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In this work, we have developed a new approach for the synthesis of fluoroglycoside analogues. This strategy used a simple alkylation protocol and allowed the installation of a simple aglyconic alkane with the β configuration. Moreover, the glycosylation of fluorinated glucoside analogues with 4′-demethylepipodophyllotoxin furnished novel fluoroetoposide analogues. In these cases, the α anomers were formed as major products with an S configuration at the C-4 of the aglycone.

In this work, we synthesized all mono-, di-, and trifluorinated glucopyranose analogues at positions C-2, C-3, C-4, and C-6. This systematic investigation allowed us to perform direct comparison of 19F resonances of fluorinated glucose analogues and also to determine their lipophilicities. Compounds with a fluorine atom at C-6 are usually the most hydrophilic, whereas those with vicinal polyfluorinated motifs are the most lipophilic. Finally, the solvation energies of fluorinated glucose analogues were assessed for the first time by using density functional theory. This method allowed the log P prediction of fluoroglucose analogues, which was comparable to the C log P values obtained from various web-based programs.

The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono- and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation-optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the 19F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C-3 and C-4 showed weaker affinities with LecA as compared to those with the fluorine atom at C-2 or C-6. This research has focused on the chemical synthesis of “drug-like” low-molecular-weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.

An expansive NMR-based structural analysis of elusive glycosyl cations derived from natural and non-natural monosaccharides in superacids is disclosed. For the first time, it has been possible to explore the consequence of deoxygenation and halogen substitution at the C2 position in a series of 2-halogenoglucosyl, galactosyl, and mannosyl donors in the condensed phase. These cationic intermediates were characterized using low-temperature in situ NMR experiments supported by DFT calculations. The 2-bromo derivatives display intramolecular stabilization of the glycosyl cations. Introducing a strongly electron-withdrawing fluorine atom at C2 exerts considerable influence on the oxocarbenium ion reactivity. In a superacid, these oxocarbenium ions are quenched by weakly coordinating SbF6? anions, thereby demonstrating their highly electrophilic character and their propensity to interact with poor nucleophiles.

Affinity data, such as dissociation constants (KD) or inhibitory concentrations (IC50), are widely used in drug discovery. However, these parameters describe an equilibrium state, which is often not established in vivo due to pharmacokinetic effects and they are therefore not necessarily sufficient for evaluating drug efficacy. More accurate indicators for pharmacological activity are the kinetics of binding processes, as they shed light on the rate of formation of protein–ligand complexes and their half-life. Nonetheless, although highly desirable for medicinal chemistry programs, studies on structure–kinetic relationships (SKR) are still rare. With the recently introduced analytical tool kinITC this situation may change, since not only thermodynamic but also kinetic information of the binding process can be deduced from isothermal titration calorimetry (ITC) experiments. Using kinITC, ITC data of 29 mannosides binding to the bacterial adhesin FimH were re-analyzed to make their binding kinetics accessible. To validate these kinetic data, surface plasmon resonance (SPR) experiments were conducted. The kinetic analysis by kinITC revealed that the nanomolar affinities of the FimH antagonists arise from both (i) an optimized interaction between protein and ligand in the bound state (reduced off-rate constant koff) and (ii) a stabilization of the transition state or a destabilization of the unbound state (increased on-rate constant kon). Based on congeneric ligand modifications and structural input from co-crystal structures, a strong relationship between the formed hydrogen-bond network and koff could be concluded, whereas electrostatic interactions and conformational restrictions upon binding were found to have mainly an impact on kon.

Mycothiol cysteine ligase (MshC) is a key enzyme in the mycothiol (MSH) biosynthesis and a promising target for developing new anti-mycobacterial compounds. Herein, we report on the synthesis of substrate analogues, as potential inhibitors, for the MshC e

2-Deoxy-2-fluoroglycosides bearing dibenzyl phosphate and phosphonate aglycones were synthesised and tested as covalent inactivators of several retaining α- and β-glycosidases. β-d-Gluco-, -manno- and -galacto-configured benzyl-benzylphosphonate derivatives efficiently inactivated β-gluco-, β-manno- and β-galactosidases, while α-gluco- and α-manno-configured phosphate and phosphonate derivatives served instead as slow substrates. This journal is the Partner Organisations 2014.

Validation of the 2-fluoro substituent as an inert steering group to control chemical glycosylation is presented. A molecular editing study has revealed that the exceptional levels of diastereocontrol in glycosylation processes by using 2-fluoro-3,4,6-tri-O-benzyl glucopyranosyl trichloroacetimidate (TCA) scaffolds are a consequence of the 2R,3S,4S stereotriad. This study has also revealed that epimerization at C4, results in a substantial enhancement in β-selectivity (up to β/α 300:1). Copyright

Introducing selenium: The synthesis and full characterization of human hepatic Se metaboliteA has been accomplished by using a robust, efficient, and Cys-specific selenenylation protocol (see scheme; NaPi=sodium phosphate). The selenenylsulfide linkage is sufficiently stable to allow quantification of Se-containing glycoconjugates in biological fluids by using atomic detection methods. Copyright

The present invention provides: a method for synthesizing a halogen-substituted saccharide from a leaving group-substituted saccharide in a short-time and continuously; a reaction composition; and a device for synthesis of same, i.e., the method being for synthesizing a halogen-substituted saccharide from a leaving group-substituted saccharide by a halogen-substituted saccharide synthesis reaction using a subcritical fluid or a supercritical fluid as the reaction solvent; the reaction composition of the same being an aqueous solution of halogen-substituted saccharide; and the device for synthesis being a device for producing the same, the method being for producing a halogen-substituted saccharide with a subcritical fluid or a supercritical fluid at a temperature of 100 to 400°C and a pressure of 0.1 to 40 MPa or a mixed solvent of aprotic organic solvent or inorganic solvent mixed therein as the reaction solvent, under a catalyst-free condition, by introducing the leaving group-substituted saccharide and the reaction solvent into a circulating-type high-temperature and high-pressure device to produce selectively a halogen-substituted saccharide at high yield, high selectivity, high speed and continuously, while reducing the amount of energy consumption and the amount of waste.

Recently, we reported an efficient chemical method for the synthesis of a variety of naturally occurring nucleoside diphosphate (NDP) sugars. This method, which is based on the cycloSal approach, can also be used, in principle, for the preparation of rare or even nonnatural NDP sugars. Herein, the syntheses of sulfoquinovose-, glucose-6-sulfate-, L-galactose-, and 2-fluoroglycopyranoside- containing NDP sugars are presented, as well as the synthesis of NDP sugars with non-natural nucleosides. The reactions described gavestereoisomerically defined NDP sugars in high yields and short reaction times.

Everything's under control: A stabilizing fluorine electrostatic interaction has been exploited to control oxonium ion conformation in 2-fluoropyranose derivatives (see scheme). When matched with the inductive nature of the protecting groups, the glycosyl

A new approach to the synthesis of 2-fluoro-2-deoxy-d-glucose (FDG, [ 19/18F]-3) is described, which employs supported perfluoroalkylsulfonate precursors 33-36, where the support consists of insoluble polystyrene resin beads. Treatment of these resins with [ 19F]fluoride ion afforded protected FDG [19F]-18 as the major product, and the identities of the main byproducts were determined. Acidic removal of the acetal protecting groups from [19F]-18 was shown to produce [19F]FDG. The method has been applied to the efficient radiosynthesis of the imaging agent [18F]FDG, and was shown to produce the radiochemical tracer in good radiochemical yield (average 73%, decay corrected). The Royal Society of Chemistry 2009.

para-Nitrophenol-tagged sialyl galactosides containing sialic acid derivatives in which the C5 hydroxyl group of sialic acids was systematically substituted with a hydrogen, a fluorine, a methoxyl or an azido group were successfully synthesized using an efficient chemoenzymatic approach. These compounds were used as valuable probes in high-throughput screening assays to study the importance of the C5 hydroxyl group of sialic acid in the recognition and the cleavage of sialoside substrates by bacterial sialidases.

Modified d-glucose and d-mannose analogs are potentially clinically useful metabolic inhibitors. Biological evaluation of 2-deoxy-2-halo analogs has been impaired by limited availability and lack of efficient methods for their preparation. We have develop

The P2Y14 receptor, a nucleotide signaling protein, is activated by uridine-5′-diphosphoglucose 1 and other uracil nucleotides. We have determined that the glucose moiety of 1 is the most structurally permissive region for designing analogues of this P2Y14 agonist. For example, the carboxylate group of uridine-5′-diphosphoglucuronic acid proved to be suitable for flexible substitution by chain extension through an amide linkage. Functionalized congeners containing terminal 2-acylaminoethylamides prepared by this strategy retained P2Y14 activity, and molecular modeling predicted close proximity of this chain to the second extracellular loop of the receptor. In addition, replacement of glucose with other sugars did not diminish P2Y14 potency. For example, the [5′′]ribose derivative had an EC50 of 0.24 μM. Selective monofluorination of the glucose moiety indicated a role for the 2′′- and 6′′-hydroxyl groups of 1 in receptor recognition. The β-glucoside was twofold less potent than the native α-isomer, but methylene replacement of the 1′′-oxygen abolished activity. Replacement of the ribose ring system with cyclopentyl or rigid bicyclo[3.1.0]hexane groups abolished activity. Uridine-5′-diphosphoglucose also activates the P2Y2 receptor, but the 2-thio analogue and several of the potent modified-glucose analogues were P2Y14-selective.

The synthesis of 2″-deoxy-2″-fluoro-adenophostin A framework starting from tri-O-acetylglucal and adenosine is described. The key steps are the formation of the 2-deoxy-2-fluoroglycosyl donor by electrophilic fluorination of tri-O-acetylglucal and the ste

(Chemical Equation Presented) Scintillating synthesis: 18F- Containing radiopharmaceuticals can be prepared by using [18F] fluoride ions to displace a sulfonate linker and release a radiotracer from a solid support (see scheme; EOM =

A series of 4,6-O-benzylidene-protected 2-O-benzyl-3-deoxy-3-fluoro- and 3-O-benzyl-2-deoxy-2-fluorogluco-and mannopyranosyl thioglycosides were synthesized and their coupling reactions with a series of alcohols, on preactivation with 1-benzenesulfinylpip

This paper addresses the existence and role of a catalytic nucleophile in retaining glycoside hydrolases and retaining glycosyl transferases. Although the former has now been established beyond doubt, such is not the case with the latter. We report reliable procedures for the synthesis of various 2-deoxy-2-fluoro glycosyl nucleoside diphosphates, useful donor analogues for the study of the mechanism of action of retaining glycosyl transferases.

The reaction of D-glucal and its derivatives with the electrophilic N-F-fluorination reagents F-TEDA tetrafluoroborate and triflate was studied by means of 19F NMR spectroscopy. In all cases mixtures of 2-deoxy-2-fluoro-D-gluco- and -D-mannopyranose derivatives were formed, the ratio of which was dependent on the nature of the O-protecting groups. Concerning the products arising from the direct addition of reagents across the double bond, the D-gluco-configured compounds (13-20) generally showed higher hydrolysis rates than their D-manno-counterparts (21-28). Product separation was only achieved when single anomers (e.g., 2,4-dinitrophenyl glycosides 29e/37e and disaccharidic fluorides 35d/43d) or per-O-acetates (e.g. 29f/37f) were formed.

Nucleotide linked 2-deoxy-2-fluoroglycosides are employed as potent competitive inhibitors of glycosyltransferases. More particularly, uridine-5'-diphospho-2-deoxy-2-fluoro-galactose (UDP-2F-Gal), guanidine-5'-diphospho-2-deoxy-2-fluoro-L-fucose (GDP-2F-Fuc), uridine-51-diphospho-2-deoxy-2-fluoro-D-glucose (UDP-2F-Glu), guanosine-5'-diphospho-2-deoxy-2-fluoro-D-mannose (GDP-2F-Man), cytosine-5'-monophospho-2-deoxy-2-fluoro-D-sialic acid, and cytosine-5'-monophospho-2-deoxy-2-KDO may be employed as inhibitors of β-1,4-galactosyltransferase, α-1,3-fucosyltransferase, glucosyltransferases, N-acetylglucosaminyltransferases, (α-mannosyltransferases, α-sialyltransferases, and KDO-transferases, respectively. Synthesis of nucleotide-linked-2-deoxy-2-fluoroglycosides is achieved using either chemoenzymatic or chemical methodologies.

Two fluorinated hexoses were prepared from optically active cis-diols 1, which were obtained by microbial oxidation of the corresponding halobenzenes with E. coli JM109 (pDTG 601). The stereochemistry of the products was controlled by careful introduction of fluorine onto the periphery of the cis-diols via opening of epoxides with tetrabutylphosphoniumfluoride dihydrofluoride (TBPF-DF). Oxidative cleavage of the cyclohexene skeleton followed by reductive cyclization led to the fluorinated hexoses.

Disclosed are novel analogues of kojibiose and pharmaceutical compositions comprising such analogues.

The syntheses of several analogues of disaccharide Manα(1->6)Manα-OCH3 (1) and of trisaccharide Manα(1->6)3)>Manα-OCH3 (2) are reported.The syntheses are described of the diastereomeric 6-methyl derivatives 9a and 9b, which are representatives o

In order to study structure-activity relationships of lipid A derivatives, a series of fluorinated analogues of lipid X was synthesized. Subsequently, these were converted enzymatically into the corresponding disccaharidic lipid A analogues using lipid A

The regiospecific syn-addition of acetyl hypofluorite to glycals derived from pentopyranoses led to mixtures of stereoisomers.Stereospecific reactions occured with furanoid glycals, the direction of addition being governed by the nature of the substituent at C-3.Whereas a benzyloxy group caused attack from the opposite, less-hindered face of the double bond, a hydroxyl group induced addition from the same side.From these reactions, 2-deoxy-2-fluoro derivatives of β-D-arabino-, α-D-ribo-, β-D-lyxo-, and α-D-xylo-pyranose as well as β-D-manno-, α-D-guco-, α-D-ribo-, and β-D-arabino-furanose were obtained; their 1H-, 13C-, and 19F-n.m.r. data are given.

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The reaction of 1,2-anhydro-3,4:4,5-di-O-isopropylidene-1-C-nitro-D-mannitol (2) with potassium hydrogenfluoride in ethylene glycol under anhydrous conditions provides a route to 2-deoxy-2-fluoro-D-glucose, the (18)F-labeled analog of which is an important radiopharmaceutical of use in medical imaging.The reaction is accompained to a minor extent by epimerization at C-2 of the initially formed fluoro aldehyde and also results in attack by solvent at C-2 in 2.

The action of sulfur tetrafluoride on glyoxal leads to the formation of the 1,2-difluoroethylene glycol orthosulfite.The reactions of dimeric glyceraldehyde and aldol with sulfur tetrafluoride are accompanied by dehydration, leading to fluorine-containing ethers or unsaturated compounds.In the case of tetraacetylglucopyranose the free hydroxyl group is substituted by a fluorine atom.

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1,5-Anhydro-2-deoxy-D-arabino- (D-glucal), 1,5-anhydro-2-deoxy-D-lyxo- (D-galactal), and 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-lyxo-hex-1-enitol (3,4,6-tri-O-acetyl-D-galactal) (3) were fluorinated in water and organic solvent-water with molecular fluorine and, for 18F-labelled compounds, with 18F>fluorine.Chemical yields of 40 and 10percent were obtained for 2-deoxy-2-fluoro-D-glucose and 2-deoxy-2-fluoro-D-mannose, respectively, and 35 and 5percent for 2-deoxy-2-fluoro-D-galactose (12) and 2-deoxy-2-fluoro-D-talose (13), respectively.In the fluorination of 3, the chemical yields of 12 and 13 were 38 and 6percent, respectively.An l.c. separationof 2-deoxy-2-fluoro-D-hexoses is described.

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The useful electrophilic fluorinating agent, acetyl hypofluorite, was obtained by passing F2 diluted in N2 through columns containing complexes of alkali metal acetates with acetic acid.Acetyl hypofluorite obtained from KOAc(HOAc)1.5 and o.14percent F2 in N2 was reacted with tri-O-acetyl-D-glucal in CCl3F to obtain tetra-O-acetyl-2-deoxy-2-fluoro-D-glucose in 68percent yield based on F2.These conditions are appropriate to the radiosynthesis of 18F-labeled 2-deoxy-2-fluoro-D-glucose for positron emission tomography.Important variables were the metal cation used, the ratio of HOAc to MOAc and the water content of the complex.

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Acetyl hypofluorite has been added to six unsaturated carbohydrates that contain a vinyl ether moiety.All reactions were rapid (5 min at -78 deg C) and gave, with one exception, high yields of isomerically pure products.The hypofluorite was shown to add

1,3,4,6-Tetra-O-acetyl-2-deoxy-2-fluoro-α-D-glucopyranose (4) and 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-α-D-galactopyranose (5) have been synthesized in 78percent and 84percent yields respectively in 5 min by the reaction of acetyl hypofluorite with the corresponding tri-O-acetylglycal (2,3) at -78 deg C.