Glucosamine Derivatives Research Articles

Terminal alkenes as versatile chemical reporter groups for metabolic oligosaccharide engineering.

The Diels-Alder reaction with inverse electron demand (DAinv reaction) of 1,2,4,5-tetrazines with electron rich or strained alkenes was proven to be a bioorthogonal ligation reaction that proceeds fast and with high yields. An important application of the DAinv reaction is metabolic oligosaccharide engineering (MOE) which allows the visualization of glycoconjugates in living cells. In this approach, a sugar derivative bearing a chemical reporter group is metabolically incorporated into cellular glycoconjugates and subsequently derivatized with a probe by means of a bioorthogonal ligation reaction. Here, we investigated a series of new mannosamine and glucosamine derivatives with carbamate-linked side chains of varying length terminated by alkene groups and their suitability for labeling cell-surface glycans. Kinetic investigations showed that the reactivity of the alkenes in DAinv reactions increases with growing chain length. When applied to MOE, one of the compounds, peracetylated N-butenyloxycarbonylmannosamine, was especially well suited for labeling cell-surface glycans. Obviously, the length of its side chain represents the optimal balance between incorporation efficiency and speed of the labeling reaction. Sialidase treatment of the cells before the bioorthogonal labeling reaction showed that this sugar derivative is attached to the glycans in form of the corresponding sialic acid derivative and not epimerized to another hexosamine derivative to a considerable extent.

Expanding the scope of cyclopropene reporters for the detection of metabolically engineered glycoproteins by Diels-Alder reactions.

Monitoring glycoconjugates has been tremendously facilitated by the development of metabolic oligosaccharide engineering. Recently, the inverse-electron-demand Diels–Alder reaction between methylcyclopropene tags and tetrazines has become a popular ligation reaction due to the small size and high reactivity of cyclopropene tags. Attaching the cyclopropene tag to mannosamine via a carbamate linkage has made the reaction even more efficient. Here, we expand the application of cyclopropene tags to N-acylgalactosamine and N-acylglucosamine derivatives enabling the visualization of mucin-type O-glycoproteins and O-GlcNAcylated proteins through Diels–Alder chemistry. Whereas the previously reported cyclopropene-labeled N-acylmannosamine derivative leads to significantly higher fluorescence staining of cell-surface glycoconjugates, the glucosamine derivative gave higher labeling efficiency with protein preparations containing also intracellular proteins.

Correction of doxorubicin-induced hepatotoxicity by glucosamine derivatives and their combinations with quercetin in rats

Correction of doxorubicin-induced hepatotoxicity by glucosamine derivatives and their combinations with quercetin in rats

Synthesis and anti-HIV-1 activity of the conjugates of gossypol with oligopeptides and d-glucosamine

Abstract A series of novel gossypol derivatives were synthesized and screened for their in vitro anti-HIV-1 activity. The results showed that replacing the aldehyde groups of gossypol with certain oligopeptides and d -glucosamine not only reduced the cytotoxicity of gossypol derivatives but also enhanced their antiviral activity against HIV-1. Interestingly, d -glucosamine derivative of gossypol that lacked the COONa group also exhibited the same potent anti-HIV-1 activity as oligopeptide derivatives with the COONa group. These compounds blocked the entry of HIV-1 IIIB into target cell, which was similar to T20. Furthermore, the molecular docking analysis rationalized their anti-HIV-1 activity. The results also implied that certain oligopeptides and d -glucosamine were important moities to prepare gossypol derivatives as HIV-1 entry inhibitors besides certain amino acids.

Synthesis of hyaluronic acid oligosaccharides and exploration of a fluorous-assisted approach

The synthesis of hyaluronic acid oligomers (tri- and tetrasaccharide) is described. We have followed a pre-glycosylation oxidation strategy. Glucuronic acid units were directly employed in coupling reactions with suitably protected glucosamine derivatives. In order to simplify the purification of synthetic intermediates, a fluorous-assisted strategy has been also explored. Using this approach, a hyaluronic acid trisaccharide was prepared.

Advance of Glucosamine and Their Derivatives as Chiral Ligands in Asymmetric Syntheses

Glucosamine is a chiral compound degraded from widely existed natural product chitosan. It is becoming an ideal raw material for preparation chiral amine, amine/phosphine ligands due to its more chiral centers and strong coordination ability. The application of glucosamine derivatives as chiral ligands in asymmetric organic reactions has become a very active research area. In this paper, the application of glucosamine derivatives in asymmetric allylic alkylation, Heck reaction, 1,4conjugate addition reaction, epoxidation reaction of olefins and cyclopropanation of olefin has been reviewed.

Synthesis and characterization of N-acyl-tetra-O-acyl glucosamine derivatives

Novel 1,3,4,6-tetra-O-acyl-N-acyl-D-glucosamine derivatives were synthesized from glucosamine hydrochloride (GlcN·HCl) by the acylation with pyridine as a catalyst. A derivative of tetra-O-acetyl glucosamine contained ketoprofen, a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic effects, was first synthesized. In analysis of the NMR spectra, the ratio of α:β-anomer showed that penta-acyl-D-glucosamine derivatives and N-acetylated glucosamines containing O-acyl groups have been only the α-anomer. Meanwhile, both the intermediates and the glucoconjugate compound of ketoprofen have only the β-anomer.

Differential O-3/O-4 selectivity in the glycosylation of N-dimethylmaleoyl-protected hexosamine acceptors: effect of a conformationally armed (superarmed) glycosyl donor

An assessment of the relative O-3/O-4 reactivities of both α- and β-methyl glycosides of N-dimethylmaleoyl (DMM) glucosamine and allosamine acceptors protected at O-6 with a benzyl group using a d-glucopyranosyl conformationally armed donor (superarmed donor) counterpart is presented. The glycosylation of glucosamine derivatives followed the trends already observed for disarmed donors. On the other hand, the glycosylation of allosamine derivatives gave exclusively substitution on the equatorial O-4, in spite that with a disarmed donor the point of substitution is exclusively on the more hindered, electronically-preferred O-3.

Synthesis of α‐Amino Acids from Glucosamine‐HCl and its Derivatives by Aerobic Oxidation in Water Catalyzed by Au Nanoparticles on Basic Supports

The golden wonder: Various α-amino acids such as glucosaminic acid, galactosaminic acid, or N-acetyl-glucosaminic acid can be obtained from the corresponding glucosamine derivatives (amino sugars). This is achieved through an aqueous oxidation that catalyzed by Au nanoparticles dispersed on basic support under mild reaction conditions in water.

A novel glucosamine derivative exerts anti-inflammatory actions via inhibition of nuclear factor-kappaB

Glucosamine suppresses lipopolysaccharide (LPS)-induced upregulation of pro-inflammatory mediators both in vivo and in culture systems of mouse microglia or macrophage. In the present study, we show that the novel glucosamine derivative, 2-deoxy-2-[(o-methylbenzylidene)]-β-glucopyranoside (NK-4), significantly reduced LPS-induced production of nitric oxide (NO) in BV2 microglia, RAW264.7 macrophage, and primary cultured peritoneal macrophages cells. NK-4 inhibited LPS-induced upregulation of inducible NO synthase (iNOS), cyclooxygenase-2, interleukin-6, tumor necrosis factor-α, and interleukin-1β in RAW264.7 cells in a time- and concentration-dependent manner. Furthermore, administering NK-4 significantly inhibited the induction of inflammatory cytokine mRNAs in the brains of LPS-injected mice. Although NK-4 inhibited LPS-induced nuclear factor-kappaB (NF-κB) activation, IκB-α degradation was not changed. Instead, NK-4 inhibited LPS-induced DNA-binding activity of NF-κB by suppressing p50 and c-Rel binding to NF-κB binding site of the iNOS promoter.

Synthesis of all four stereoisomers of 5-formyl-4-hydroxymethyl-1,3-oxazolidin-2-ones from d-glucosamine

All four stereoisomers of 5-formyl-4-hydroxymethyl-1,3-oxazolidin-2-ones (FHOs) were conveniently prepared from d-glucosamine by base-catalyzed epimerizations. 2-N,3-O-Carbonyl-d-glucosamine (7) was successively treated with NaBH4 and NaIO4 to give (4S,5R)-FHO 18, which was epimerized with DBU in DMF to give (4S,5S)-FHO 20. The glucosamine derivative 7 was epimerized to 2-N,3-O-carbonyl-d-mannosamine 23, from which (4R,5R)- and (4R,5S)-FHO derivatives (27 and 31) were prepared. The NMR measurements revealed that the 4,5-cis-4(or 5)-formyl-5(or 4)-hydroxymethyl-oxazolidinone derivatives form five-membered lactol ring, whereas the 4,5-trans-disubstituted derivatives form the hydrate or methanol adduct of the open-chain aldehyde, or the symmetrical dimer.

Design and synthesis of novel 18F-radiolabelled glucosamine derivatives for cancer imaging

The radiosynthesis of glucosamine and similar analogues would be of great interest due to their role in the biochemical synthesis of glycosylated proteins and lipids. This biochemistry can be exploited for visualisation of cancer cells via molecular imaging. This report details the synthesis of a number of 18F-labelled glucosamine derivatives and evaluation of their tumour uptake and normal tissue distribution in vivo in a mouse model of cancer by positron emission tomography (PET) imaging.

Streptozotocin induction of type 2 diabetes in tree shrew

The aim of this study was to induce type 2 diabetes in tree shrew (Tupaia belangeri chinensis). Streptozotocin (STZ), a glucosamine derivative of nitrosourea and preferentially toxic to pancreatic beta cells, has been commonly used to induce type 1 and 2 diabetes in experimental animals. Tree shrews were treated with different low doses of STZ (60, 70, and 80 mg/kg), with six control tree shrews receiving citrate buffer. After STZ injection, tree shrews displayed increased fasting blood and urine glucose, impaired oral glucose tolerance test, and disturbed lipids metabolism and renal function. However, STZ induced tree shrews showed no diabetic complications such as diabetic lactic acidosis and hyperglycemic hyperosmolar. Animals with the above type 2 diabetic-like symptoms were variable across the three groups from 66.7% to 100%, and mortality ranged from 16.7% to 33.3%. Thus, two 80 mg/kg STZ dose injections were appeared more appropriate than other doses to induce tree shrew model of type 2 diabetes. Our results demonstrated that type 2 diabetes could be induced with favorable STZ application in tree shrew.

Synthesis and selective anticancer activity of steroidal glycoconjugates

The synthesis of glucosamine derivatives of the steroidal sapogenins diosgenin and hecogenin using the N-phthaloyl protected trichloroacetimidate of d-glucosamine as donor and TMSOTf as promoter is reported. The corresponding glycoconjugates were transformed into their acetamido derivatives and the hydrochloride salt (from diosgenin) and tested against HeLa, CaSki, and ViBo cervicouterine cancer cells. These compounds showed low cytotoxicity values on tumor cells and human lymphocytes, indicating that the main cell death process is presumably not necrosis. Significantly, the antiproliferative activity of these compounds on tumor cells did not affect the proliferative potential of peripheral blood lymphocytes.

Synthesis and evaluation of inhibitors of E. coli PgaB, a polysaccharide de-N-acetylase involved in biofilm formation

Many medically important biofilm forming bacteria produce similar polysaccharide intercellular adhesins (PIA) consisting of partially de-N-acetylated β-(1 → 6)-N-acetylglucosamine polymers (dPNAG). In Escherichia coli, de-N-acetylation of the β-(1 → 6)-N-acetylglucosamine polymer (PNAG) is catalysed by the carbohydrate esterase family 4 deacetylase PgaB. The de-N-acetylation of PNAG is essential for productive PNAG-dependent biofilm formation. Here, we describe the development of a fluorogenic assay to monitor PgaB activity in vitro and the synthesis of a series of PgaB inhibitors. The synthesized inhibitors consist of a metal chelating functional group on a glucosamine scaffold to target the active site metal ion of PgaB. Optimal inhibition was observed with N-thioglycolyl amide (K(i) = 480 μM) and N-methyl-N-glycolyl amide (K(i) = 320 μM) glucosamine derivatives. A chemoenzymatic synthesis of an N-thioglycolyl amide PNAG pentasaccharide led to an inhibitor with an improved K(i) of 280 μM.

Glucosamine derivative modified nanostructured lipid carriers for targeted tumor delivery

Stearyl-2-amino-2-deoxyglucose (2-DG) modified nanostructured lipid carriers (NLC) were developed as novel vehicles for tumor-targeted delivery. The NLC were prepared using a melted-ultrasonic method, with glyceryl monostearate (MS) as a solid lipid and oleic acid (OA) as a liquid lipid. The physical properties of the NLC, including particle size, zeta potential, surface morphology, crystal structure, and storage stability, were characterized by standard methods. 2-DG, a glucosamine derivative, serving as a broad tumor targeting ligand, was conjugated to the surface of NLC (2-DG-NLC) for targeted delivery. Fluorescent dyes (fluorescein and cypate) and anticancer drug (paclitaxel, PTX) were used as model drugs to optimize the constituents of the NLC for drug entrapment efficiency and in vitrodrug release. The dynamic behavior of 2-DG-NLC in normal mice was investigated with a near infrared (NIR) fluorescence imaging system. The in vitro and in vivo tumor targeting capabilities of 2-DG-NLC were evaluated in MCF-7 tumor cells and tumor bearing mice, respectively. Results demonstrated that 2-DG-NLC actively and efficiently accumulated at the site of the tumor. Paclitaxel encapsulated 2-DG-NLC (2-DG-PTX-NLC) had good antitumor effectiveness and low toxicity in MCF-7 tumor bearing mice. The study indicates the broad potential of this carrier for tumor diagnosis as well as for targeted chemotherapy.

Synthesis of octyl S-glycosides of tri- to pentasaccharide fragments related to the GPI anchor of Trypanosoma brucei

The three oligosaccharide octyl-S-glycosides Man-α1,6-Man-α1,4-GlcNH 2-α1, S-Octyl ( 19), Man-α1,6-(Gal-α1,3)Man-α1,4-GlcNH 2-α1, S-Octyl ( 27) and Man-α1,2-Man-α1,6-(Gal-α1,3)Man-α1,4-GlcNH 2-α1, S-Octyl ( 37), related to the GPI anchor of Trypanosoma brucei were prepared by a stepwise and block-wise approach from octyl 2-azido-2-deoxy-3,6-di- O-benzyl-1-thio-α- d-glucopyranoside ( 8) and octyl 2- O-benzoyl-4,6- O-(1,1,3,3-tetraisopropyl-1,3-disiloxane-1,3-diyl)-1-thio-α- d-mannopyransoside ( 9). Glucosamine derivative 8 was obtained from 1,3,4,6-tetra- O-acetyl-2-azido-2-desoxy-β- d-glucopyranose ( 1) in five steps. Mannoside 9 was converted into the corresponding imidate 12 and coupled with 8 to give disaccharide octyl-S-glycoside 13 which was further mannosylated to afford trisaccharide 19 upon deprotection. Likewise, mannoside 9 was galactosylated, converted into the corresponding imidate and coupled with 8 to give trisaccharide 25. Mannosylation of the latter afforded tetrasaccharide 27 upon deprotection. Condensation of 25 with disaccharide imidate 35 gave, upon deprotection of the intermediates, the corresponding pentasaccharide octyl-S-glycoside 37. Saccharides 19, 27 and 37 are suitable substrates for studying the enzymatic glycosylation pattern of the GPI anchor of T. brucei.

ChemInform Abstract: Glucosamine‐Based Primary Amines as Organocatalysts for the Asymmetric Aldol Reaction.

AbstractA number of glycosamines is prepared.

A conformational study of N-acetyl glucosamine derivatives utilizing residual dipolar couplings

The conformational analyses of six non-rigid N-acetyl glucosamine (NAG) derivatives employing residual dipolar couplings (RDCs) and NOEs together with molecular dynamics (MD) simulations are presented. Due to internal dynamics we had to consider different conformer ratios existing in solution. The good quality of the correlation between theoretically and experimentally obtained RDCs show the correctness of the calculated conformers even if the ratios derived from the MD simulations do not exactly meet the experimental data. If possible, the results were compared to former published data and commented.

Effects of glucosamine derivatives and uronic acids on the production of glycosaminoglycans by human synovial cells and chondrocytes

Glucosamine (GlcN) has been widely used to treat osteoarthritis (OA) in humans. However, its chondroprotective action on the joint is poorly understood. In this study, to elucidate the chondroprotective action of GlcN, we examined the effects of GlcN-derivatives (GlcN and N-acetyl-D-glucosamine) and uronic acids (D-glucuronic acid and D-galacturonic acid) (0.1-1mM) on the production of glycosaminoglycans (GAG), such as hyaluronic acid (HA), keratan sulfate and sulfated GAG by human synovial cells and chondrocytes. The results indicate that among GlcN-derivatives and uronic acids, GlcN but not N-acetyl-D-glucosamine, D-glucuronic acid and D-galacturonic acid induce the production of HA by synovial cells and chondrocytes at >0.25 and >0.1mM (p<0.05), respectively, and the production levels are much higher (>10-fold) in synovial cells compared to chondrocytes. In contrast, neither N-acetyl-D-glucosamine, D-glucuronic acid nor D-galacturonic acid affected the production of keratan sulfate and sulfated GAG by these cells. Moreover, the experiments with 3H-labeled GlcN indicated that GlcN can be incorporated and utilized for the production of GAG (including HA) by synovial cells and chondrocytes. In addition, GlcN (1mM) up-regulates the expression of HA-synthesizing enzymes (hyaluronan synthases) in synovial cells and chondrocytes. Together these observations indicate that GlcN may exhibit chondroprotective action on joint diseases such as OA by modulating the expression of HA-synthesizing enzymes and inducing the production of HA (a major component of GAG contained in synovial fluid) especially by synovial cells.