thiotrisaccharide was synthesized via the coupling of 7 with 6-O-acetyl-4-S-(3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-beta-D-glucopyranosyl)-2-azido-3-O-benzyl-2-deoxy-4-thio-alpha-D-glucopyranosyl trichloroacetimidate (25) also newly synthesized. After optimization of the reaction conditions, the desired thiotrisaccharide 4-O-[6-O-acetyl-4-S-(3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-beta-D-glucopyranosyl)-2-azido-3-O-benzyl-2-deoxy-4-thio-beta-D-glucopyranosyl]-1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-beta-D-glucopyranoside (26beta) was obtained in 57% yield. These conditions led to an anomeric mixture in favor of the desired beta-anomer (alpha:beta 1:4.7) that was separated from the alpha-anomer by normal-phase HPLC on a PrepNova Pack(R) silica gel cartridge. The work described here shows that thiodisaccharide glycosyl donors behave quite differently from the analogous O-disaccharide used previously to synthesize nodulation factors.

Carbohydrate Sequence↗
PubMed1994

Synthetic studies toward pyruvate acetal-containing saccharides: en route to the efficient synthesis of Rhizobium-related exopolysaccharide fragments.

The disaccharide building block benzyl O-(2,3-di-O-benzoyl-4,6-O-[(R)-1-(methoxycarbonyl) ethylidene]-beta-D-galactopyranosyl)-(1-->3)-2-O-benzoyl-4,6-O-[(S)-1- (methoxycarbonyl)ethylidene]-alpha-D-glucopyranoside (13), related to a Rhizobium exopolysaccharide, was prepared by coupling various 4,6-O-[(R)-1-(methoxycarbonyl)ethylidene]-D-galactosyl donors (benzoyl-protected chloride 1, pivaloyl-protected chloride 2, and benzoyl-protected fluorides 3 and 4, and trichloroacetimidate 5) with benzyl 2-O-benzoyl-4,6-O-[(S)-1- (methoxycarbonyl)ethylidene]-alpha-D-glucopyranoside (10) and the corresponding 2,3-O-tetraisopropyldisiloxane-protected glucoside 12. The best results, with respect to beta-selectivity and yield of the coupling, were obtained with 5 and 10 in dichloromethane. The beta-linked (13) and alpha-linked (14) disaccharides were efficiently converted via the 1-OH derivatives 17 and 21 into the corresponding trichloroacetimidates 18 and 22. The latter were used for the synthesis of the disaccharide ligands 4,6-(R)-pyruvate-beta-D-Galp-(1-->3)-4,6-(S)-pyruvate-beta-D-Glcp-O(CH2) 5NH2 (20), and 4,6-(R)-pyruvate-alpha-D-Galp-(1-->3)-4,6-(S)-pyruvate-beta-D-Glcp-O (CH2)5NH2 (24). The corresponding tri- and tetra-saccharide derivatives 4,6-(R)-pyruvate-beta-D-Galp-(1-->3)-4,6-(S)-pyruvate-beta-D-Glcp-(1-->4 )-beta- D-Glcp-O(CH2)5NH2 (28) and 4,6-(R)-pyruvate-beta-D-Galp-(1-->3)-4,6-(S)-pyruvate-beta-D-Glcp-(1-->4 )-beta- D-Glcp-(1-->4)-beta-D-Glcp-O(CH2)25NH2 (36) were obtained similarly.

Carbohydrate Conformation↗
PubMed1997

Synthetic approach towards sulfated chondroitin di-, tri- and tetrasaccharides corresponding to the repeating unit.

Chondroitin di-, tri- and tetrasaccharides, as well as their 4-, 6-mono- and 4,6-disulfates as their 4-methoxyphenyl glycosides, were systematically synthesized. Target disaccharides having beta GalNAc-(1-->4)-beta GlcA sequences were obtained starting from the corresponding pivotal chondroitin disaccharide precursor. A trisaccharide intermediate, which was synthesized by coupling of glucuronate imidate with a known disaccharide acceptor, was transformed into the sulfated and non-sulfated chondroitin trisaccharides. Chondroitin tetrasaccharide and the corresponding 4-disulfate, 6-disulfate as well as 4,6-tetrasulfate were also obtained based on the strategy developed above starting from the reported tetrasaccharide having [beta GalN3-(1-->4)-beta GlcA2] sequence.

Carbohydrate Sequence↗
PubMed1998

The glycosyl-aldonolactone approach for the synthesis of beta-D-Galf-(1-->3)-D-Manp and 3-deoxy-beta-D-xylo-hexofuranosyl-(1-->3)-D-Manp.

A convenient synthesis of free beta-D-Galf-(1-->3)-D-Manp (8a) is reported. The disaccharide is present as external unit in the lipopeptidophosphoglycan (LPPG) of Trypanosoma cruzi and internally in the lipophosphoglycan (LPG) of Leishmania. Condensation of 2,5,6-tri-O-benzoyl-D-mannono-1,4-lactone (1) with 1,2,3,5,6-penta-O-benzoyl-D-galactofuranose, promoted by SnCl4, led to the beta-glycosyl-lactone, a key intermediate for disaccharide 8a, readily obtained by successive reduction of the lactone with diisoamylborane and debenzoylation. As in the LPG of Leishmania the HO-3 group of the galactofuranose is glycosylated by alpha-D-Galp, we also synthesized 3-deoxy-beta-D-xylo-hexofuranosyl-(1-->3)-D-Manp (8b) and p-nitrophenyl 3-deoxy-beta-D-xylo-hexofuranoside for studying the influence of HO-3 in the interaction with specific glycosidases. The disaccharide 8a, and its corresponding alditol, were good substrates for the beta-D-galactofuranosidase from Penicillium fellutanum, whereas the 3-deoxyglycosides were not hydrolyzed by the enzyme.

Carbohydrate Sequence↗
PubMed1997

Heparan sulfate isomers in cerebral arteries of Japanese women with aging and with atherosclerosis--heparitinase and high-performance liquid chromatography determinations.

Composition of heparan sulfate (HS) isomers from unaffected and atherosclerotic cerebral arteries (isolated by autopsy) of Japanese women, of various ages, was studied. HS isomers were separated as disaccharide units by high-performance liquid chromatography after degeneration with HS and heparin lyases. Heparitinase facilitated differentiation of eight unsaturated disaccharides (deltaDi-S(HS)) of vascular HS isomers. The HS isomers in the cerebral arteries consisted of approximately half the total glycosaminoglycans (GAGs). Both HS (and GAGs) tended to increase with the processes of aging but decreased with the advancing development of atherosclerosis. The HS isomers consisted of a higher proportion of non-sulfated disaccharide, about 2/3 of the total HS, followed by mono-sulfated and bis-sulfated saccharides; in addition, heparin existed, albeit in minute amounts. The proportion of deltaDi-S(HS) rich in sulfate compared with HS isomers tended to increase with aging but most decreased during formation of the atheroma. Putative functions of HS isomers in cerebral arteries are discussed, based on the characteristic distribution of HS components.

Adolescent↗
PubMed1981

Structure of carbohydrate part of receptor on human uroepithelial cells for pyelonephritogenic Escherichia coli.

The binding of pyelonephritogenic Escherichia coli strains to human uroepithelial cells from patients with and without P blood group antigens was investigated. Uroepithelial cells from p phenotypes bound pyelonephritogenic e. coli to a significantly lesser extent than did cells from P1 and P2 phenotypes. The binding of pyelonephritogenic E. coli to urinary epithelial cells of P1 phenotypes was blocked by the synthetic disaccharide alpha-D-Galp-(1 leads to 4)-beta-D-Galp whose structures is related to that of the P blood group antigens. Coating of P1 cells with a synthetic disaccharide derivative increased the binding of bacteria. None of 30 individuals of p phenotype had had urinary tract infection. The findings show that the disaccharide alpha-D-Galp-(1 leads to 4)-beta-D-Galp, previously shown to be the erythrocyte receptor for the fimbriae of pyelonephritongenic E. coli, is also the receptor structure on uroepithelial cells.

Adhesiveness↗
PubMed1997

Sensitive high-performance liquid chromatographic method with fluorometric detection for the determination of heparin and heparan sulfate in biological samples: application to human urinary heparan sulfate.

A sensitive high-performance liquid chromatographic method for the determination of unsaturated disaccharides produced from heparin and heparan sulfate is described. Heparan sulfate was depolymerized using a combination of heparin lyase I (EC 4.2.2.7), heparin lyase II and heparin lyase III (EC 4.2.2.8). Seven unsaturated disaccharides were separated under isocratic conditions within 25 min using acetonitrile-H2O-0.2 M sodium phosphate buffer (pH 7.0)-3.0 M ammonium chloride (32:10:1:1) and were monitored by fluorescence detection using 2-cyanoacetamide as a post-column derivatizing reagent. As little as 2 pmol of a disaccharide could be detected with excitation at 346 nm and emission at 410 nm. This method was applied to the analysis of normal human urine. It was revealed that the concentration of normal human urinary heparan sulfate is 1.53+/-0.36 mg/mg creatinine (n=4).

Adult↗
PubMed2000

Differential antibacterial activity of moenomycin analogues on gram-positive bacteria.

The moenomycin trisaccharide degradation product and synthetic disaccharide analogues based on the disaccharide core were bactericidal to gram-positive bacteria, inhibited lipid II polymerization, and inhibited cell wall synthesis in Enterococcus faecalis. Truncating moenomycin to the trisaccharide, and building upon the core disaccharide have both led to molecules possessing properties not shared with their respective parent structures.

Aminoglycosides↗
PubMed2001

Ranking of gas-phase acidities and chloride affinities of monosaccharides and linkage specificity in collision-induced decompositions of negative ion electrospray-generated chloride adducts of oligosaccharides.

Negative ion electrospray-tandem mass spectrometry has been employed to study chloride adducts of saccharide molecules. Decompositions of [M + Cl]- obtained under identical low-energy collision conditions allow the approximate ranking of chloride affinities and gas-phase acidities of a series of isomeric monosaccharides. The ketohexoses are found to be more acidic than the aldohexoses. Chloride adduct decompositions are examined for a glucopyranosyl fructose and a glucopyranosyl glucose series. For each disaccharide series, the linkage position is shown to markedly influence the favored pathways of [M + Cl]- decompositions, initiated either by loss of neutral HCl to form [M - H]- and possibly leading to further (consecutive) decompositions, or by loss of M to form Cl-. Upon formation of [M - H]-, both cross-ring cleavages and glycosidic bond decompositions were observed in varying degrees for the two series of disaccharides. Remarkably, for three non-reducing polysaccharides that each contain a terminal sucrose group at the "downstream" end, chlorine-containing product ions arising from cleavage of the Glcalpha-2Fru linkage have been observed. Apart from Cl-, chlorine-containing product ions are not observed for any of the other disaccharides investigated, and they appear to be specifically diagnostic of a terminal Glcalpha-2Fru linkage. Their appearance is rationalized based upon a substantially reduced tendency for HCl loss from these non-reducing polysaccharides.

Algorithms↗
PubMed1987

Structure of the major carbohydrate fragment of the Leishmania donovani lipophosphoglycan.

The major carbohydrate fragment from the lipophosphoglycan of Leishmania donovani was generated by mild acid hydrolysis (0.02 N HCl, 5 min, 100 degrees C) and purified by chromatography on DE-52 cellulose and thin layer. By a combination of analyses including gas-liquid chromatography-mass spectrometry and 1H NMR, the structure of the fragment was elucidated as PO4----6Gal(beta 1----4)Man. Approximately 16 of these phosphorylated disaccharide units occur in the overall glycoconjugate structure. NMR analysis of an alkaline phosphatase treated phosphorylated tetrasaccharide generated from lipophosphoglycan showed that the phosphorylated disaccharide units are linked together via alpha-glycosidic linkages. Complete characterization of the phosphorylated disaccharide units of lipophosphoglycan provides the first example of a defined carbohydrate anchored in membranes by a derivative of phosphatidylinositol.

Animals↗
PubMed1996

Evaluation of isofagomine and its derivatives as potent glycosidase inhibitors.

A pseudo-aza-monosaccharide and several pseudo-aza-disaccharide compounds were constructed based on replacement of the anomeric carbon with a nitrogen and the ring oxygen with a carbon. The inhibition constants of these compounds toward five different glycosidases, alpha-glucosidase, beta-glucosidase, isomaltase, alpha-mannosidase, and glucoamylase, were obtained. Isofagomine, the pseudo-aza-monosaccharide, shows a broad spectrum of strong inhibition against glycosidases. It is the most potent inhibitor of beta-glucosidase from sweet almonds reported to date and also a strong inhibitor of glucoamylase, isomaltase, and alpha-glucosidase. Isofagomine inhibits beta-glucosidase, glucoamylase, and isomaltase more strongly than 1-deoxynojirimycin where the ring oxygen has been replaced with a nitrogen. The alpha-1,6- linked pseudo-disaccharide showed very strong inhibition toward glucoamylase, being nearly as potent an inhibitor as acarbose. Pseudo-disaccharides in which the anomeric nitrogen was methylated to favor formation of either the alpha or beta substrate linkage generally had weakened inhibition for the glycosidases studied most likely due to steric interference with the various active sites. These results indicate that the presence of a basic group at the anomeric center is important for carbohydrase inhibition. The presence of a charged carboxylate group near the anomeric carbon which interacts with the basic nitrogen is suggested for these enzymes, particularly for beta-glucosidase. The presence of a second alpha-linked glucosyl residue is also critical for strong inhibition of glucoamylase.

Carbohydrate Sequence↗
PubMed1998

Identification of a glycosaminoglycan binding surface on human interleukin-8.

The activation of leukocytes by chemokines is believed to be mediated via binding of chemokines to glycosaminoglycan chains of the extracellular matrix. The binding site on the chemokine interleukin-8 (IL-8) for the glycosaminoglycan heparin has been characterized using a systematic series of site-directed mutants of IL-8 in which the basic residues of the protein have been replaced by alanine. Mutation of K64 and R68 caused the largest decrease in affinity for a heparin Sepharose matrix, with smaller effects seen with mutations of K20, R60, and K67. Heparin-derived disaccharides that could disrupt the IL-8-heparin Sepharose interaction were identified by a competitive binding assay. Heteronuclear NMR spectroscopic titration of 15N-labeled IL-8 with a trisulfated disaccharide revealed a cluster of residues on IL-8 which were perturbed by disaccharide binding. These data identify a heparin-binding surface on IL-8 that includes the C-terminal alpha-helix and the proximal loop around residues 18-23. The heparin-binding site is spatially distinct from the residues involved in receptor binding.

Affinity Labels↗
PubMed2005

Mimicking the properties of antifreeze glycoproteins: synthesis and characterization of a model system for ice nucleation and antifreeze studies.

Synthesis of beta-D-Gal-(1 --> 3)-beta-D-GalNAc coupled to HOC2H4NHCOC15H30SH is described. This compound was coadsorbed at various proportions with C2H5OC2H4NHCOC15H30SH to form statistically mixed self-assembled monolayers (SAMs) on gold in an attempt to mimic the properties of the active domain in antifreeze glycoproteins (AFGPs). The monolayers were characterized by null ellipsometry, contact angle goniometry, X-ray photoelectron spectroscopy, and infrared reflection-absorption spectroscopy. The disaccharide compound adsorbed preferentially, and SAMs prepared at a solution molar ratio >0.3 displayed total wetting. The mixed SAMs showed well-organized alkyl chains up to a disaccharide surface fraction of 0.8. The amount of gauche conformers in the alkyls increased rapidly above this point, and the monolayers became disordered and less densely packed. Furthermore, the generated mixed SAMs were subjected to water vapor at constant relative humidity and the subsequent ice crystallization on a cooled substrate was monitored via an optical microscope. Interestingly, rapid crystallization occurred within a narrow range of temperatures on mixed SAMs with a high disaccharide content, surface fraction >0.3. The reported crystallization temperatures and the ice layer topography were compared with results obtained for a much simpler reference system composed of -OH/-CH3 terminated n-alkanethiols in order to account for changes in topography of the water/ice layer with surface energy. Although preliminary, the obtained results can be useful in the search for the molecular mechanism behind the antifreeze activity of AFGPs.

Alkanes↗
PubMed1998

Differential chemoprotection against acetaminophen-induced hepatotoxicity by latentiated L-cysteines.

Novel thiazolidine prodrugs were prepared by the condensation of L-cysteine with aldose disaccharides. Using a disaccharide in prodrug construction allows for a terminal cyclic sugar moiety to be present on the prodrug, which may allow the delivery of the agent to specific receptors, such as the asialoglycoprotein receptor (ASGPR) of hepatocytes, that require specific structural motifs for recognition. Three L-cysteine prodrugs were synthesized with a pendant cyclic galactose moiety; two related glucose-bearing prodrugs were synthesized for comparison. The prodrugs were designed to release L-cysteine, which is then available to support glutathione (GSH) biosynthesis and provide cytoprotection against a variety of toxic insults. Protection studies in Swiss-Webster mice used acetaminophen (575 mg/kg), a well-documented hepatotoxin which depletes GSH at overdose. Three prodrugs performed exceptionally well against acetaminophen-induced hepatotoxicity, as measured by increased survival and improved histological profiles of liver tissue after 48 h. In further experimentation, two of the disaccharide-based prodrugs, prepared from alpha- and beta-lactose, were compared with the monosaccharide-based compound prepared from ribose. Co-administration of the selected prodrugs with a 400 mg/kg dose of acetaminophen to Swiss-Webster mice prevented the short-term depletion in hepatic GSH and also reduced hepatotoxicity as determined by histological damage and serum levels of alanine aminotransferase. A single dose of the prodrugs alone had no effect on hepatic drug metabolizing enzymes [glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), and cytochrome P450], but, concordant with the reduction of hepatotoxicity, the latentiated forms prevented the significant elevation in QOR activity and mRNA and GST mRNA elicited by acetaminophen itself. GST activity, UGT activity and mRNA, and cytochrome P450 concentration were all unaffected by acetaminophen or the prodrugs. These studies identified novel L-cysteine prodrugs with potentially useful hepatoprotective activity. However, no structure-activity relationships were obvious. In addition, the occurrence of targeted delivery to hepatocytes remains ambiguous.

Acetaminophen↗
PubMed1997

Efficient modelling protocols for oligosaccharides: from vacuum to solvent.

The determination of conformational preferences of oligosaccharides is best approached by describing their preferred conformations on potential energy surfaces as a function of the glycosidic linkage phi, psi torsional angles. For proper molecular mechanics modelling the flexibility of the rotatable pendant groups must also be considered. The so called adiabatic maps partially mimic the flexibility within the 10 dimensional conformational space of the pendant groups of the given disaccharide. These molecular mechanics maps are considered to be the state-of-the art of the phi, psi potential energy surface of disaccharides recently calculated. The RAMM (RAndom Molecular Mechanics) method was shown to be able to calculate such profiles automatically. Additionally, based on the continuum solvent approach, RAMM allows the calculation of the effects of solvent on conformational energy profiles. Molecular dynamics simulations are also useful tools to study the influence of solvent on conformational behaviour of oligosaccharides. The capability of the RAMM calculational protocol to locate low-energy conformers on the multidimensional potential energy hypersurfaces of disaccharides is illustrated and compared with molecular dynamics simulations with and without inclusion of the solvent.

Carbohydrate Conformation↗