D-glucosamine Derivatives Research Articles

Synthesis of Novel 3-Deoxy-3-thio Derivatives of d-Glucosamine and Their Application as Ligands for the Enantioselective Addition of Diethylzinc to Benzaldehyde.

A series of novel thio-derivatives of d-glucosamine has been synthesized using double inversion procedures at the C3 atom. New compounds were applied as ligands for the diethylzinc addition to benzaldehyde and the products of the addition were obtained with a low to good enantiomeric ratio. The direction and the level of the asymmetric induction were highly dependent on the type of protecting groups on the nitrogen and sulfur atoms.

Para-Methoxybenzylidene Acetal-Protected D-Glucosamine Derivatives as pH-Responsive Gelators and Their Applications for Drug Delivery.

Carbohydrate-based low molecular weight gelators (LMWGs) are compounds with the capability to self-assemble into complex molecular networks within a solvent, leading to solvent immobilization. This process of gel formation depends on noncovalent interactions, including Van der Waals, hydrogen bonding, and π-π stacking. Due to their potential applications in environmental remediation, drug delivery, and tissue engineering, these molecules have emerged as an important area of research. In particular, various 4,6-O-benzylidene acetal-protected D-glucosamine derivatives have shown promising gelation abilities. In this study, a series of C-2-carbamate derivatives containing a para-methoxy benzylidene acetal functional group were synthesized and characterized. These compounds exhibited good gelation properties in several organic solvents and aqueous mixtures. Upon removal of the acetal functional group under acidic conditions, a number of deprotected free sugar derivatives were also synthesized. Analysis of these free sugar derivatives revealed two compounds were hydrogelators while their precursors did not form hydrogels. For those protected carbamates that are hydrogelators, removal of the 4,6-protection will result in a more water-soluble compound that produces a transition from gel to solution. Given the ability of these compounds to form gels from solution or solution from gels in situ in response to acidic environments, these compounds may have practical applications as stimuli-responsive gelators in an aqueous medium. In turn, one hydrogelator was studied for the encapsulation and release of naproxen and chloroquine. The hydrogel exhibited sustained drug release over a period of several days, with the release of chloroquine being faster at lower pH due to the acid lability of the gelator molecule. The synthesis, characterization, gelation properties, and studies on drug diffusion are discussed.

4,6-O-Phenylethylidene Acetal Protected D-Glucosamine Carbamate-Based Gelators and Their Applications for Multi-Component Gels.

The self-assembly of carbohydrate-based low molecular weight gelators has led to useful advanced soft materials. The interactions of the gelators with various cations and anions are important in creating novel molecular architectures and expanding the scope of the small molecular gelators. In this study, a series of thirteen new C-2 carbamates of the 4,6-O-phenylethylidene acetal-protected D-glucosamine derivatives has been synthesized and characterized. These compounds are rationally designed from a common sugar template. All carbamates synthesized were found to be efficient gelators and three compounds are also hydrogelators. The resulting gels were characterized using optical microscopy, atomic force microscopy, and rheology. The gelation mechanisms were further elucidated using 1H NMR spectroscopy at different temperatures. The isopropyl carbamate hydrogelator 7 formed hydrogels at 0.2 wt% and also formed gels with several tetra alkyl ammonium salts, and showed effectiveness in the creation of gel electrolytes. The formation of metallogels using earth-abundant metal ions such as copper, nickel, iron, zinc, as well as silver and lead salts was evaluated for a few gelators. Using chemiluminescence spectroscopy, the metal–organic xerogels showed enzyme-like properties and enhanced luminescence for luminol. In addition, we also studied the applications of several gels for drug immobilizations and the gels showed sustained release of naproxen from the gel matrices. This robust sugar carbamate-derived gelator system can be used as the scaffold for the design of other functional materials with various types of applications.

Synthesis of Carbohydrate Based Macrolactones and Their Applications as Receptors for Ion Recognition and Catalysis.

Glycomacrolactones exhibit many interesting biological properties, and they are also important in molecular recognitions and for supramolecular chemistry. Therefore, it is important to be able to access glycomacrocycles with different sizes and functionality. A new series of carbohydrate-based macrocycles containing triazole and lactone moieties have been designed and synthesized. The synthesis features an intramolecular nucleophilic substitution reaction for the macrocyclization step. In this article, the effect of some common sulfonate leaving groups is evaluated for macrolactonization. Using tosylate gave good selectivity for monolactonization products with good yields. Fourteen different macrocycles have been synthesized and characterized, of which eleven macrocycles are from cyclization of the C1 to C6 positions of N-acetyl D-glucosamine derivatives and three others from C2 to C6 cyclization of functionalized D-glucosamine derivatives. These novel macrolactones have unique structures and demonstrate interesting anion binding properties, especially for chloride. The macrocycles containing two triazoles form complexes with copper sulfate, and they are effective ligands for copper sulfate mediated azide-alkyne cycloaddition reactions (CuAAC). In addition, several macrocycles show some selectivity for different alkynes.

Ultrasonication-Assisted Synthesis of a d-Glucosamine-Based β-CD Inclusion Complex and Its Application as an Aqueous Heterogeneous Organocatalytic System.

For the first time, an inclusion complex has been crafted between a carbohydrate-based molecule and a β-cyclodextrin (CD) hydrophobic cavity for asymmetric catalytic applications. This novel d-glucosamine-based inclusion compound has been synthesized in high yields using an innovative and proficient acoustic cavitation technology and well characterized using various techniques, such as infrared spectroscopy, nuclear magnetic resonance spectroscopy, ultraviolet-visible spectroscopy, thermogravimetric analysis, scanning electron microscopy, and other spectroscopic techniques. It was observed that the inclusion of a d-glucosamine derivative into the hydrophobic cavity of β-CD increased its surface area and thermal stability. This catalytic system worked well in water for the direct aldol reaction to afford the products in excellent yields with high diastereo- and enantioselectivities.

Synthesis of the tetrasaccharide repeating unit of the O-antigen from Pseudomonas putida BIM B-1100 having rare D-Quip3NAc

Chemical synthesis of the complex tetrasaccharide repeating unit of the O-antigen from Pseudomonas putida BIM B-1100 is accomplished in the form of its 2-aminoethyl glycoside to leave the scope for further glycoconjugate formation without hampering the anomeric stereochemistry. A [2 + 2] strategy is followed to complete the total synthesis and a late stage TEMPO mediated oxidation is used to install the required uronic acid. A radical mediated 6-deoxygenation with subsequent protecting group manipulation strategy is used for the preparation of the rare D-FucpNAc and D-Quip3NAc derivatives from suitable d-glucosamine derivatives.

A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution

The title compounds were synthesized from the selectively protected N-acylated d-glucosamine derivatives, containing α-halo carboxylic acid moieties, via intramolecular 3-O-alkylation. It was found that if the starting compound contains asymmetric electrophilic center, isomuramic acid derivatives were mainly formed, regardless of the configuration of the electrophilic carbon atom. An explanation for the observed stereochemical results was proposed on the basis of the analysis of steric interactions in the molecules of the starting compounds, as well as using the concept of anchimeric assistance. It was shown that N-acetylation of the obtained lactam derivatives and subsequent methanolysis under mild conditions led to the selective cleavage of δ-lactam ring resulting in the formation of the corresponding ester derivatives of N-acetylmuramic acid or its analogues in high yields.

Novel 99mTc-Labeled Glucose Derivative for Single Photon Emission Computed Tomography: A Promising Tumor Imaging Agent.

In this study, a d-glucosamine derivative with an isonitrile group (CN5DG) was synthesized and it was chosen to coordinate with 99mTc for preparing 99mTc-CN5DG. 99mTc-CN5DG could be readily obtained with high radiochemical purity (>95%) and had great in vitro stability and metabolic stability in urine. The radiotracer demonstrated a positive response to the administration of glucose and insulin in S180 and A549 tumor cells in vitro, suggesting the mechanism of 99mTc-CN5DG into tumor cells was related to glucose transporters. Biodistribution studies in mice bearing A549 xenografts showed 99mTc-CN5DG had a high tumor uptake and high tumor-to-background ratios. SPECT/CT images further supported its ability for tumor imaging. As a cheap, conveniently made and widely available probe, 99mTc-CN5DG would become a potential "working horse" and be a breakthrough in 99mTc-labeled radiopharmaceuticals for tumor detection.

PO-515 Novel water-solube [60]fullerene nanotherapeutic agent for pancreatic cancer treatment

IntroductionThe rapid development of nanotechnology is of great interest to researchers focused on translational medicine and novel targeted cancer treatment. This novel ‘nano’ approach has been used by medicinal chemist to design potential drugs which could easily broke almost any biological barriers. It has been published earlier, that engineered nanoparticles, including carbon nanomaterials, could enter tumours via their leaky vessels system and retain due to a weak drainage in the tumour microenvironment. Here we prestent the synthesis of water-soluble d-glucosamine derivatives used as drug delivery tools and selective FYN and LCK kinase inhibitor for pancreatic cancer treatment.Material and methodsHuman PDAC line PANC-1, ASCP-1 and PAN-O2 was obtained from American Type Culture Collection (ATCC, USA) or from National Cancer Institute. Nuclear magnetic resonance spectra were measured on a Bruker 400 MHz NMR Spectrometer with TMS as an internal standard. MS datasets were collected using Autoflex II MALDI-TOF mass spectrometer, and MS electrospray ionisation time-of-flight (ESI-microTOF) mass spectrometer, both instruments from Bruker Daltonics Inc (Fremont, CA). High-resolution spectra were performed using Shimadzu IT-ToF LC-MS System and flash chromatography was performed using Agilent 971-FP Flash Purification System.Results and discussionsTo date we have designed and synthesised three glucosamine-based, water-soluble [60]fullerene derivatives with high wate solubility up to 400 mg/ml. It was observed that all fullerenes form two aggregate fraction 20–30 nm and 400–500 nm. Initial dark cytotoxicity studies on pancreatic cancer cell line PANC1 have been carried out using flow cytometry and propidium iodide (PI) apoptosis staining. It has been shown that all 3 glycofullerenes are non-toxic even in high concentrations (up to 1 mg/ml, incubation 3 and 24 hours). Moreover, synthesised [60]fullerene derivative localises preferentially in the nucleus of PSC cells, with some localization in the cell cytoplasm.ConclusionOur results show predominant cellular nuclear internalisation of our novel hexakis glucosamine C60 derivative. In addition, synthesised nanotherapeutic is inherently non-toxic up to concentrations of 1 mg/ml, and displays strong photodynamic cytotoxic behaviour, when illuminated with both blue and green light. Moreover designed nanotherapeutic is showing selective inhibition to two kinases FYN A and LCK.MS thanks National Science Centre (Poland) for the support (grant UMO- 2016/23/D/NZ7/00912)

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.

Synthesis and self-assembling properties of 4,6−O-benzylidene acetal protected D-glucose and D-glucosamine β−1,2,3−triazole derivatives

Sugar based low molecular weight gelators (LMWGs) are useful small molecules that can form reversible supramolecular gels with many applications. Selective functionalization of common monosaccharides has resulted in several classes of effective LMWGs. Recently we found that certain peracetylated sugars containing anomeric triazole functional groups were effective gelators. In this study we synthesized two series of 4,6-O-benzylidene acetal protected β-1,2,3-triazolyl glycoside of D-glucose and N-acetyl D-glucosamine derivatives and evaluated their self-assembling properties in a few solvents. Several gelators were obtained and the gelation properties of these compounds rely on the structures of the 4-triazolyl substituents. Typically, alkyl derivatives resulted in effective gelation in organic solvents and aqueous mixtures of ethanol and dimethyl sulfoxide. But further acetylation of these compounds resulted in loss of gelation properties. The gels were characterized using optical microscopy, rheology, and FTIR spectroscopy. We also analyzed the molecular assemblies, using 1H NMR spectroscopy to probe the influences of the hydroxyl, amide, and triazole functional groups. Naproxen was used as a model drug and it formed co-gels with compound 25 in DMSO water mixtures. Using UV spectroscopy, we found that naproxen was slowly released from the gel to aqueous solution. The general structure and gelation trend obtained here can be useful in designing sugar based biomaterials. We expect that further structural optimization can lead to more effective gelators that are compatible with different drug molecules for encapsulation and sustained release.

Synthesis and biological evaluation of water-soluble derivatives of chiral gossypol as HIV fusion inhibitors targeting gp41

A series of novel or known water-soluble derivatives of chiral gossypol were synthesized and screened in vitro for their anti-HIV-1 activity. (−)-gossypol derivative was more active against HIV-1 than the corresponding (+)-gossypol derivative, respectively. Among these derivatives, d-glucosamine derivative of (−)-gossypol, oligopeptide derivative of (−)-gossypol and taurine derivative of (−)-gossypol, such as compounds 1a, 3a and 14a, showed significant inhibitory activities against HIV-1 replication, HIV-1 mediated cell-cell fusion and HIV gp41 6-helix bundle formation as some amino acid derivatives of (−)-gossypol.

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.

Synthesis of Lactames of Muramic, Isomuramic and Normuramic Acids by Intramolecular Alkylation and Employment of 4-OH Derivatives of d-Glucosamine Containing a Cyclic Protective δ-Lactame Group as a Reactive Glycosyl Acceptor

Synthesis of Lactames of Muramic, Isomuramic and Normuramic Acids by Intramolecular Alkylation and Employment of 4-OH Derivatives of d-Glucosamine Containing a Cyclic Protective δ-Lactame Group as a Reactive Glycosyl Acceptor

Synthesis and in vitro cytotoxicity of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine.

Background: Derivatives of D-glucosamine and D-galactosamine represent an important family of the cell surface glycan components and their fluorinated analogs found use as metabolic inhibitors of complex glycan biosynthesis, or as probes for the study of protein–carbohydrate interactions. This work is focused on the synthesis of acetylated 3-deoxy-3-fluoro, 4-deoxy-4-fluoro and 3,4-dideoxy-3,4-difluoro analogs of D-glucosamine and D-galactosamine via 1,6-anhydrohexopyranose chemistry. Moreover, the cytotoxicity of the target compounds towards selected cancer cells is determined.Results: Introduction of fluorine at C-3 was achieved by the reaction of 1,6-anhydro-2-azido-2-deoxy-4-O-benzyl-β-D-glucopyranose or its 4-fluoro analog with DAST. The retention of configuration in this reaction is discussed. Fluorine at C-4 was installed by the reaction of 1,6:2,3-dianhydro-β-D-talopyranose with DAST, or by fluoridolysis of 1,6:3,4-dianhydro-2-azido-β-D-galactopyranose with KHF2. The amino group was introduced and masked as an azide in the synthesis. The 1-O-deacetylated 3-fluoro and 4-fluoro analogs of acetylated D-galactosamine inhibited proliferation of the human prostate cancer cell line PC-3 more than cisplatin and 5-fluorouracil (IC50 28 ± 3 μM and 54 ± 5 μM, respectively).Conclusion: A complete series of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine is now accessible by 1,6-anhydrohexopyranose chemistry. Intermediate fluorinated 1,6-anhydro-2-azido-hexopyranoses have potential as synthons in oligosaccharide assembly.

Combined experimental/theoretical study of d-glucosamine promoted Ullmann-type C–N coupling catalyzed by copper(i): does amino really count?

Ullmann type C–N coupling reaction catalyzed by copper(i) with d-glucosamine derivatives as promoters was studied by means of combined experimental/theoretical investigation.

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.

Influence of a δ-lactam-type cyclic protecting group on the reactivity of a 4-hydroxy glycosyl acceptor derivative of d-glucosamine

A new 4-hydroxy glycosyl acceptor derivative of d-glucosamine containing a lactam-type N-protecting group was synthesized. The new glycosyl acceptor containing a hydroxy group at the C(4) atom was shown to be highly reactive in the glycosylation despite the presence of the amide (lactam) NH group. The high efficiency of the synthesized acceptor derivative is apparently attributed to the transformation of the (Z)-amide function that is present in amino sugar derivatives containing an acyclic acyl N-protecting group into the (E)-amide group in derivatives containing a lactam-type cyclic N-protecting group. This transformation leads to a radical change in the hydrogen bonding conditions and the character of molecular association. The observed effect can be employed to design new N-protecting groups providing high reactivity of glycosyl acceptor derivatives of D-glucosamine.

Synthesis and characterization of pH responsive D-glucosamine based molecular gelators.

Small molecular gelators are a class of compounds with potential applications for soft biomaterials. Low molecular weight hydrogelators are especially useful for exploring biomedical applications. Previously, we found that 4,6-O-benzylidene acetal protected D-glucose and D-glucosamine are well-suited as building blocks for the construction of low molecular weight gelators. To better understand the scope of D-glucosamine derivatives as gelators, we synthesized and screened a novel class of N-acetylglucosamine derivatives with a p-methoxybenzylidene acetal protective group. This modification did not exert a negative influence on the gelation. On the contrary, it actually enhanced the gelation tendency for many derivatives. The introduction of the additional methoxy group on the phenyl ring led to low molecular weight gelators with a higher pH responsiveness. The resulting gels were stable at neutral pH values but degraded in an acidic environment. The release profiles of naproxen from the pH responsive gels were also analyzed under acidic and neutral conditions. Our findings are useful for the design of novel triggered release self-assembling systems and can provide an insight into the influence of the the structure on gelation.

2,3,4,6-tetra-O-Acetyl-D-Gluconic Acid: Crystal Structure and Application in the Synthesis of N-(D-gluconyl) Derivatives of D-Glucosamine

2,3,4,6-tetra-O-Acetyl-D-gluconic acid was synthesized and coupled with 1,3,4, 6-tetra-O-acetyl-2-amino-2-deoxy-β-D-glucopyranose and diosgenyl 3,4,6-tri-O-acetyl-2-amino-2-deoxy-β-D-glucopyranoside to afford N-gluconyl derivatives of diosgenyl 2-amino-2-deoxy-D-glucopyranoside using the methods of solution-phase peptide synthesis. Both coupling reactions suffered from acetyl O→N migration, which caused the N-acetyl derivatives to be formed together with the N-(D-gluconyl) derivatives of D-glucosamine. Additionally, single-crystal X-ray diffraction and high-resolution NMR spectral data for 2,3,4,6-tetra-O-acetyl-D-gluconic acid were analyzed to reveal that this acyclic carbohydrate has adopted the 2G− conformation instead of a typical zigzag conformation. The planarity and cis geometry of the acetoxyl groups are demonstrated.