Glucosamine Derivatives Research Articles

The experimental study of the local irritating action of N-acetylglucosamine and quercetin in intramuscular administration

The current problem of the modern medical and pharmaceutical industry is the insufficient number of effective and safe drugs with the polytropic action for the treatment of ischemic and inflammatory-destructive diseases of various organs. In this regard, pharmaceutical combinations, which are based on derivatives of glucosamine and quercetin in parenteral dosage forms, are of scientific interest.Aim. To study experimentally the local irritating action of N-acetylglucosamine, quercetin and their combination in intramuscular administration.Materials and methods. The study was carried out using 40 intact rats. To assess the local irritating action of the drugs studied the histomorphological study of the state of the rat muscle tissue at the site of administration was carried out using standard methods of bright field microscopy.Results. In the course of the study it was shown that after a 10-day administration of the solution of N-acetylglucosamine and its combination with quercetin in the muscle tissue of rats there were no significant changes, which would indicate the local irritating action of these drugs. At the same time, the solution of quercetin had a moderate local irritating effect with a pronounced reversible nature. The results obtained indicate a high level of safety and wide possibilities of using the drugs studied in clinical practice in the intramuscular route of administration.Conclusions. N-acetylglucosamine, quercetin and their combination under the conditions of intramuscular injection do not have a significant local irritating effect, which makes it advisable to introduce these drugs in dosage forms for injection.

Glucosamine Hydrochloride and N-Acetylglucosamine Influence the Response of Bovine Chondrocytes to TGF-β3 and IGF in Monolayer and Three-Dimensional Tissue Culture.

Glucosamine hydrochloride (GlcN·HCl) has been shown to inhibit cell growth and matrix synthesis, but not with N-acetyl-glucosamine (GlcNAc) supplementation. This effect might be related to an inhibition of critical growth factors (GF), or to a different metabolization of the two glucosamine derivatives. The aim of the present study was to evaluate the synergy between GlcN·HCl, GlcNAc, and GF on proliferation and cartilage matrix synthesis. Bovine chondrocytes were cultivated in monolayers for 48h and in three-dimensional (3D) chitosan scaffolds for 30days in perfusion bioreactors. Serum-free (SF) medium was supplemented with either growth factors (GF) TGF-β (5ngmL-1) and IGF-I (10ngmL-1), GlcN·HCl or GlcNAc at 1mM each or both. Six groups were compared according to medium supplementation: (a) SF control; (b) SF + GlcN·HCl; (c) SF + GlcNAc; (d) SF + GF; (e) SF + GF + GlcN·HCl; and (f) SF + GF + GlcNAc. Cell proliferation, proteoglycan, collagen I (COL1), and collagen II (COL2) synthesis were evaluated. The two glucosamines showed opposite effects in monolayer culture: GlcN·HCl significantly reduced proliferation and GlcNAc significantly augmented cellular metabolism. In the 30days 3D culture, the GlcN·HCl added to GF stimulated cell proliferation more than when compared to GF only, but the proteoglycan synthesis was smaller than GF. However, GlcNAc added to GF improved the cell proliferation and proteoglycan synthesis more than when compared to GF and GF/GlcN·HCl. The synthesis of COL1 and COL2 was observed in all groups containing GF. GlcN·HCl and GlcNAc increased cell growth and stimulated COL2 synthesis in long-time 3D culture. However, only GlcNAc added to GF improved proteoglycan synthesis.

Preparation of 123-iodine labeled glucosamine derivative and investigation of its biological properties

Search and synthesis of glucose derivatives for nuclear medicine is of great current interest. Being a promising analogue of glucose, D-glucosamine iodine labeled glucose derivatives can be applied in rheumatoid arthritis radionuclide diagnostics and therapy as a radiopharmaceutical. The purpose of the study. Synthesis of a new iodine labeled D-glucosamine derivative; development of the iodine-123 labeling method and the obtained glucose derivative biostudy. Materials and methods. Synthesis of 2-N-(6-iodohexanoyl)-D-glucosamine was carried out through established techniques in organic chemistry. Infrared spectroscopy and nuclear magnetic resonance spectroscopy were used to establish the test compound structure. Isotope change between iodine-127 and iodine-123 of glucosamine derivative was conducted using the heating of mix of the compound and Na123I in acetone. The radio-TLC method was applied to estimate the radiochemical purity of 2-N- (6-iod-123-hexanoyl) -D-glucosamine. The safe application and test of drug pharmacokinetic parameters study was performed on intact Wistar male rats. Results. An original 2-N-(6-iodohexanoyl)-D-glucosamine synthesis method was proposed. According to the method, an intermediate synthesis succimide-1-yl 6-iodohexanoate was obtained by the cyclohexanone oxidative cleavage reaction. The radiochemical purity of 2-N-(6-iodo-123-hexanoyl)-D-glucosamine was more than 97%. Conclusion. 2-N-(6-iodohexanoyl)-D-glucosamine was synthesized and iodine-123 labeled. When investigating the proposed radiopharmaceutical safety and pharmacokinetics, it was shown the drug lacks acute toxicity through intravenous injection and is excreted renally by glomerular filtration.

The study of the effect of the combination of quercetin and glucosamine derivatives on the course of the membranous kidney damage in the experiment

The search for effective and affordable drugs for the treatment of chronic kidney disease (CKD) is an important problem in modern medicine. Development of CKD leads to imminent renal failure, disability of patients and the loss of social activity. Today most patients with CKD do not have the opportunity to receive the specialized medical care in Ukraine.Aim. To study experimentally the effect of the combination of quercetin and glucosamine derivatives on the course of the membranous kidney damage in rats.Materials and methods. The studies were performed on the model of doxorubicin nephropathy in 60 rats. In animals the urine was studied; the kidney mass ratio, the glomerular filtration rate and the urea blood level were determined.Results. In the course of the study it was shown that under the effect of the combination of quercetin and glucosamine derivatives studied there was a significant decrease of the level of proteinuria, the kidney mass ratio, blood urea and an increase of the GFR index. It indicates normalization of the functional state of the kidneys. At the same time, by the degree of its effect the combination was superior to the activity of the reference drugs – quercetin and lespefril.Conclusions. The combination of quercetin with glucosamine derivatives studied under the conditions of the doxorubicin nephropathy development in rats has a pronounced nephroprotective effect and is a promising drug for correction of chronic kidney disease.

Experimental study of the effect of combination of quercetin and glucosamine derivatives on the course of renal failure

Topicality. Chronic kidney disease (CKD) is the most significant pathology among diseases of the urinary system. Its course leads to the inevitable development of renal failure, disability of patients and loss of social activity. In this way, the search for effective drugs of correcting CKD is an urgent task of modern pharmacology.Aim. Experimental study of the effect of a combination of quercetin and glucosamine derivatives on the course of renal failure in rats.Materials and methods. The study was performed on the model of mercuric chloride nephropathy in 60 rats. In animals relative diuresis, proteinuria level, glomerular filtration rate, urea content in blood and urine, and urea clearance were determined.Results and discussion. Under the influence of the studied combination of quercetin with glucosamine derivatives there was a significant increase relatively to untreated animals of the relative diuresis, the GFR index and a decrease of the level of proteinuria, which indicates the normalization of the functional state of the kidneys. There was also a positive effect on nitrogen metabolism, which was manifested in a significant decrease of the blood urea level and an increase of the urea clearance rate. At the same time by the degree of influence the tested combination significantly exceeded the activity of the comparative drugs quercetin and lespephril.Conclusions. The investigated combination of quercetin with glucosamine derivatives in conditions of development of sulfa nephropathy in rats exerts a pronounced hypoazotemic and nephroprotective effect and is a promising means of correction of renal failure.

Comparative experimental study of nephroprotective properties of glucosamine derivatives in combination with quercetin

Topicality. Optimization in treatment of chronic kidney disease (CKD) is an important problem in modern medicine. In Ukraine there are about 500 thousands patients with CKD, most of whom can not receive specialized medical care. Therefore, the search for effective drugs with nephroprotective action is an actual task for modern experimental pharmacology.Aim. Comparative study of nephroprotective properties of glucosamine derivatives in combination with quercetin in conditions of membranous nephropathy development in rats.Materials and methods. The study was performed on the model of doxorubicin nephropathy in 119 rats. In animals, the level of proteinuria, the kidney mass coefficient, the glomerular filtration rate were determined and the overall index of nephroprotective activity was calculated.Results and discussion. In the course of the study, it was shown that the combination of glucosamine derivatives with quercetin leads to a significant increase of the nephroprotective activity, which was most pronounced at the study of combinations with a ratio 3 : 1. The highest level of activity, 89.9 %, was shown by a combination containing glucosamine hydrochloride, N-acetylglucosamine and quercetin in a ratio 3 : 3 : 2.Conclusions. Derivatives of glucosamine in combination with quercetin have a nephroprotective effect, which is most pronounced at the ratio of aminosugars and quercetin 3 : 1. It is advisable to further study of the nephroprotective properties of these combinations.

A novel glucosamine derivative with low cytotoxicity enhances chondrogenic differentiation of ATDC5.

Glucosamine (GlcN) is a component of native cartilage extracellular matrix and useful in cartilage repair, but it was limited by toxicity in high concentrations. With the aim of altering bioactive properties of GlcN to reduce the toxicity and to facilitate chondrogenesis for hyaline cartilage formation, we introduced an amino-group modification with double bond into GlcN to produce N-acryloyl-glucosamine (AGA). The cell ATDC5 was chosen to evaluate its cytotoxicity and chondrogenesis capability. Cell proliferation and cytotoxicity assay showed that AGA had significantly reduced the cytotoxicity compared to GlcN, and promoted ATDC5 proliferation. Alcian blue staining and biochemical analysis indicated that AGA enhanced extracellular matrix deposition. Both the mRNA and protein levels of articular cartilage markers, like Collagen II and Aggrecan were up-regulated, as shown by quantitative real-time PCR and immunofluorescence staining. Moreover, the level of fibrocartilage marker Collagen I and hypertrophic marker Collagen Χ weren't significantly changed. Overall, these results demonstrated that the AGA achieved the functional double-bond, reduction in toxicity and enhancement in chondrogenesis could be more potential in cartilage repair.

Synthesis and Study of Molecular Assemblies Formed by 4,6-O-(2-Phenylethylidene)-Functionalized d-Glucosamine Derivatives.

Low-molecular-weight gelators are interesting small molecules with potential applications as advanced materials. Carbohydrate-based small molecular gelators are especially useful because they are derived from renewable resources and are more likely to be biocompatible and biodegradable. Various 4,6-benzylidene acetal protected α-methyl 2-d-glucosamine derivatives have been found to be effective low-molecular-weight gelators. To understand the influence of the 4,6-benzylidene acetal functional group toward molecular self-assembly and to obtain effective molecular gelators, we synthesized and analyzed a new series of d-glucosamine derivatives in which the phenyl group of the acetal is replaced by a benzyl group. The homologation of the acetal protection from aromatic to aliphatic functional groups allows us to probe the effect of increasing structural flexibility on molecular self-assembly and gelation. In this study, nine representative amides and nine urea analogs were synthesized, and their gelation properties were analyzed in a series of organic solvents and aqueous solutions. The resulting amide and urea derivatives are versatile organogelators forming gels in toluene, ethanol, isopropanol, ethylene glycol, and aqueous mixtures of organic solvents. More interestingly, the amide analogs are also effective gelators for pump oil and engine oil. NMR spectroscopy at variable temperatures was used to analyze the molecular assemblies and intermolecular forces. The selected gelators with several drug and dye molecules in DMSO and water were studied for their effectiveness of encapsulation and release of these agents.

Solid-Phase O-Glycosylation with a Glucosamine Derivative for the Synthesis of a Glycopeptide

An efficient synthesis of the O-linked glycosylamino acid Fmoc–l-Ser((Ac)3–β-d-GlcNAc)-OH building block is described. The utility of the method was demonstrated with direct solid-phase O-glycosylation of the hydroxyl group on the amino acid (Ser) side chain of a human α-A crystallin-derived peptide (AIPVSREEK) in nearly quantitative glycosylation yield.

N-acetylglucosamine 2-Epimerase from Pedobacter heparinus: First Experimental Evidence of a Deprotonation/Reprotonation Mechanism

The control of cellular N-acetylmannosamine (ManNAc) levels has been postulated to be an effective way to modulate the decoration of cell surfaces with sialic acid. N-acetylglucosamine 2-epimerase catalyzes the interconversion of N-acetylglucosamine (GlcNAc) and ManNAc. Herein, we describe the cloning, expression, purification and biochemical characterization of an unstudied N-acetylglucosamine 2-epimerase from Pedobacter heparinus (PhGn2E). To further characterize the enzyme, several N-acylated glucosamine derivatives were chemically synthesized, and subsequently used to test the substrate specificity of PhGn2E. Furthermore, NMR studies of deuterium/hydrogen exchange at the anomeric hydroxy group and C-2 positions of the substrate in the reaction mixture confirmed for the first time the postulated epimerization reaction via ring-opening/enolate formation. Site-directed mutagenesis of key residues in the active site showed that Arg63 and Glu314 are directly involved in proton abstraction and re-incorporation onto the substrate. As all mechanistically relevant active site residues also occur in all mammalian isoforms, PhGn2E can serve as a model N-acetylglucosamine 2-epimerase for further elucidation of the active site mechanism in these enzymes.

IKKα inibition by a glucosamine derivative enhances Maspin expression in osteosarcoma cell line

Chronic inflammation has been associated to cancer development by the alteration of several inflammatory pathways, such as Nuclear Factor-κB pathway. In particular, IκB kinase α (IKKα), one of two catalytic subunit of IKK complex, has been described to be associated to cancer progression and metastasis in a number of cancers. The molecular mechanism by which IKKα affects cancer progression is not yet completely clarified, anyway an association between IKKα and the expression of Maspin (Mammary Serine Protease Inhibitor or SerpinB5), a tumor suppressor protein, has been described. IKKα shuttles between cytoplasm and nucleus, and when is localized into the nuclei, IKKα regulates the expression of several genes, among them Maspin gene, whose expression is repressed by high amount of nuclear IKKα. Considering that high levels of Maspin have been associated with reduced metastatic progression, it could be hypothesized that the repression of IKKα nuclear translocation could be associated with the repression of metastatic phenotype. The present study is aimed to explore the ability of a glucosamine derivative, 2-(N-Carbobenzyloxy)l-phenylalanylamido-2-deoxy-β-d-glucose (NCPA), synthesized in our laboratory, to stimulate the production of Maspin in an osteosarcoma cell line, 143B.Immunofluorescence and Western blotting experiments showed that NCPA is able to inhibit IKKα nuclear translocation, and to stimulate Maspin production. Moreover, in association with stimulation of Maspin production we found the decrease of β1 Integrin expression, the down-regulation of metalloproteases MMP-9 and MMP-13 production and cell migration inhibition.Taking in account that β1 Integrin and MMP-9 and -13 have been correlated with the invasiveness of osteosarcoma, considering that NCPA affects the invasiveness of 143B cell line, we suggest that this molecule could affect the osteosarcoma metastatic ability.

Chondroprotective activity of N-acetyl phenylalanine glucosamine derivative on knee joint structure and inflammation in a murine model of osteoarthritis

Osteoarthritis (OA), the most common chronic degenerative joint disease, is characterized by joint structure changes and inflammation, both mediated by the IκB kinase (IKK) signalosome complex. The ability of N-acetyl phenylalanine derivative (NAPA) to increase cartilage matrix components and to reduce inflammatory cytokines, inhibiting IKKα kinase activity, has been observed invitro. The present study aims to further clarify the effect of NAPA in counteracting OA progression, in an invivo mouse model after destabilization of the medial meniscus (DMM). 26 mice were divided into three groups: (1) DMM surgery without treatment; (2) DMM surgery treated after 2weeks with one intra-articular injection of NAPA (2.5mM) and (3) no DMM surgery. At the end of experimental times, both knee joints of the animals were analyzed through histology, histomorphometry, immunohistochemistry and microhardness of subchondral bone (SB) tests. The injection of NAPA significantly improved cartilage thickness (CT) and reduced Chambers and Mankin modified scores and fibrillation index (FI), with weaker MMP13, ADAMTS5, MMP10 and IKKα staining. The microhardness measurements did not shown statistically significant differences between the different groups. NAPA markedly improved the physical structure of articular cartilage while reducing catabolic enzymes, extracellular matrix (ECM) remodeling and IKKα expression, showing to be able to exert a chondroprotective activity invivo.

Exploring the Chiral Recognition of Carboxylates by C2-Symmetric Receptors Bearing Glucosamine Pendant Arms.

Two urea-based receptors containing a glucosamine derivative were synthesized and investigated in terms of their ability to recognize chiral and achiral anions. Both receptors demonstrated a high affinity toward carboxylates in very competitive DMSO/water mixtures. The chiral recognition properties of these compounds were studied using structurally differentiated guests derived from mandelic acid and α-amino acids. We found that receptor 1 exhibits significantly higher enantioselectivities than compound 2 for all anions investigated, with a KS/KR ratio of up to 2. This low enantiodiscrimination in the case of receptor 2 is attributed to a lack of interactions between its sugar moieties and the side chain of chiral anions, due to their inadequate spatial arrangement.

Block synthesis of A (type 2) and B (type 2) tetrasaccharides related to the human ABO blood group system

Herein we report the synthesis of 3-aminopropyl glycosides of A (type 2) and B (type 2) tetrasaccharides via [3 + 1] block scheme. Peracetylated trichloroacetimidates of A and B trisaccharides were used as glycosyl donors. The well-known low reactivity of 4-OH group of N-acetyl-d-glucosamine forced us to test four glucosamine derivatives (3-Bz-1,6-anhydro-GlcNAc and 3-trifluoroacetamidopropyl β-glycosides of 3-Ac-6-Bn-GlcNAc, 3-Ac-6-Bn-GlcN3, and 3-Ac-6-Bn-GlcNAc2) to select the best glycosyl acceptor for the synthesis of type 2 tetrasaccharides. The desired tetrasacchrides were not isolated, when 3-trifluoroacetamidopropyl glycosyde of 3-Ac-6-Bn-GlcNAcβ was glycosylated. Glycosylation of 3-Bz-1,6-anhydro-GlcNAc derivative resulted in α-glycoside as a major product. High stereospecificity was achieved only in the synthesis of B (type 2) tetrasaccharide, when 3-trifluoroacetamidopropyl 3-Ac-6-Bn-GlcNAc2β was applied as the glycosyl acceptor (β/α 5:1), whereas glycosylation with trichloroacetimidate of A trisaccharide was not stereospecific (β/α 1.3:1). Glycosylation of 3-trifluoroacetamidopropyl glycoside of 3-Ac-6-Bn-GlcN3β with trichloroacetimidates of A and B trisaccharides provided the same stereochemical yield (β/α 1.5:1).

Potent anti-proliferative actions of a non-diuretic glucosamine derivative of ethacrynic acid

Ethacrynic acid (EA), a known inhibitor of the neoplastic marker glutathione S-transferase P1 and other GSTs, exerts a weak antiproliferative activity against human cancer cells. The clinical use of EA (Edecrin) as an anticancer drug is limited by its potent loop diuretic activity. In this study, we developed a non-diuretic 2-amino-2-deoxy-d-glucose conjugated EA (EAG) to target tumors cells via the highly expressed glucose transporter 1 (GLUT1). Cell survival assays revealed that EAG had little effect on normal cells, but was cytotoxic 3 to 4.5-fold greater than EA. Mechanistically, the EAG induced selective cell death in cancer cells by inhibiting GSTP1 and generating abundant reactive oxygen species. Furthermore, EAG induced p21cip1 expression and a G2/M cell cycle block irrespective of the p53 gene status in tumor cells. These data encourage the development of new EA analogs.

Comparison of Active Ingredient Consistency of Some Brand and Generically Available Glucosamine Products in Iranian Pharmacies

Glucosamine is used by patients with osteoarthritis and rheumatoid arthritis. Wide variety of simple or complex Glucosamine products are offered with great different prices in Iranian pharmacies. Glucosamine is a small molecule therefore its absorption and bioavailability after oral administration is nearly complete and irrelevant to its formulation. The aim of this report is to consider Glucosamine content of such products and have a comparison to discuss if generics are as effective as brand ones. A total of 15 products containing Glucosamine were assessed to measure Glucosamine content, at first derivatization was performed by adding phenylisothiocyanate. Then phenylthiourea derivative of Glucosamine was determined by spectrophotometer at 240 nm. To ensure non-interference of other substances, Glucosamine content of complex products also were determined with high-performance liquid chromatography (HPLC), C18 column and mobile phase phosphate buffer/acetonitrile (90/10 1 ml/min) with UV detector at 240 nm. Glucosamine compared with amount had been mentioned in label was ranging from 93.22% to 125.14%. Almost 85% of products had active ingredient more than amount claimed on label. Comparison of HPLC analysis with spectrophotometric data indicated acceptable selectivity of spectrophotometric method for Glucosamine determination in two sample products and those containing Glucosamine plus other active ingredients such as chondroitin and methylsulfonylmethane (MSM). One way analysis of variance (ANOVA) performed for comparison of means achieved after several Glucosamine determinations in one brand. In the basis of our study and appropriate bioavailability of Glucosamine, generic products of that also would be acceptable despite lower prices.

ChemInform Abstract: Efficient and Catalyst‐Free Michael Addition of D‐Glucosamines to Acetylenic and Vinylic Compounds: Access to Vinylogous Carbamates of D‐Glucosamine Derivatives.

An efficient, catalyst-free methodology has been developed for the Michael addition reaction between d -glucosamine derivatives and various Michael acceptors. All reactions proceeded smoothly at room temperature to furnish novel sugar-derived vinylogous carbamates in high chemical yields and excellent stereoselectivity.

Efficient and Catalyst-Free Michael Addition of d-Glucosamines to Acetylenic and Vinylic Compounds: Access to Vinylogous Carbamates of d-Glucosamine Derivatives

An efficient, catalyst-free methodology has been developed for the Michael addition reaction between d -glucosamine derivatives and various Michael acceptors. All reactions proceeded smoothly at room temperature to furnish novel sugar-derived vinylogous carbamates in high chemical yields and excellent stereoselectivity.

A robust synthesis of N-glycolyl muramyl dipeptide via azidonitration/reduction.

A novel synthetic route leading to N-glycolyl muramyl dipeptide (MDP), a bacterial glycopeptide of particular interest in studies of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), is described. The synthetic strategy hinges on the alkylation of benzylidene-protected glucal with 2-bromopropionic acid and thus circumvents a challenging and non-reproducible SN2 step at the C-3 position of glucosamine derivatives. The subsequent sequence includes an azidonitration and an unusual azide reduction/acylation step via an aza ylide/oxaphospholidine intermediate. This approach generates a protected N-glycolyl MDP that can be either subjected to a one-step global deprotection or differentially deprotected to obtain further derivatives.

Glucosamine Derivatives Sulfo Disaccharides Co-Working with Klotho

I found sulfo disaccharides which co-working with Klotho. The disaccharides have glucosamine structure and similar structure with hyalunoic acid and chondroitin. Relations of the disaccharide, Klotho, hyaluronic acid, chondroitin, glucosamine with health and anti-ageing were discussed. Klotho makes disaccharide from glucosamin and glucuronic acid and co-works on site with produced disaccharide and gives stable Ca homeostasis and consequent health, anti-aging and long life.