D-glucose Derivatives Research Articles

NAD+ -Dependent Dehydrogenase PctP and Pyridoxal 5'-Phosphate Dependent Aminotransferase PctC Catalyze the First Postglycosylation Modification of the Sugar Intermediate in Pactamycin Biosynthesis.

The unique five-membered aminocyclitol core of the antitumor antibiotic pactamycin originates from d-glucose, so unprecedented enzymatic modifications of the sugar intermediate are involved in the biosynthesis. However, the order of the modification reactions remains elusive. Herein, we examined the timing of introduction of an amino group into certain sugar-derived intermediates by using recombinant enzymes that were encoded in the pactamycin biosynthesis gene cluster. We found that the NAD+ -dependent alcohol dehydrogenase PctP and pyridoxal 5'-phosphate dependent aminotransferase PctC converted N-acetyl-d-glucosaminyl-3-aminoacetophonone into 3'-amino-3'-deoxy-N-acetyl-d-glucosaminyl-3-aminoacetophenone. Further, N-acetyl-d-glucosaminyl-3-aminophenyl-β-oxopropanoic acid ethyl ester was converted into the corresponding 3'-amino derivative. However, PctP did not oxidize most of the tested d-glucose derivatives, including UDP-GlcNAc. Thus, modification of the GlcNAc moiety in pactamycin biosynthesis appears to occur after the glycosylation of aniline derivatives.

High pressure studies on structural and secondary relaxation dynamics in silyl derivative of D-glucose

In this paper, broadband dielectric spectroscopy was applied to investigate molecular dynamics of 1,2,3,4,6-penta-O-(trimethylsilyl)-D-glucopyranose (S-GLU) at ambient and elevated pressures. Our studies showed that apart from the structural relaxation, one well resolved asymmetric secondary process (initially labeled as β) is observed in the spectra measured at p = 0.1 MPa. Analysis with the use of the coupling model and criterion proposed by Ngai and Capaccioli indicated that the β-process in S-GLU is probably a Johari-Goldstein relaxation of intermolecular origin. Further high pressure experiments demonstrated that there are in fact two secondary processes contributing to the β-relaxation. Therefore, one can postulate that the coupling model is a necessary, but not sufficient criterion to identify the true nature of the given secondary relaxation process. The role of pressure experiments in better understanding of the molecular origin of local mobility seems to be much more important. Interestingly, our research also revealed that the structural relaxation in S-GLU is very sensitive to compression. It was reflected in an extremely high pressure coefficient of the glass transition temperature (dTg/dp = 412 K/GPa). According to the literature data, such a high value of dTg/dp has not been obtained so far for any H-bonded, van der Waals, or polymeric glass-formers.

Synthesis and preliminary biological assay of uridine glycoconjugate derivatives containing amide and/or 1,2,3-triazole linkers

A series of UDP-sugar analogues was synthesized and their preliminary biological activity was evaluated. Glycoconjugates of uridine 1 and 2 were synthesized by condensation of uridine-5′-carboxylic acid and 1-amino sugars derivatives of d-glucose and d-galactose, glycoconjugates 3 and 4 were synthesized by azide-alkyne 1,3-dipolar cycloaddition (CuAAC) of 1-azido sugars and propargylamide derivatives of uridine while glycoconjugates 5 and 6 were synthesized by CuAAC of propargyl β-O-glycosides and 5′-azido uridine. Evaluation of inhibitory activity of compounds 1–6 against commercially available β-1,4-galactosyltransferase I (β4GalT) show that compound 5 inhibited the enzyme in µmolar range. Additionally, the antitumor activity of the obtained glycoconjugates 1–6 were tested using MTT assay.

Corrosion inhibition of mild steel in 1M HCl by D-glucose derivatives of dihydropyrido [2,3-d:6,5-d\u2032] dipyrimidine-2, 4, 6, 8(1H,3H, 5H,7H)-tetraone

D-glucose derivatives of dihydropyrido-[2,3-d:6,5-d′]-dipyrimidine-2, 4, 6, 8(1H,3H, 5H,7H)-tetraone (GPHs) have been synthesized and investigated as corrosion inhibitors for mild steel in 1M HCl solution using gravimetric, electrochemical, surface, quantum chemical calculations and Monte Carlo simulations methods. The order of inhibition efficiencies is GPH-3 > GPH-2 > GPH-1. The results further showed that the inhibitor molecules with electron releasing (-OH, -OCH3) substituents exhibit higher efficiency than the parent molecule without any substituents. Polarization study suggests that the studied compounds are mixed-type but exhibited predominantly cathodic inhibitive effect. The adsorption of these compounds on mild steel surface obeyed the Langmuir adsorption isotherm. SEM, EDX and AFM analyses were used to confirm the inhibitive actions of the molecules on mild steel surface. Quantum chemical (QC) calculations and Monte Carlo (MC) simulations studies were undertaken to further corroborate the experimental results.

Neuroprotective Caffeoylquinic Acid Derivatives from the Flowers of Chrysanthemum morifolium

Three new caffeoylquinic acid derivatives, chrysanthemorimic acids A-C (1-3), and 11 known compounds (4-14) were isolated and characterized from the flowers of Chrysanthemum morifolium. Their structures were confirmed by spectroscopic data as well as by comparison of the experimental and calculated electronic circular dichroism spectra. Chrysanthemorimic acids A-C possess a rare 8-oxa-bicyclo[3.2.1]oct-3-en-2-one ring that is formed through a [5+2] cycloaddition of caffeoylquinic acid with a d-glucose derivative. Compounds 1-3, 6-8, 12, and 13 displayed significant effects against hydrogen peroxide-induced neurotoxicity in SH-SY5Y cells at 10 μM.

Dodecyl Amino Glucoside Enhances Transdermal and Topical Drug Delivery via Reversible Interaction with Skin Barrier Lipids.

Skin permeation/penetration enhancers are substances that enable drug delivery through or into the skin. To search for new enhancers with high but reversible activity and acceptable toxicity, we synthesized a series of D-glucose derivatives, both hydrophilic and amphiphilic. Initial evaluation of the ability of these sugar derivatives to increase permeation and penetration of theophylline through/into human skin compared with a control (no enhancer) or sorbitan monolaurate (Span 20; positive control) revealed dodecyl 6-amino-6-deoxy-α-D-glucopyranoside 5 as a promising enhancer. Furthermore, this amino sugar 5 increased epidermal concentration of a highly hydrophilic antiviral cidofovir by a factor of 7. The effect of compound 5 on skin electrical impedance suggested its direct interaction with the skin barrier. Infrared spectroscopy of isolated stratum corneum revealed no effect of enhancer 5 on the stratum corneum proteins but an overall decrease in the lipid chain order. The enhancer showed acceptable toxicity on HaCaT keratinocyte and 3T3 fibroblast cell lines. Finally, transepidermal water loss returned to baseline values after enhancer 5 had been removed from the skin. Compound 5, a dodecyl amino glucoside, is a promising enhancer that acts through a reversible interaction with the stratum corneum lipids.

Synthesis and photophysical properties of a bichromophoric system hosting a disaccharide spacer.

The synthesis of an efficient energy donor-acceptor system is reported, together with its photophysical properties. The bichromophoric species has been conceived to show potentialities for biological applications since a biocompatible disaccharide spacer, constituted of d-galactose and d-glucose derivatives, was used in compound 12 to connect two BODIPY units with different absorption/emission properties. The luminescence spectrum in acetonitrile of 12 shows an intense fluorescence band with a maximum at about 770 nm that is almost identical to that of the lowest-energy BODIPY, regardless of the excitation wavelength used. The quantum yield is 0.2 with an excited state lifetime of 2.5 ns. Excitation and ultrafast transient absorption spectroscopy demonstrates that a very efficient energy transfer takes place in 12 from the highest-energy lying BODIPY subunit to the lowest-energy emissive BODIPY moiety, with a time constant of about 31 ps. Noteworthily, the emission of 12 falls in the near infrared window, suitable for potential biological applications.

Synthesis of the ABCDEF-ring of ciguatoxin 3C

The synthesis of the ABCDEF-ring of ciguatoxin 3C was achieved via a route that included anion coupling of a dimethyldithioacetal mono-S-oxide derivative corresponding to the AB-ring and an aldehyde corresponding to the EF-ring, followed by cyclization using reductive etherification. The AB-ring was synthesized from a known d-glucose derivative based on ring-closing olefin metathesis, and the EF-ring was prepared by a process employing chirality-transferring Ireland-Claisen rearrangement and ring-closing olefin metathesis.

Development and validation of a capillary electrophoresis method for the characterization of sulfoethyl cellulose.

To characterize sulfoethyl cellulose el samples, a capillary electrophoresis method was developed and validated sulfoethyl cellulose el was hydrolyzed, and the resulting d-glucose derivatives were analyzed after reductive amination with 4-aminobenzoic acid using 150 mM boric acid, pH 9.5, as background electrolyte at 20°C and a voltage of 28 kV. Peak identification was derived from capillary electrophoresis with mass spectrometry using 25 mM ammonia adjusted to pH 6.2 by acetic acid as electrolyte. Besides mono-, di-, and trisulfoethyl d-glucose small amounts of disaccharides could be identified resulting from incomplete hydrolysis. The linearity of the borate buffer-based capillary electrophoresis method was evaluated using d-glucose in the concentration range of 3.9-97.5 μg/mL, while limits of detection and quantification derived from the signal-to-noise ratio of 3 and 10 were 0.4 ± 0.1 and 1.2 ± 0.3 μg/mL, respectively. Reproducibility and intermediate precision were determined using a hydrolyzed sulfoethyl cellulose el sample and ranged between 0.2 and 8.8% for migration times and between 0.3 and 10.4% for peak area. The method was applied to the analysis of the degree of substitution of synthetic sulfoethyl cellulose el samples obtained by variation of the synthetic process and compared to data obtained by elemental analysis.

Four Different Regioisomeric Polycarbonates Derived from One Natural Product, d-Glucose

Strategies for the preparation of polycarbonates, derived from the natural product d-glucose, which have the potential to degrade back into their bioresorbable starting material and CO2, were developed. By employing established carbohydrate protection/deprotection chemistries, two d-glucose derivatives, methyl 4,6-O-benzylidene-α-d-glucopyranoside or methyl α-d-glucopyranoside, were converted into four different regioisomeric diol monomers, i.e., 1,4-, 1,6-, 2,6-, or 3,6-diols, as confirmed by nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, and mass spectrometry. Each type of regioisomeric monomer was then employed in a condensation polymerization with phosgene, generated in situ from triphosgene, as a comonomer, in the presence of pyridine, to produce four types of polycarbonates with different backbone regio-connectivity, as characterized by size exclusion chromatography, NMR spectroscopy, and IR spectroscopy. Interestingly, their thermal properties, i.e., glass transition tem...

Syntheses of D-Glucose Derivatives Emitting Blue Fluorescence through Pd-Catalyzed C-N Coupling.

Green fluorescence-emitting D-glucose derivatives such as 2-NBDG have been effectively used to monitor D-glucose uptake through glucose transporters GLUTs at the single cell level. By contrast, GLUT-permeable D-glucose derivatives emitting blue fluorescence have been long awaited. A glucose tracer, 2-deoxy-2-(2-oxo-2H-chromen-7-yl)amino-D-glucose (CDG) (1), together with related compounds have been synthesized by Pd-catalyzed C-N coupling. Of these, CDG (1) is a promising blue fluorescence-emitting candidate molecule that may enter into mammalian cells through GLUTs.

Concise and highly stereoselective syntheses of d-fagomine and 2-epi-fagomine

Highly stereoselective total syntheses of polyhydroxylated piperidines d-fagomine and 2-epi-fagomine have been developed starting from 3,4,6-tri-O-benzyl-d-glucal which is a derivative of d-Glucose. Key steps in the synthesis of these azasugars involved N-Boc-protected amine preparation from oxime followed by stereo specific iodination of alcohol and cascade cyclization triggered by N-Boc deprotection.

Abstract B48: Optical toolbox for in vivo analysis of glucose uptake, vascular oxygenation, and mitochondrial membrane potential in breast cancer

Abstract The goal of this work is development of a fast and repeatable optical assay that uses a novel combination of fluorophores and endogenous contrast to report on the metabolic phenotype of cancers in vivo. The proportions of ATP generated by glycolysis and oxidative phosphorylation relate to inherent tumor behaviors that affect treatment response. The need for instruments measuring metabolic endpoints is demonstrated by the widespread use of Seahorse extracellular flux analyzers in cancer research. The assays provide valuable insight into two primary arms of cellular metabolism by reporting on extracellular acidification rate (ECAR) related to glycolysis and oxygen consumption rate (OCR) related to mitochondrial respiration [1]. The ratio OCR/ECAR obtained by Seahorse was used to compare a panel of breast cancer cell lines and show that basal subtypes were often highly glycolytic, which suggested better therapeutic outcome [2]. While the Seahorse is an excellent research tool, the technique requires special cell preparation and continual testing of cell media, and is therefore not applicable in vivo. Being able to measure both oxidative and glycolytic metabolism in vivo in a repeatable way would aid the identification of appropriate therapies based on tumor phenotype. We developed an in vivo metabolic imaging strategy for use on a dorsal skin flap chamber model and are developing tools to analyze the same endpoints in solid tumors [3-5]. Vascular oxygen saturation (SO2) is calculated using endogenous absorption contrast from oxy- and deoxy- hemoglobins (520-620nm in 10nm increments). Glucose uptake is measured using a fluorescent D-glucose derivative (2-NBDG, Ex/Em 470/525nm). We have previously optimized 2-NBDG imaging [4], and have recently incorporated a fluorescent cationic dye (TMRE, Ex/Em 545/590nm) to report on mitochondrial membrane potential (MMP). Delivery-corrected 2-NBDG was measured 60 minutes post-injection (2-NBDG60/RD) and TMRE was measured 50 minutes post-injection (TMRE50) in dorsal windows containing metastatic (4T1) or non-metastatic (4T07, 67NR) sibling tumor lines. When images were segmented into spatial maps and parsed by regional SO2, phenotypic differences between metastatic and nonmetastatic tumors emerged. To increase the range of SO2, some animals were subject to hypoxia. In 4T1 tumors, glucose uptake decreased significantly (p<0.01 for 0<SO2<10 vs. 40<SO2<60) and MMP increased slightly as SO2 increased. However, in 4T07 and 67NR tumors there is minimal change in glucose uptake or MMP with changes in SO2. Differences in global averages were also apparent. Glucose uptake was significantly increased in 4T1 relative to either 4T07 (p<0.01) or nontumor tissue (p<0.02). Interestingly, glucose uptake was comparable between 4T07 and nontumor. On the other hand, MMP was increased in 67NR (p<0.02) and 4T1 (p<0.01) relative to nontumor, suggesting generally increased oxidative metabolism in tumors. MMP was indistinguishable for 67NR and 4T1. Average SO2 was comparable across groups. Strikingly, the ratio of average glucose uptake/average MMP was 0.45 for metastatic and 0.12 for nonmetastatic tumors. These data indicate the importance of considering both the overall quantity of metabolic demand and the ratio of glycolytic and oxidative metabolism. In conclusion, our data show a shift toward glycolysis in a metastatic relative to a nonmetastatic sibling breast cancer line, demonstrating the potential of our method to identify unique metabolic phenotypes in vivo. Our future efforts focus on transitioning the assay into an optical spectroscopy platform appropriate for long-term monitoring of tumor growth or therapy response. [1] Seahorse Bioscience online [2] Dennison, Clin Cancer Res 2013 [3] Rajaram, PLOS ONE 2013 [4] Frees, PLOS ONE 2014 [5] Rajaram, PLOS ONE 2015 Citation Format: Amy Frees Martinez, Samuel S. McCachren, III, Narasimhan Rajaram, Mark W. Dewhirst, Nimmi Ramanujam. Optical toolbox for in vivo analysis of glucose uptake, vascular oxygenation, and mitochondrial membrane potential in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B48.

Uptake of a fluorescent L-glucose derivative 2-NBDLG into three-dimensionally accumulating insulinoma cells in a phloretin-sensitive manner.

Of two stereoisomers of glucose, only d- and not l-glucose is abundantly found in nature, being utilized as an essential fuel by most organisms. The uptake of d-glucose into mammalian cells occurs through glucose transporters such as GLUTs, and this process has been effectively monitored by a fluorescent d-glucose derivative 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose (2-NBDG) at the single cell level. However, since fluorescence is an arbitrary measure, we have developed a fluorescent analog of l-glucose 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-l-glucose (2-NBDLG), as a negative control substrate for more accurately identifying the stereoselectivity of the uptake. Interestingly, a small portion of mouse insulinoma cells MIN6 abundantly took up 2-NBDLG at a late culture stage (≳10 days in vitro, DIV) when multi-cellular spheroids exhibiting heterogeneous nuclei were formed, whereas no such uptake was detected at an early culture stage (≲6 DIV). The 2-NBDLG uptake was persistently observed in the presence of a GLUT inhibitor cytochalasin B. Neither d- nor l-glucose in 50 mM abolished the uptake. No significant inhibition was detected by inactivating sodium/glucose cotransporters (SGLTs) with Na+-free condition. To our surprise, the 2-NBDLG uptake was totally inhibited by phloretin, a broad spectrum inhibitor against transporters/channels including GLUTs and aquaporins. From these, a question might be raised if non-GLUT/non-SGLT pathways participate in the 2-NBDLG uptake into spheroid-forming MIN6 insulinoma. It might also be worthwhile investigating whether 2-NBDLG can be used as a functional probe for detecting cancer, since the nuclear heterogeneity is among critical features of malignancy.Electronic supplementary materialThe online version of this article (doi:10.1007/s13577-015-0125-3) contains supplementary material, which is available to authorized users.

Acylation of D-Glucose Derivatives over C5H5N: Spectral Characterization and in vitro Antibacterial Activities

Methyl α-D-glucopyranoside was easily prepared by the treatment of D-glucose with anhydrous methyl alcohol in presence of hydrogen chloride at freezing temperature in good yield. Then N-acetylsulfanilylation of methyl α-D-glucopyranoside has been carried out by the direct method and afforded the 6-O-N-acetylsulfanilyl derivative in an excellent yield. In order to obtain newer products, the 6-O-N-acetylsulfanilyl derivative was further transformed to a series of 2,3,4-tri-O-acyl derivatives containing a wide variety of functionalities in a single molecular framework. The chemical structures of the newly synthesized compounds were elucidated by Fourier Transform Infrared spectroscopy (FTIR), H-NMR (Proton nuclear magnetic resonance) spectroscopy elemental and physicochemical properties analysis. All the newly synthesized D-glucose derivatives were tested for their in vitro antibacterial activity against some human pathogenic bacterial strains. The study revealed that a good number of acylated products exhibited promising antibacterial activities. It is expected that the acylated derivatives of D-glucose may be considered as a potential source for developing new and better antibacterial agents against a number of pathogenic organism.

Copolyesters made from 1,4-butanediol, sebacic acid, and D-glucose by melt and enzymatic polycondensation.

Biotechnologically accessible 1,4-butanediol and vegetal oil-based diethyl sebacate were copolymerized with bicyclic acetalized D-glucose derivatives (Glux) by polycondensation both in the melt at high temperature and in solution at mild temperature mediated by polymer-supported Candida antarctica lipase B (CALB). Two series of random copolyesters (PB(x)Glux(y)Seb and PBSeb(x)Glux(y)) were prepared differing in which d-glucose derivative (Glux diol or Glux diester) was used as comonomer. The three parent homopolyesters PBSeb, PBGlux, and PGluxSeb were prepared as well. Both methods were found to be effective for polymerization although significant higher molecular weights were achieved by melt polycondensation. The thermal properties displayed by the copolyesters were largely dependent on composition and also on the functionality of the replacing Glux unit. The thermal stability of PBSeb was retained or even slightly increased after copolymerization with Glux, whereas crystallinity and melting temperature were largely depressed. On the contrary, the glass-transition temperature noticeably increased with the content in Glux units. PGluxSeb distinguished in displaying both T(g) and T(m) higher than PBSeb because a different crystal structure is adopted by this homopolyester. The hydrolytic degradability of PBSeb in water was enhanced by copolymerization, in particular, when biodegradation was assisted by lipases.

Synthesis of ether-linked [60]fullerene glycoconjugates by nucleophilic cyclopropanation

AbstractEthyl acetoacetate-sugar derivatives were prepared by standard alkylation of primary or secondary hydroxyls of diacetonide-protected sugars with ethyl 4-chloroacetoacetate. The obtained d-fructose, d-galactose, d-glucose and d-allose derivatives were conjugated to C

Delivery-corrected imaging of fluorescently-labeled glucose reveals distinct metabolic phenotypes in murine breast cancer.

When monitoring response to cancer therapy, it is important to differentiate changes in glucose tracer uptake caused by altered delivery versus a true metabolic shift. Here, we propose an optical imaging method to quantify glucose uptake and correct for in vivo delivery effects. Glucose uptake was measured using a fluorescent D-glucose derivative 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxy-D-glucose (2-NBDG) in mice implanted with dorsal skin flap window chambers. Additionally, vascular oxygenation (SO2) was calculated using only endogenous hemoglobin contrast. Results showed that the delivery factor proposed for correction, “RD”, reported on red blood cell velocity and injected 2-NBDG dose. Delivery-corrected 2-NBDG uptake (2-NBDG60/RD) inversely correlated with blood glucose in normal tissue, indicating sensitivity to glucose demand. We further applied our method in metastatic 4T1 and nonmetastatic 4T07 murine mammary adenocarcinomas. The ratio 2-NBDG60/RD was increased in 4T1 tumors relative to 4T07 tumors yet average SO2 was comparable, suggesting a shift toward a “Warburgian” (aerobic glycolysis) metabolism in the metastatic 4T1 line. In heterogeneous regions of both 4T1 and 4T07, 2-NBDG60/RD increased slightly but significantly as vascular oxygenation decreased, indicative of the Pasteur effect in both tumors. These data demonstrate the utility of delivery-corrected 2-NBDG and vascular oxygenation imaging for differentiating metabolic phenotypes in vivo.

Design, synthesis and bioactivity of N-glycosyl-N'-(5-substituted phenyl-2-furoyl) hydrazide derivatives.

Condensation products of 5-substituted phenyl-2-furoyl hydrazide with different monosaccharides d-glucose, d-galactose,d-mannose, d-fucose and d-arabinose were prepared. The anomerization and cyclic-acyclic isomers were investigated by 1H NMR spectroscopy. The results showed that, except for the d-glucose derivatives, which were in the presence of β-anomeric forms, all derivatives were in an acyclic Schiff base form. Their antifungal and antitumor activities were studied. The bioassay results indicated that some title compounds showed superior effects over the commercial positive controls.

A Synthetic Approach of D-Glucose Derivatives: Spectral Characterization and Antimicrobial Studies

A new series of methyl 4,6-O-(4-methoxyben- zylidene)-α-D-glucopyranoside derivatives was synthe- sized using the direct acylation method. Methyl-α-D- glucopyranoside was selectively converted to methyl 4,6- O-(4-methoxybenzylidene)-α-D-glucopyranoside by the reaction with 4-methoxybenzaldehyde dimethylacetal in a reasonable yield. Using a wide variety of acylating agents, a series of 2,3-di- O-acyl derivatives of this product was also prepared in order to gather additional information for structure elucidation. The structures of the newly synthesized compounds were elucidated by their spectral and elemental analysis. All synthesized compounds were screened for in vitro antimicrobial activities against ten human pathogenic bacteria and four plant pathogenic fungi. Encouragingly, a number of test compounds showed better antimicrobial activity than the standard antibiotics employed. It observed that the test compounds were more effective against fungal phytopathogens than those of the bacterial organisms.