Production Scientifique 2014-2016
The Staudinger/aza-Wittig/Grignard reaction as key step for the concise synthesis of 1-C-Alkyl-iminoalditol glycomimetics
Zoidl, M.; Gonzalez Santana, A.; Torvisco, A.; Tysoe, C.; Siriwardena, A.; Withers, S. G.; Wrodnigg, T. M.
Carbohydr. Res. 2016, 429, 62-70.
The scope of a one-pot tandem approach for the synthesis of C-1 alkyl iminoalditol derivatives with a Staudinger/aza-Wittig/Grignard cascade has been evaluated. The reaction conditions have been optimized for two azidodeoxy aldose substrates and a range of Grignard reagents. The nature of both, substrate as well as nucleophile, was found to control the stereoselectivity of the alkyl addition to the cyclic iminium intermediate at position C-1. This approach enabled the synthesis of a collection of C-alkyl iminoalditols, which were biologically evaluated as inhibitors against a set of standard glycoside hydrolases. All compounds were found to exhibit highly selective inhibition of beta-glucosidase activity.
A quantitative method to discriminate between non-specific and specific lectin-glycan interactions on silicon-modified surfaces
Yang, J.; Siriwardena, A.; Boukherroub, R.; Ozanam, F.; Szunerits, S.; Gouget-Laemmel, A. C.
J. Colloid Interface Sci. 2016, 464, 198-205.
Essential to the success of any surface-based carbohydrate biochip technology is that interactions of the particular interface with the target protein be reliable and reproducible and not susceptible to unwanted nonspecific adsorption events. This condition is particularly important when the technology is intended for the evaluation of low-affinity interactions such as those typically encountered between lectins and their monomeric glycan ligands. In this paper, we describe the fabrication of glycan (mannoside and lactoside) monolayers immobilized on hydrogenated crystalline silicon (111) surfaces. An efficient conjugation protocol featuring a key "click"-based coupling step has been developed which ensures the obtention of interfaces with controlled glycan density. The adsorption behavior of these newly developed interfaces with the lectins, Lens culinaris and Peanut agglutinin, has been probed using quantitative IR-ATR and the data interpreted using various isothermal models. The analysis reveals that protein physisorption to the interface is more prevalent than specific chemisorption for the majority of washing protocols investigated. Physisorption can be greatly suppressed through application of a strong surfactinated rinse. The coexistence of chemisorption and physisorption processes is further demonstrated by quantification of the amounts of adsorbed proteins distributed on the surface, in correlation with the results obtained by atomic force microscopy (AFM). Taken together, the data demonstrates that the nonspecific adsorption of proteins to these glycan-terminated surfaces can be effectively eliminated through the proper control of the chemical structure of the surface monolayer combined with the implementation of an appropriate surface-rinse protocol.
Affinity of Glycan-Modified Nanodiamonds towards Lectins and UropathogenicEscherichia Coli
Turcheniuk, V.; Turcheniuk, K.; Bouckaert, J.; Barras, A.; Dumych, T.; Bilyy, R.; Zaitsev, V.; Siriwardena, A.; Wang, Q.; Boukherroub, R.; Szunerits, S.
ChemNanoMat 2016, 2, 307-314.
Nanodiamond particles (NDs) modified with glycan ligands are revealing themselves to have great promise as new nanomaterials for combating biofilm formation and as promising anti-adhesive scaffolds. Currently, the strategies at hand to formulate glycan-modified NDs (glyco-NDs) are limited to a few reports. We demonstrate herein that the photoinduced covalent attachment of unmodified sugars results in glyco-NDs with high binding affinity to lectins and a uropathogenic Escherichia coli strain (E. coli UTI89). While the binding affinities of glyco-NDs to different lectins is partially sacrificed when monosaccharides such as mannose are photochemically integrated onto NDs, in the case of disaccharides and oligosaccharides the binding affinity of glyco-NDs to lectins is preserved. Moreover, mannan-modified NDs show strong interactions with uropathogenic E. coli., suggesting the effectiveness of photochemically formed glyco-NDs for disruption of E. coli-mediated biofilms.
Differentiation of Crohn's Disease-Associated Isolates from Other Pathogenic Escherichia coli by Fimbrial Adhesion under Shear Force
Szunerits, S.; Zagorodko, O.; Cogez, V.; Dumych, T.; Chalopin, T.; Alvarez Dorta, D.; Sivignon, A.; Barnich, N.; Harduin-Lepers, A.; Larroulet, I.; Yanguas Serrano, A.; Siriwardena, A.; Pesquera, A.; Zurutuza, A.; Gouin, S. G.; Boukherroub, R.; Bouckaert, J.
Biology (Basel) 2016, 5.
Shear force exerted on uropathogenic Escherichia coli adhering to surfaces makes type-1 fimbriae stretch out like springs to catch on to mannosidic receptors. This mechanism is initiated by a disruption of the quaternary interactions between the lectin and the pilin of the two-domain FimH adhesin and transduces allosterically to the mannose-binding pocket of FimH to increase its affinity. Mannose-specific adhesion of 14 E. coli pathovars was measured under flow, using surface plasmon resonance detection on functionalized graphene-coated gold interfaces. Increasing the shear had important differential consequences on bacterial adhesion. Adherent-invasive E. coli, isolated from the feces and biopsies of Crohn's disease patients, consistently changed their adhesion behavior less under shear and displayed lower SPR signals, compared to E. coli opportunistically infecting the urinary tract, intestines or loci of knee and hip prostheses. We exemplified this further with the extreme behaviors of the reference strains UTI89 and LF82. Whereas their FimA major pilins have identical sequences, FimH of LF82 E. coli is marked by the Thr158Pro mutation. Positioned in the inter-domain region known to carry hot spots of mutations in E. coli pathotypes, residue 158 is indicated to play a structural role in the allosteric regulation of type-1 fimbriae-mediated bacterial adhesion.
An efficient lactamisation/N-acyliminium Pictet-Spengler domino strategy for the diasteroselective synthesis of polyhydroxylated quinoxalinone, beta-carboline and quinazolinone derivatives
Subba Reddy, B. V.; Reddy, B. P.; Reddy, P. V.; Siriwardena, A.
Org. Biomol. Chem. 2016, 14, 4276-82.
A novel cascade strategy has been developed for the synthesis of polyhydroxylated tetrahydroindolo[1,2-a]pyrrolo[2,1-c]quinoxaline, tetrahydrodipyrrolo[1,2-a:2',1'-c]quinoxaline, hexahydro-1H-indolizino[8,7-b]indole, hexahydrobenzo[6,7]pyrrolo[1',2':1,2]azepino[3,4-b]indole, tetrahydrobenzo[4,5]imidazo[1,2-c]pyrrolo[1,2-a]quinazoline, and tetrahydropyrrolo[1,2-a]tetrazolo[1,5-c]quinazoline scaffolds. The key step is a lactamisation/Pictet-Spengler condensation of a bifunctional sugar-derived hydroxy-gamma-lactone component with an appropriate bifunctional aromatic amine component. This modular approach features the in situ-generation of a cyclic N-acyliminium intermediate that allows the diastereoselective assembly of these diverse polycyclic systems efficiently under mild and operationally simple conditions.
Towards Renewable Iodide Sources for Electrolytes in Dye-Sensitized Solar Cells
Sagaidak, I.; Huertas, G.; Nguyen Van Nhien, A.; Sauvage, F.
Energies 2016, 9, 241.
A novel family of iodide salts and ionic liquids based on different carbohydrate core units is herein described for application in dye-sensitized solar cell (DSC). The influence of the molecular skeleton and the cationic structure on the electrolyte properties, device performance and on interfacial charge transfer has been investigated. In combination with the C106 polypyridyl ruthenium sensitizer, power conversion efficiencies lying between 5.0% and 7.3% under standard Air Mass (A.M.) 1.5G conditions were obtained in association with a low volatile methoxypropionitrile (MPN)-based electrolyte.
Improvement of Gold-Catalyzed Oxidation of Free Carbohydrates to Corresponding Aldonates Using Microwaves
Omri, M.; Pourceau, G.; Becuwe, M.; Wadouachi, A.
ACS Sustainable Chemistry & Engineering 2016, 4, 2432-2438.
An efficient microwave-assisted methodology for the oxidation of free carbohydrates to corresponding aldonates is described. Supported gold catalyst, hydrogen peroxide and a mineral base were used to perform the oxidation reaction in water under microwave irradiation. These conditions combined with Au/Al2O3 catalyst allowed to reach in 10 minutes a quantitative conversion of glucose.The catalyst was highly selective and reusable and only 0.004 mol % of gold compared to sugar was used. The reaction was performed using a variety of substrates (mono or oligosaccharides, neutral or acidic sugars) and good to excellent conversion yields and selectivity to corresponding aldonates were obtained. After filtration and freeze-drying, sodium or potassium aldonates were obtained without any purification. Thanks to very high turn-over frequencies (up to 438 000 h-1), this methodology improves significantly the previously described methods for the gold-catalyzed oxidation of carbohydrates.
Synthesis and Applications of Silyl 2-Methylprop-2-ene-1-sulfinates in Preparative Silylation and GC-Derivatization Reactions of Polyols and Carbohydrates
Markovic, D.; Tchawou, W. A.; Novosjolova, I.; Laclef, S.; Stepanovs, D.; Turks, M.; Vogel, P.
Chemistry 2016, 22, 4196-205.
Trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl 2-methylprop-2-ene-1-sulfinates were prepared through (CuOTf)2C6H6-catalyzed sila-ene reactions of the corresponding methallylsilanes with SO2 at 50 degrees C. Sterically hindered, epimerizable, and base-sensitive alcohols gave the corresponding silyl ethers in high yields and purities at room temperature and under neutral conditions. As the byproducts of the silylation reaction (SO2 +isobutylene) are volatile, the workup was simplified to solvent evaporation. The developed method can be employed for the chemo- and regioselective semiprotection of polyols and glycosides and for the silylation of unstable aldols. The high reactivity of the developed reagents is shown by the synthesis of sterically hindered per-O-tert-butyldimethylsilyl-alpha-D-glucopyranose, the X-ray crystallographic analysis of which is the first for a per-O-silylated hexopyranose. The per-O-silylation of polyols, hydroxy carboxylic acids, and carbohydrates with trimethylsilyl 2-methylprop-2-ene-1-sulfinate was coupled with the GC analysis of nonvolatile polyhydroxy compounds both qualitatively and quantitatively.
Physico-chemical properties and cytotoxic effects of sugar-based surfactants: Impact of structural variations
Lu, B.; Vayssade, M.; Miao, Y.; Chagnault, V.; Grand, E.; Wadouachi, A.; Postel, D.; Drelich, A.; Egles, C.; Pezron, I.
Colloids Surf., B 2016, 145, 79-86.
Surfactants derived from the biorefinery process can present interesting surface-active properties, low cytotoxicity, high biocompatibility and biodegradability. They are therefore considered as potential sustainable substitutes to currently used petroleum-based surfactants. To better understand and anticipate their performances, structure-property relationships need to be carefully investigated. For this reason, we applied a multidisciplinary approach to systematically explore the effect of subtle structural variations on both physico-chem. properties and biol. effects. Four sugar-based surfactants, each with an eight carbon alkyl chain bound to a glucose or maltose head group by an amide linkage, were synthesized and evaluated together along with two com. available std. surfactants. Physico-chem. properties including soly., Krafft point, surface-tension lowering and crit. micellar concn. (CMC) in water and biol. medium were explored. Cytotoxicity evaluation by measuring proliferation index and metabolic activity against dermal fibroblasts showed that all surfactants studied may induce cell death at low concns. (below their CMC). Results revealed significant differences in both physico-chem. properties and cytotoxic effects depending on mol. structural features, such as the position of the linkage on the sugar head-group, or the orientation of the amide linkage. Furthermore, the cytotoxic response increased with the redn. of surfactant CMC. This study underscores the relevance of a methodical and multidisciplinary approach that enables the consideration of surfactant soln. properties when applied to biol. materials. Overall, our results will contribute to a better understanding of the concomitant impact of surfactant structure at physico-chem. and biol. levels.
Glycochemical Applications of Diels-Alder Reaction
Laclef, S.; Toumieux, S.; Kovensky, J.
Curr. Org. Chem. 2016, 20.
Carbohydrates and their analogs are key molecules with a wide range of biological activities. These bioactive compounds are usually synthesized through derivatization of naturally occurring carbohydrates. Nevertheless, this strategy suffers from a limited range of naturally available monosaccharide building blocks and the necessity of laborious steps of protection and deprotection. Consequently new methods began to emerge and Diels-Alder reaction appeared to be a method of choice for their de novo production. The synthesis of carbohydrates and their analogs by means of cycloaddition reactions will be reviewed here. Moreover the potentiality of the use of monosaccharides to induce chirality in Diels-Alder reaction will be presented. Efficient methods for the synthesis of di- and tri-saccharides using the developments shown previously will be also introduced.
Chapter 5 Recent Advances in the Synthesis of Sugar-based Surfactants
Kovensky, J.; Grand, E.
Biomass Sugars for Non-Fuel Applications 2016, 159-204.
Reversible anion intercalation in a layered aromatic amine: a high-voltage host structure for organic batteries
Deunf, E.; Moreau, P.; Quarez, E.; Guyomard, D.; Dolhem, F.; Poizot, P.
J. Mater. Chem. A 2016, 4, 6131-6139.
Cation insertion reactions in inorg. host frameworks are well-established phenomena. Over the last 40 years, a myriad of examples have been documented, which have given rise to key applications such as for electrochem. storage devices. By contrast, materials able to reversibly insert anions into their host lattice are rare, and consist essentially of graphite intercalation compds. (GICs), thus limiting their potential use. Org. materials, conversely, if properly designed, could pave the way for future developments in anionic insertion electrochem., by virtue of the rational incorporation of p-type redox-active org. moieties. Here, we report the discovery of a p-type org. host lattice based on a simple crystd. arom. diamine. The reversible anion insertion process relies on the electrochem. activity of neutral secondary amino groups incorporated into a robust terephthalate backbone. XRD, TEM and EELS studies reveal the attainment of a unique lamellar structure conducive to the oxidative insertion of anions (including the bulky TFSI-). In a dual-ion cell configuration using lithium as the neg. electrode, this org. structure can react reversibly at high operating potential (〈E〉 ≈ 3.22 V vs. Li+/Li) with good cycling performance even without carbon addn., hence generating further avenues for the development of org. batteries and more generally, the field of intercalation chem.
The origin of the stereoselective alkylation of 3-substituted-2-oxopiperazines: A computational investigation
Cézard, C.; Bouvier, B.; Dassonville-Klimpt, A.; Sonnet, P.
Computational and Theoretical Chemistry 2016, 1078, 1-8.
2-Oxopiperazines and their derivatives are important pharmacophores found in numerous bioactive products. The potency of these compounds depends on the nature and/or position of their substituent(s) as well as on their chirality. Hence, it is important to develop, control and optimize synthetic routes leading to enantiomerically pure substituted 2-oxopiperazines. In this work we report on the origin of this stereoselectivity, upon alkylation of 2-oxopiperazines at position C3, studied by means of quantum chemistry calculations. Indeed, this alkylation with methyl chloride is predicted to afford mainly the exo product with a 98:2 ratio. To this purpose, we model the reaction path leading to both enantiomers by scrutinizing the structures and energetics of the pre-reaction complexes, the transition states and the post-reaction complexes. The computational results are in good agreement with the experimental observations, and provide valuable insights into the origins of this specificity. From the conformational analysis of the piperazine ring and of intramolecular interaction patterns, we show that the enantiofacial discrimination is achieved by a subtle balance between sterical hindrance and control of the conformation of the piperazine ring.
Optimizing the Multivalent Binding of the Bacterial Lectin LecA by Glycopeptide Dendrimers for Therapeutic Purposes
J. Chem. Inf. Model. 2016, 56, 1193-1204.
Bacterial lectins are nonenzymic sugar-binding proteins involved in the formation of biofilms and the onset of virulence. The weakness of individual sugar-lectin interactions is compensated by the potentially large no. of simultaneous copies of such contacts, resulting in high overall sugar-lectin affinities and marked specificities. Therapeutic compds. functionalized with sugar residues can compete with the host glycans for binding to lectins only if they are able to take advantage of this multivalent binding mechanism. Glycopeptide dendrimers, featuring treelike topologies with sugar moieties at their leaves, have already shown great promise in this regard. However, optimizing the dendrimers' amino acid sequence is necessary to match the dynamics of the lectin active sites with that of the multivalent ligands. This work combines long-time-scale coarse-grained simulations of dendrimers and lectins with a reasoned exploration of the dendrimer sequence space in an attempt to suggest sequences that could maximize multivalent binding to the galactose-specific bacterial lectin LecA. These candidates are validated by simulations of mixed dendrimer/lectin solns., and the effects of the dendrimers on lectin dynamics are discussed. This approach is an attractive first step in the conception of therapeutic compds. based on the dendrimer scaffold and contributes to the understanding of the various classes of multivalency that underpin the ubiquitous "sugar code".
Radical Coupling Allows a Fast and Tuned Synthesis of Densely Packed Polyrotaxanes Involving γ-Cyclodextrins and Polydimethylsiloxane
Blin, F.; Przybylski, C.; Bonnet, V.; Clément, M.-J.; Curmi, P. A.; Choppinet, P.; Nakajima, T.; Chéradame, H.; Jarroux, N.
Macromolecules 2016, 49, 3232-3243.
The first radical end-coupling synthesis of polydimethylsiloxane (PDMS)−γ-cyclodextrins (γ-CDs) based polyrotaxane is reported. Conversely to usual chemical way, the radical process leads to fast both controlled size and structure with minimal side reaction while exhibiting very high conversion rate (w/w, 80%). Pure PDMS−γ-CDs molecular necklaces were successfully isolated by preparative size exclusion chromatography and finely characterized both by 1D/2D/STD 1H and 13C NMR and MALDI-TOF mass spectrometry. The observations give clear evidence of the supramolecular assembly synthesis where the filling ratio (γ-CD/monomer unit) of PDMS chains is as high as 40% of γ-CDs. Combination of such radical-based coupling supported by detailed analytical characterizations appears at the forefront of a fast, suitable, and easily amenable scaling-up CDs-based polyrotaxane synthesis process.
Asymmetric synthesis of new antimalarial aminoquinolines through Sharpless aminohydroxylation
Bentzinger, G.; De Souza, W.; Mullié, C.; Agnamey, P.; Dassonville-Klimpt, A.; Sonnet, P.
Tetrahedron: Asymmetry 2016, 27, 1-11.
Recently, the asymmetric synthesis and biological activity of (R)- and (S)-4-aminoquinolinemethanols 1 as mefloquine analogues were reported. Several compounds showed very promising antimalarial activity, in the nanomolar range, against Plasmodium falciparum 3D7 and W2. Enantiomers with an (S)-absolute configuration were more active than their (R)-counterparts by a factor ranging from 2 to 15-fold, according to the compound and the plasmodial strain considered. In continuation of our work, three novel series of enantiopure aminoquinolines 2a, 2b, and 3 were synthesized via an asymmetric aminohydroxylation reaction. These compounds were obtained in 2 or 4 steps from a common amidoalcohol key-intermediate 4. They displayed IC50 values close to the micromolar against the two P. falciparum strains 3D7 and W2. The study of the structure–activity relationships allows us to better understand the importance of the substitution and of the stereochemistry at C11 and C12 position of the quinoline and gives tracks for the design of new compounds more active against the plasmodial strains.
Multivalent sialylation of β-thio-glycoclusters by Trypanosoma cruzi trans sialidase and analysis by high performance anion exchange chromatography
Agustí, R.; Cano, M. E.; Cagnoni, A. J.; Kovensky, J.; de Lederkremer, R. M.; Uhrig, M. L.
Glycoconjugate J. 2016, 1-10.
The synthesis of multivalent sialylated glycoclusters is herein addressed by a chemoenzymatic approach using the trans-sialidase of Trypanosoma cruzi (TcTS). Multivalent β-thio-galactopyranosides and β-thio-lactosides were used as acceptor substrates and 3′-sialyllactose as the sialic acid donor. High performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) was shown to be an excellent technique for the analysis of the reaction products. Different eluting conditions were optimized to allow the simultaneous resolution of the sialylated species, as well as their neutral precursors. The TcTS efficiently transferred sialyl residues to di, tri, tetra and octa β-thiogalactosides. In the case of an octavalent thiolactoside, up to six polysialylated compounds could be resolved. Preparative sialylation reactions were performed using the tetravalent and octavalent acceptor substrates. The main sialylated derivatives could be unequivocally assigned by MALDI mass spectrometry. Inhibition of the transfer to the natural substrate, N-acetyllactosamine, was also studied. The octalactoside caused 82 % inhibition of sialic acid transfer when we used equimolar concentrations of donor, acceptor and inhibitor.
Carbohydrate microarray for the detection of glycan-protein interactions using metal-enhanced fluorescence
Yang, J.; Moraillon, A.; Siriwardena, A.; Boukherroub, R.; Ozanam, F.; Gouget-Laemmel, A. C.; Szunerits, S.
Anal. Chem. 2015, 87, 3721-8.
Carbohydrate arrays are potentially one of the most attractive tools to study carbohydrate-based interactions. This paper describes a new analytical platform that exploits metal-enhanced fluorescence for the sensitive and selective screening of carbohydrate-lectin interactions. The chip consists of a glass slide covered with gold nanostructures, postcoated with a thin layer of amorphous silicon-carbon alloy (a-Si0.8C0.2:H). An immobilization strategy based on the formation of a covalent bond between propargyl-terminated glycans and surface-linked azide groups was used to attach various glycans at varying surface densities onto the interface and to fabricate a carbohydrate array via efficient local "click" chemistry strategy. The specific association of the new interface with fluorescently labeled lectins was assessed by fluorescence imaging and an excellent selectivity to specific proteins was achieved. Optimization of the surface architecture and the plasmonic transducer resulted in an enhancement of the fluorescence intensity by 1 order of magnitude, when compared to the corresponding substrate devoid of gold nanostructures. The limit of detection (LOD) of such microarrays is in the picomolar range, making it a promising system for development in pharmaceutical or biomedical applications.
Unprecedented inhibition of glycosidase-catalyzed substrate hydrolysis by nanodiamond-grafted O-glycosides
Siriwardena, A.; Khanal, M.; Barras, A.; Bande, O.; Mena-Barragán, T.; Mellet, C. O.; Garcia Fernández, J. M.; Boukherroub, R.; Szunerits, S.
RSC Adv. 2015, 5, 100568-100578.
We report herein the unprecedented finding that [small alpha]-O-glucosides and also [small alpha]-O-mannosides, when conjugated on nanodiamond particles (ND), are not only stable towards the hydrolytic action of the corresponding matching glycosidases, but are also endowed with the ability to inhibit them. Moreover, conjugation of the O-glycosides to ND (glyco-ND) sees them transformed into inhibitors of mismatching enzymes (for which they do not serve as substrates even when in their monovalent, free form). The effects of the glyco-NDs have been demonstrated on a panel of commercial glycosidases and the inhibition found to be competitive and reversible and not to be related to any denaturation of enzymes by the ND-conjugates. Values for Ki in the low micromolar range have been measured for certain glyco-ND (for example, a Ki value of 5.5 +/- 0.2 [small mu ]M was measured for the glucopyranosyl-coated NDs against the [small alpha]-glucosidase from baker's yeast) and found to depend on both the identity of the enzyme and the glyco-ND. The latter Ki value compares well with that obtained for the natural glucosidase inhibitor, 1-deoxynojirimycin (Ki of 25 [small mu ]M against the [small alpha]-glucosidase from baker's yeast under identical assay conditions). The monovalent control O-glycosides was hydrolysed efficiently by the appropriate glycosidase. Glyco-ND bearing 50% loading of O-glycoside as well ND conjugated with both O-glucosides and O-mannosides (mixed) have also been assayed and shown also to inhibit the panel of glycosidases with potencies and selectivities different from those recorded for the 100% loaded ND and also from one another. The impact on factors such as glycotope density and heteromultivalency on inhibition is reminiscent of that typically encountered in carbohydrate-lectin recognition events. The abilities of the glyco-ND to bind, cross-link and aggregate concanavalin A, a lectin known to recognize both [small alpha]-O-d-mannosides and [small alpha]-O-d-glucosides, was assessed by a range of methods including an enzyme-linked lectin assay (ELLA), a two-site sandwich ELLA and a turbidimetry assay, respectively and indeed seen to reflect their expected per glycotope affinity enhancements as compared to monovalent controls: the high avidity of the lectin for each respective glycosylated ND particle was consistent with the manifestation of potent multivalent effects driving lectin recognition and binding.
Wnt/beta-catenin signaling mediates osteoblast differentiation triggered by peptide-induced alpha5beta1 integrin priming in mesenchymal skeletal cells
Saidak, Z.; Le Henaff, C.; Azzi, S.; Marty, C.; Da Nascimento, S.; Sonnet, P.; Marie, P. J.
J. Biol. Chem. 2015, 290, 6903-12.
The alpha5beta1 integrin is a key fibronectin (FN) receptor that binds to RGD-containing peptides to mediate cell adhesion. We previously reported that alpha5beta1 integrin promotes osteogenic differentiation in mesenchymal skeletal cells (MSCs), but the underlying mechanisms are not fully understood. In this study, we determined the signaling mechanisms induced by alpha5beta1 integrin interaction with its high-affinity ligand CRRETAWAC in murine and human MSCs and in vivo. We show that cyclized CRRETAWAC fully displaced MSC adhesion to FN, whereas related peptides lacking the full RRET sequence produced a partial displacement, indicating that RRET acts as an RGD-like sequence that is required to antagonize FN-mediated cell adhesion. However, all peptides increased focal adhesion kinase phosphorylation, OSE2 transcriptional activity, osteoblast gene expression, and matrix mineralization in MSCs, indicating that peptide-induced alpha5beta1 integrin priming can promote osteogenic differentiation independently of the RRET sequence. Biochemical analyses showed that peptide-induced alpha5beta1 integrin priming transiently increased PI3K/Akt phosphorylation and promoted Wnt/beta-catenin transcriptional activity independently of RRET. Consistently, pharmacological inhibition of PI3K activity reduced osteoblast differentiation and abolished Wnt regulatory gene expression induced by alpha5beta1 integrin priming. In vivo, systemic delivery of cyclized GACRETAWACGA linked to (DSS)6 to allow delivery to bone-forming sites for 6 weeks increased serum osteocalcin levels and improved long bone mass and microarchitecture in SAMP-6 senescent osteopenic mice. The results support a mechanism whereby alpha5beta1 integrin priming by high-affinity ligands integrates Wnt/beta-catenin signaling to promote osteoblast differentiation independently of cell adhesion, which could be used to improve bone mass and microarchitecture in the aging skeleton.
Probing the common alkali metal affinity of native and variously methylated [small beta]-cyclodextrins by combining electrospray-tandem mass spectrometry and molecular modeling
Przybylski, C.; Bonnet, V.; Cezard, C.
Phys. Chem. Chem. Phys. 2015, 17, 19288-19305.
In the study herein, we investigated the solution and gas phase affinity of native and variously methylated [small beta]-cyclodextrins (CDs) as hosts towards three common alkali metals as guests namely lithium, sodium and potassium. For this purpose, two complementary approaches have been employed: electrospray-tandem mass spectrometry (ESI-MS/MS) with two energetic regimes: Collision Induced Dissociation (CID) and Higher Collision Dissociation (HCD), respectively, and DFT molecular modeling. These approaches have been achieved by taking into account the interaction of either one or two alkali metals with the host molecules. The results showed a good agreement between experimental and theoretical data. It was demonstrated that increasing the methylation degree strengthened the gas phase affinity towards all studied alkali metals. Furthermore, it was established that the cation selectivity was Na+ > Li+ > K+ and Li+ > Na+ > K+ for the solution and gas phase, respectively.
Chapter 6 - Perspectives in Lithium Batteries A2 - Chagnes, Alexandre
Poizot, P.; Dolhem, F.; Gaubicher, J.; Renault, S.
Lithium Process Chemistry 2015, 191-232.
Abstract Li-ion batteries still fall short of fulfilling the ever-increasing storage needs while keeping their environmental footprint as low as possible. In this chapter, without being exhaustive we tackle what next promising Li-based battery technologies could be; through the implementation of alternative (electro)chemistries including the use of more abundant components and/or less-polluting processing solutions. Li-chalcogen (O2 and S) batteries are presented herein as quite promising systems especially for the market of electrically powered vehicles thanks to particularly high (expected) energy density values. Li-aqueous batteries, beyond the obvious environmental benefit in using water-based electrolytes, offer also some attractive perspectives to promote low-cost electrical storage solutions, potentially interesting for stationary applications. Finally, electroactive organic compounds could play an important role in the forthcoming battery technologies, since they exhibit several assets such as the possibility of being prepared from renewable resources and eco-friendly processes coupled with a simplified recycling management.
Cooperative DNA Recognition Modulated by an Interplay between Protein-Protein Interactions and DNA-Mediated Allostery
Merino, F.; Bouvier, B.; Cojocaru, V.
PLoS Comput. Biol. 2015, 11, e1004287.
Pluripotent stem cells can give rise to all somatic lineages. When taken out of the context of the embryo they can be maintained and for this a core transcriptional regulatory circuitry is crucial. OCT4 and SOX2, two factors of this network, are also critical for the induction of pluripotency in somatic cells. In pluripotent cells, OCT4 and SOX2 associate on DNA regulatory regions, enhancing or modifying each other's sequence specificity. In contrast, in the early stages during induction of pluripotency, it was proposed that OCT4 explores the genome independent of SOX2. Here we report the mechanism by which SOX2 influences the orientation, dynamics, and unbinding free energy profile of OCT4. This involves an interplay of protein-protein interactions and DNA-mediated allostery. We consider that this mechanism enables OCT4 to use its DNA binding domains and the interaction partners available in a certain biological context to access alternative genome exploration routes. This study enhances the understanding of the context specific function of OCT4 and provides a general perspective on how DNA-binding cooperativity is modulated by different types of interactions.
Metal-Free Oxidative Lactonization of Carbohydrates Using Molecular Iodine
Maxime, B. F.; Vincent, C.; Solen, J.; Nicolas, D.; Guillaume, A.; Denis, P.
Carbohydrate Chemistry 2015, 33-38.
Metal-Free, Diamine-Mediated, Oxidative Monoamidation of Benzylated Carbohydrates
Maxime, B. F.; Vincent, C.; Christophe, D.; Denis, P.
Carbohydrate Chemistry 2015, 27-32.
Presents reliable and tested protocols for preparation of intermediates for carbohydrate synthesis Offers a unique resource in carbohydrate chemistry, compiling useful information in one reference Explores carbohydrate chemistry from both the academic and industrial points of view Features contributions from world-renowned experts and is overseen by a highly respected series editor
A rechargeable lithium/quinone battery using a commercial polymer electrolyte
Lecuyer, M.; Gaubicher, J.; Barres, A.-L.; Dolhem, F.; Deschamps, M.; Guyomard, D.; Poizot, P.
Electrochem. Commun. 2015, 55, 22-25.
The present study reports superior electrochem. performance with capacity doubled for org. pos. electrodes based on a small redox-active mol. when using the Lithium Metal Polymer (LMP) technol. Particularly, the simple use of the regular solid polymer electrolyte currently employed in com. LMP cells allows obtaining for the first time an efficient two-electron cycling of tetramethoxy-p-benzoquinone with high-rate capability at temps. as high as 100 °C. With no optimization, the restored capacity represents 80% of the theor. value (190 mAh/g) after 20 cycles operated at a C rate. On the contrary, when cycled in conventional carbonate-based electrolytes, this quinone compd. exhibits quite poor electrochem. features such as a very limited depth of discharge (∼ 50% of the theor. capacity in the first cycle) followed by rapid capacity decay. After cycling, preliminary post-mortem characterizations did not evidence any obvious degrdn. in the cell. Although the adverse effect of the diffusion of the active material is not fully inhibited, the coulombic efficiency is close to 100% while the Li/electrolyte interface appears stable.
Ligand-free Pd-catalyzed and copper-assisted C-H arylation of quinazolin-4-ones with aryl iodides under microwave heating
Laclef, S.; Harari, M.; Godeau, J.; Schmitz-Afonso, I.; Bischoff, L.; Hoarau, C.; Levacher, V.; Fruit, C.; Besson, T.
Org. Lett. 2015, 17, 1700-3.
A microwave-assisted method for the palladium-catalyzed direct arylation of quinazolin-4-one has been developed under copper-assistance. This method is applicable to a wide range of aryl iodides and substituted (2H)-quinazolin-4-ones. This protocol provides a simple and efficient way to synthesize biologically relevant 2-arylquinazolin-4-one backbones.
Toward multifunctional "clickable" diamond nanoparticles
Khanal, M.; Turcheniuk, V.; Barras, A.; Rosay, E.; Bande, O.; Siriwardena, A.; Zaitsev, V.; Pan, G. H.; Boukherroub, R.; Szunerits, S.
Langmuir 2015, 31, 3926-33.
Nanodiamonds (NDs) are among the most promising new carbon based materials for biomedical applications, and the simultaneous integration of various functions onto NDs is an urgent necessity. A multifunctional nanodiamond based formulation is proposed here. Our strategy relies on orthogonal surface modification using different dopamine anchors. NDs simultaneously functionalized with triethylene glycol (EG) and azide (-N3) functions were fabricated through a stoichiometrically controlled integration of the dopamine ligands onto the surface of hydroxylated NDs. The presence of EG functionalities rendered NDs soluble in water and biological media, while the -N3 group allowed postsynthetic modification of the NDs using "click" chemistry. As a proof of principle, alkynyl terminated di(amido amine) ligands were linked to these ND particles.
Inhibition of type 1 fimbriae-mediated Escherichia coli adhesion and biofilm formation by trimeric cluster thiomannosides conjugated to diamond nanoparticles
Khanal, M.; Larsonneur, F.; Raks, V.; Barras, A.; Baumann, J. S.; Martin, F. A.; Boukherroub, R.; Ghigo, J. M.; Ortiz Mellet, C.; Zaitsev, V.; Garcia Fernandez, J. M.; Beloin, C.; Siriwardena, A.; Szunerits, S.
Nanoscale 2015, 7, 2325-35.
Recent advances in nanotechnology have seen the development of a number of microbiocidal and/or anti-adhesive nanoparticles displaying activity against biofilms. In this work, trimeric thiomannoside clusters conjugated to nanodiamond particles (ND) were targeted for investigation. NDs have attracted attention as a biocompatible nanomaterial and we were curious to see whether the high mannose glycotope density obtained upon grouping monosaccharide units in triads might lead to the corresponding ND-conjugates behaving as effective inhibitors of E. coli type 1 fimbriae-mediated adhesion as well as of biofilm formation. The required trimeric thiosugar clusters were obtained through a convenient thiol-ene "click" strategy and were subsequently conjugated to alkynyl-functionalized NDs using a Cu(I)-catalysed "click" reaction. We demonstrated that the tri-thiomannoside cluster-conjugated NDs (ND-Man3) show potent inhibition of type 1 fimbriae-mediated E. coli adhesion to yeast and T24 bladder cells as well as of biofilm formation. The biofilm disrupting effects demonstrated here have only rarely been reported in the past for analogues featuring such simple glycosidic motifs. Moreover, the finding that the tri-thiomannoside cluster (Man3N3) is itself a relatively efficient inhibitor, even when not conjugated to any ND edifice, suggests that alternative mono- or multivalent sugar-derived analogues might also be usefully explored for E. coli-mediated biofilm disrupting properties.
Arylnaphthalene and aryltetralin-type lignans in hairy root cultures of Linum perenne, and the stereochemistry of 6-methoxypodophyllotoxin and one diastereoisomer by HPLC-MS and NMR spectroscopy
Jullian-Pawlicki, N.; Lequart-Pillon, M.; Huynh-Cong, L.; Lesur, D.; Cailleu, D.; Mesnard, F.; Laberche, J. C.; Gontier, E.; Boitel-Conti, M.
Phytochem. Anal. 2015, 26, 310-9.
INTRODUCTION: Hairy root cultures of Linum sp. are an alternative for the high production of lignans. Linum perenne is known to produce arylnaphthalene-type lignans such as justicidin B, isojusticidin and diphyllin. OBJECTIVE: To elucidate the presence of aryltetralin-type lignan diastereoisomers, besides the known arylnaphthalene-type lignans, in hairy roots of Linum perenne, and to determine the configurations of one diastereoisomer of 6-methoxypodophyllotoxin (6-MPTOX). METHODS: Lignans from hairy root cultures of Linum perenne were extracted and separated by HPLC. Arylnaphthalene-type lignans were identified by LC-MS, according to the literature. Two diastereoisomers of aryltetralin-type lignans were analysed by mass spectrometry and NMR spectroscopy. RESULTS: Numerous arylnaphthalene-type lignans (diphyllin-2-hexose-pentose, diphyllin-3-pentose and diphyllin-hexose) were identified in hairy root cultures. Methoxypodophyllotoxin, an aryltetralin-type lignan, was also identified, as well as one diastereoisomer. This aryltetralin-type lignan could be derived via 7-hydroxymatairesinol as a hypothetical biosynthetic pathway. The stereochemical configurations of aryltetralin isomers were determined. CONCLUSION: Arylnaphthalene and two diastereoisomers of aryltetralin-type lignans are produced in Linum perenne hairy root cultures. Matairesinol, the precursor of justicidin B, also seems to be converted into 6-MPTOX via 7-hydroxymatairesinol. This is the first report of the stereochemical configurations of an aryltetralin-type lignan other than podophyllotoxin (PTOX).
Cu/Pd-Catalyzed C-2-H Arylation of Quinazolin-4(3H)-ones with (Hetero)aryl Halides
Godeau, J.; Harari, M.; Laclef, S.; Deau, E.; Fruit, C.; Besson, T.
Eur. J. Org. Chem. 2015, 2015, 7705-7717.
The regiospecific C-2-H arylation of N-3-substituted quinazolin-4(3H)-ones with a wide range of aryl or (hetero)aryl halides under microwave irradn. was studied. A ligand-dependent palladium/copper bicatalytic system was developed and allowed direct cross-coupling with a variety of (hetero)aryl halides. This useful and scalable procedure promotes the construction of C(sp2)-C(sp2) bonds from arenes or (hetero)arenes and aryl or (hetero)aryl bromides and chlorides in a time-efficient strategy. The extension of the reaction to various N-3-substituted quinazolin-4(3H)-ones with iodobenzene as well as the scope and limitations of the method were also investigated.
Reactivity of D-fructose and D-xylose in acidic media in homogeneous phases
Fusaro, M. B.; Chagnault, V.; Postel, D.
Carbohydr. Res. 2015, 409, 9-19.
A review. Chem. development of renewable resources is a real challenge. Carbohydrates from biomass are complex and their use as substitutes for fossil materials remains difficult (European involvement on the incorporation of 20% raw material of plant origin in 2020). Most of the time, the transformation of these polyhydroxylated structures are carried out in acidic conditions. Recent reviews on this subject describe homogeneous catalytic transformations of pentoses, specifically toward furfural, and also the transformation of biomass-derived sugars in heterogeneous conditions. To complete these informations, the objective of this review is to give an overview of the structural variety described during the treatment of two monosaccharides (D-Fructose and D-xylose) in acidic conditions in homogeneous phases. The reaction mechanisms being not always detd. with certainty, we will also provide a brief state of the art regarding this.
Synthesis of high-mannose oligosaccharide analogues through click chemistry: true functional mimics of their natural counterparts against lectins?
Francois-Heude, M.; Mendez-Ardoy, A.; Cendret, V.; Lafite, P.; Daniellou, R.; Ortiz Mellet, C.; Garcia Fernandez, J. M.; Moreau, V.; Djedaini-Pilard, F.
Chemistry 2015, 21, 1978-91.
Terminal "high-mannose oligosaccharides" are involved in a broad range of biological and pathological processes, from sperm-egg fusion to influenza and human immunodeficiency virus infections. In spite of many efforts, their synthesis continues to be very challenging and actually represents a major bottleneck in the field. Whereas multivalent presentation of mannopyranosyl motifs onto a variety of scaffolds has proven to be a successful way to interfere in recognition processes involving high-mannose oligosaccharides, such constructs fail at reproducing the subtle differences in affinity towards the variety of protein receptors (lectins) and antibodies susceptible to binding to the natural ligands. Here we report a family of functional high-mannose oligosaccharide mimics that reproduce not only the terminal mannopyranosyl display, but also the core structure and the branching pattern, by replacing some inner mannopyranosyl units with triazole rings. Such molecular design can be implemented by exploiting "click" ligation strategies, resulting in a substantial reduction of synthetic cost. The binding affinities of the new "click" high-mannose oligosaccharide mimics towards two mannose specific lectins, namely the plant lectin concanavalin A (ConA) and the human macrophage mannose receptor (rhMMR), have been studied by enzyme-linked lectin assays and found to follow identical trends to those observed for the natural oligosaccharide counterparts. Calorimetric determinations against ConA, and X-ray structural data support the conclusion that these compounds are not just another family of multivalent mannosides, but real "structural mimics" of the high-mannose oligosaccharides.
Octyl glucoside derivatives: A tool against metal pollutants
Ferlin, N.; Grassi, D.; Ojeda, C.; Castro, M. J. L.; Cirelli, A. F.; Kovensky, J.; Grand, E.
Colloids and Surfaces A: Physicochemical and Engineering Aspects 2015, 480, 439-448.
Derivatives of octyl glucoside modified by the introduction of a chemical function (carboxylic acid, hydroxamic acid) able to enhance the complexing properties of the surfactants toward metallic cations have been used as flotation collectors to remove various metallic cations from a water phase. Flotation experiments at the laboratory scale were performed on Fe(III), Cu(II), Cr(III), Cd(II), Zn(II), Ni(II) and As(III) aqueous solutions. The most interesting results were obtained in the extraction of Fe(III) and Cu(II). Interfacial properties were studied, and the effect of the polar head structure and anomeric configuration was analyzed. Structural variations have an influence on the efficiency and the foaming ability of these compounds. The introduction of a chelating functionality preserves the interfacial performances of these surfactants. Complexes equilibrium constants and species distribution diagrams for Fe(III) and the best flotation agents 2a and 2b were determined from multi-wavelength spectrophotometric pH titration. Both compounds showed analogous values for log β1, log β2 and log β3. The bidentanted Fe(III)-hydroxamate species (2:1 surfactant-metal ratio) reached a maximum concentration in the pH range of 5.5-6.5. At this pH, the best results in the flotation experiments were obtained for both compounds.
SiO2/Ionic Liquid Hybrid Nanoparticles for Solid-State Lithium Ion Conduction
Delacroix, S.; Sauvage, F.; Reynaud, M.; Deschamps, M.; Bruyère, S.; Becuwe, M.; Postel, D.; Tarascon, J.-M.; Van Nhien, A. N.
Chem. Mater. 2015, 27, 7926-7933.
We report the physical and electrical characterization of a series of substituted imidazolium-based ionic liquids grafted on Stöber-type SiO2. This hybrid architecture affords an increase of the lithium transference to 0.56 by hindering TFSI? (bis(trifluoromethane)sulfonimide) mobility to the total ionic conductivity. When doped with 16 wt % wt LiTFSI, the resulting hybrid organic/inorganic solid material exhibits a lithium diffusion coefficient of 2 ? 10?12 m2/s at 87 °C and a conductivity of ca. 10?6 S/cm at room temperature and 10?4 S/cm at 65 °C with an activation energy barrier of 0.89 eV.
Selectivity of pyoverdine recognition by the FpvA receptor of Pseudomonas aeruginosa from molecular dynamics simulations
Bouvier, B.; Cezard, C.; Sonnet, P.
Phys. Chem. Chem. Phys. 2015, 17, 18022-18034.
The Gram-negative bacterium Pseudomonas aeruginosa, a ubiquitous human opportunistic pathogen, has developed resistances to multiple antibiotics. It uses its primary native siderophore, pyoverdine, to scavenge the iron essential to its growth in the outside medium and transport it back into its cytoplasm. The FpvA receptor on the bacterial outer membrane recognizes and internalizes pyoverdine bearing its iron payload, but can also bind pyoverdines from other Pseudomonads or synthetic analogues. Pyoverdine derivatives could therefore be used as vectors to deliver antibiotics into the bacterium. In this study, we use molecular dynamics and free energy calculations to characterize the mechanisms and thermodynamics of the recognition of the native pyoverdines of P. aeruginosa and P. fluorescens by FpvA. Based on these results, we delineate the features that pyoverdines with high affinity for FpvA should possess. In particular, we show that (i) the dynamics and interaction of the unbound pyoverdines with water should be optimized with equal care as the interface contacts in the complex with FpvA; (ii) the C-terminal extremity of the pyoverdine chain, which appears to play no role in the bound complex, is involved in the intermediate stages of recognition; and (iii) the length and cyclicity of the pyoverdine chain can be used to fine-tune the kinetics of the recognition mechanism.
Cyclodextrin nanoassemblies: a promising tool for drug delivery
Bonnet, V.; Gervaise, C.; Djedaïni-Pilard, F.; Furlan, A.; Sarazin, C.
Drug Discovery Today 2015, 20, 1120-1126.
Among the biodegradable and nontoxic compounds that can form nanoparticles for drug delivery, amphiphilic cyclodextrins are very promising. Apart from ionic cyclodextrins, which have been extensively studied and reviewed because of their application in gene delivery, our purpose is to provide a clear description of the supramolecular assemblies of nonionic amphiphilic cyclodextrins, which can form nanoassemblies for controlled drug release. Moreover, we focus on the relationship between their structure and physicochemical characteristics, which is crucial for self assembly and drug delivery. We also highlight the importance of the nanoparticle technology preparation for the stability and application of this nanodevice.
Alditol thiacrowns via a ring-closing metathesis of carbohydrate-derived α,ω-dithioallylethers
Benazza, M.; Danquigny, A.; Novogrocki, G.; Valgimigli, L.; Amorati, R.; Ferroni, F.; Demailly-Mullie, C.; Siriwardena, A.; Lesur, D.; Aubry, F.; Demailly, G.
Tetrahedron 2015, 71, 5602-5609.
We report a newly developed synthesis of a no. of alditol thiacrowns using an eco-friendly and versatile two-step strategy: the regioselective thioallyletherification of a polyhydroxylated alditol followed by a ring closing metathesis using the Grubbs second generation catalyst. This approach allows a series of target thiacrown products to be obtained in acceptable to good yields, from the corresponding α,ω-dithioallylether alditol starting materials featuring either the xylo, ribo, threo, erythro, D-manno or D-gluco configurations. The per-O-acetylated D-mannitol dithioallyether 10, easily obtained on a large scale using this approach, was selected for evaluation as both an antibacterial and an antioxidant. Although no antibacterial activity was obsd. for the bacterial strains investigated, compd. 10 is shown to be an antioxidant, and able to quench hydrogen peroxide in a stoichiometric fashion.
Cholesteryl and diosgenyl glycosteroids: synthesis and characterization of new smectic liquid crystals
Beaulieu, R.; Gottis, S.; Meyer, C.; Grand, E.; Deveaux, V.; Kovensky, J.; Stasik, I.
Carbohydr. Res. 2015, 404, 70-78.
While present in large numbers in nature, studies on the physical chemical aspects of glycosteroids are quite rare and focused on cholesterol, and all compounds studied thus far have shown liquid crystalline properties in a narrow temperature range. New glycosteroids composed by cholesterol or diosgenin and different glycosidic moieties have been synthesized here in order to analyze the influence of the structure on the formation of mesophases. These compounds have been studied by crossed polarized optical microscopy. These studies have revealed that these new glycosteroids form Smetic A liquid crystals in a broad temperature range.
Preparation of solanidine-derived glycosides and oligosaccharides as insecticides
Beaulieu, R.; Attoumbre, J.; Gobert-Deveaux, V.; Grand, E.; Stasik, I.; Kovensky, J.; Giordanengo, P.
2015, 56pp.; Chemical Indexing Equivalent to 162:219449 (FR).
The claimed synthesized solanidine derivs. I, where X = O or S and R1 = saccharidic or thiosaccharidic side-chain with 1-10 pentose and/or hexose units (esp. glucosyl, galactosyl and rhamnosyl units). The solanidine derivs. can be synthesized starting from the compd. II. Thus, glycoside I (X = O, R1 = β-glucopyranosyl) was prepd. and tested as insecticide agent against Macrosiphum euphorbiae. The compds. have toxic and/or repellent effects on aphids and other properties, including insecticidal, nematicidal, antiviral, antibacterial, and antifungal activities in agrochem. and pharmaceutical sense. The solanidine derivs. may be used as plant protective agents esp. against aphid pests.
Plasmon waveguide resonance for sensing glycan-lectin interactions
Alves, I.; Kurylo, I.; Coffinier, Y.; Siriwardena, A.; Zaitsev, V.; Harte, E.; Boukherroub, R.; Szunerits, S.
Anal. Chim. Acta 2015, 873, 71-9.
Carbohydrate-modified interfaces have been shown to be valuable tools for the study of protein-glycan recognition events. Label-free approache such as plasmonic based techniques are particularly attractive. This paper describes a new analytical platform for the sensitive and selective screening of carbohydrate-lectin interactions using plasmon waveguide resonance. Planar optical waveguides (POW), consisting of glass prisms coated with silver (50 nm) and silica (460 nm) layers were derivatized with mannose or lactose moieties. The specific association of the resulting interface with selected lectins was assessed by following the changes in its plasmonic response. The immobilization strategy investigated in this work is based on the formation of a covalent bond between propargyl-functionalized glycans and surface-linked azide groups via a Cu(I) "click" chemistry. Optimization of the surface architecture through the introduction of an oligo(ethylene glycol) spacer between the plasmonic surface and the glycan ligands provided an interface which allowed screening of glycan-lectin interactions in a highly selective manner. The limit of detection (LOD) of this method for this particular application was found to be in the subnanomolar range (0.5 nM), showing it to constitute a promising analytical platform for future development and use in a pharmaceutical or biomedical setting.
Concise synthesis of C-1-cyano-iminosugars via a new Staudinger/aza Wittig/Strecker multicomponent reaction strategy
Zoidl, M.; Müller, B.; Torvisco, A.; Tysoe, C.; Benazza, M.; Siriwardena, A.; Withers, S. G.; Wrodnigg, T. M.
Bioorg. Med. Chem. Lett. 2014, 24, 2777-2780.
A new Staudinger/aza Wittig/Strecker multicomponent reaction sequence to C-1-cyano iminoalditols has been developed. When applied to 5-azidodeoxy-d-xylose and -d-glucose as substrates the method leads smoothly in good yield and with excellent stereoselectivity to respectively, 1,5-dideoxy-1,5-imino-d-idurono nitrile and 2,6-didesoxy-2,6-imino-d-glycero-d-ido-heptononitrile.
Quantitative assessment of the multivalent protein-carbohydrate interactions on silicon
Yang, J.; Chazalviel, J. N.; Siriwardena, A.; Boukherroub, R.; Ozanam, F.; Szunerits, S.; Gouget-Laemmel, A. C.
Anal. Chem. 2014, 86, 10340-9.
A key challenge in the development of glycan arrays is that the sensing interface be fabricated reliably so as to ensure the sensitive and accurate analysis of the protein-carbohydrate interaction of interest, reproducibly. These goals are complicated in the case of glycan arrays as surface sugar density can influence dramatically the strength and mode of interaction of the sugar ligand at any interface with lectin partners. In this Article, we describe the preparation of carboxydecyl-terminated crystalline silicon (111) surfaces onto which are grafted either mannosyl moieties or a mixture of mannose and spacer alcohol molecules to provide "diluted" surfaces. The fabrication of the silicon surfaces was achieved efficiently through a strategy implicating a "click" coupling step. The interactions of these newly fabricated glycan interfaces with the lectin, Lens culinaris, have been characterized using quantitative infrared (IR) spectroscopy in the attenuated total geometry (ATR). The density of mannose probes and lectin targets was precisely determined for the first time by the aid of special IR calibration experiments, thus allowing for the interpretation of the distribution of mannose and its multivalent binding with lectins. These experimental findings were accounted for by numerical simulations of lectin adsorption.
Synthesis of Unsymmetrical Thioethers Using an Uncommon Base-Triggered 1,5-Thiol Transfer Reaction of 1-Bromo-2-alkylthiolcarbonates
Taouai, M.; Abidi, R.; Garcia, J.; Siriwardena, A.; Benazza, M.
J. Org. Chem. 2014, 79, 10743-10751.
Described herein is a convenient, odorless, metal-free, one-pot strategy for the synthesis of unsym. thioethers. The key step in this new strategy is a base-catalyzed 1,5-thiol transfer reaction via a pseudointramol. mechanism of a 1-bromo-2-alkylthiolcarbonate, which is itself obtained through a straightforward microwave-assisted thioalkylation of a 1,2-cyclic-thionocarbonate precursor with an appropriate alkyl bromide. The starting 1,2-cyclic-thionocarbonates are easily obtained from the corresponding diols. When a propargylthiolcarbonate constitutes the key alkylthiolcarbonate 1,5-shift precursor, a copper-mediated dipolar cycloaddn. reaction ("click") with azide partners is rendered possible. This increases the versatility of the approach, as a very large variety of complex triazole-tethered substrates can potentially be integrated into the target unsym. thioether final products. As an example of the scope of the reaction, four 1,5-shift reactions have been triggered simultaneously from a sugar-derived tetrathiolcarbonate precursor using base catalysis, to allow four 6-thioglucose moieties to be installed (78% yield for each sugar unit) onto a 1,3-alternate thiacalixarene scaffold in a one-pot transformation.
Triterpenes and steroids from the stem bark of Gambeya boiviniana Pierr
Rasoanaivo, L. H.; Wadouachi, A.; Andriamampianina, T.; Andriamalala, S.; Razafindrakoto, E.; Raharisololalao, A.
J Pharmacogn Phytochem 2014, 3, 68-72.
A chemical study was done on the stem bark of Gambeya boiviniana Pierre. This plant has been used in traditional medicine for treatment of different kinds of inflammation disorders. In the present study, anti- inflammatory activities of ethanolic, dichloromethane, ethyl acetate and butanolic extracts were assayed in mice using carrageenan-induced paw edema. Ethyl acetate extract was found to possess the most significant anti-inflammatory effect (67, 78%). These results are in accordance with the folk use of this plant. However, more research is needed for its use in clinical studies. The separations of the chemical compounds of ethyl acetate extract were carried out by different chromatographic technics and their structures were elucidated by spectroscopic method including nuclear magnetic, mass spectrometry, IR spectrometry, GC/MS. Nine compounds were identified during this investigation. There are lupeol acetate 3, β amyrin acetate 4, α amyrin acetate 6, taraxasterol acetate 5, fatty acid ester of lupeol 2 and fatty acid ester of β-amyrin 1, chondrillasterol 7, β-sitosterol 8, β-sitosterol-3-O-glucoside 9.
Development of an NMR metabolomics-based tool for selection of flaxseed varieties
Ramsay, A.; Fliniaux, O.; Fang, J.; Molinie, R.; Roscher, A.; Grand, E.; Guillot, X.; Kovensky, J.; Fliniaux, M.-A.; Schneider, B.; Mesnard, F.
Metabolomics 2014, 10, 1258-1267.
Flaxseed is an important source of lignans and ω-3 fatty acids, compounds which present interest in human health with many applications in food industry. It is therefore necessary to precisely know the metabolite content in flaxseed. A metabolomic approach using NMR was developed to achieve this goal. Due to particular characteristics of flaxseed (high level in oil, high amount in mucilage, and integration of the phenolics into a macromolecule), the extraction procedure had first to be optimized using an experimental design, based on the extraction time, in a water bath or an ultrasound bath, alkaline treatment, defatting, and centrifugation temperature. This methodology was then applied to several flaxseed varieties classified in function of their content in ω-3 fatty acid. The main differences in semi-polar metabolites between these varieties concern compounds of the phenylpropanoid pathway. Hydroxycinnamic acid glucoside and lignan content increase when ω-3 fatty acid content decrease whereas flavonoid content increase in the same way of ω-3 fatty acids.
On the chiroptical properties of Au(i)–thiolate glycoconjugate precursors and their influence on sugar-protected gold nanoparticles (glyconanoparticles)
Pourceau, G.; Valle-Carrandi, L. d.; Di Gianvincenzo, P.; Michelena, O.; Penadés, S.
RSC Adv. 2014, 4, 59284-59288.
Chiral gold nanoparticles passivated with glycoconjugates were prepared. By extensive washing, they lost their chiroptical activity, whereas highly luminescent compounds isolated from the washing reproduced the original ellipticity. A systematic characterization of these compounds, Au(i) precursors and glyconanoparticles allowed us to unravel the origin of the observed chiroptical activity.
Cyclodextrin-grafted polymers functionalized with phosphanes: a new tool for aqueous organometallic catalysis
Potier, J.; Menuel, S.; Mathiron, D.; Bonnet, V.; Hapiot, F.; Monflier, E.
Beilstein J. Org. Chem. 2014, 10, 2642-2648, 7 pp.
New cyclodextrin (CD)-grafted polymers functionalized with water-sol. phosphanes were synthesized in three steps starting from N-succinimidyl acrylate homopolymer. Once characterized by NMR spectroscopy and size-exclusion chromatog., they were used as additives in Rh-catalyzed hydroformylation of 1-hexadecene. The combined supramol. and coordinating properties of these polymers allowed increasing the catalytic activity of the reaction without affecting the selectivities.
A green approach to the synthesis of novel phytosphingolipidyl β-cyclodextrin designed to interact with membranes
Miao, Y.; Djedaini-Pilard, F.; Bonnet, V.
Beilstein J. Org. Chem. 2014, 10, 2654-2657, 4 pp.
This work reports the synthesis of a new family of mono-substituted amphiphilic cyclodextrins using a green methodol. Reactions using greener and safer catalysts with more environmentally friendly purifn. solvents were performed. Four unreported mono-substituted cyclodextrins bearing a phytosphingolipidyl chain and a fatty acid chain (C10, C12, C14 and C18) were successfully obtained with a promising yield.
The synthesis of a glucoconjugate of the peptidic fragment of cryptophycin-24
Mezrai, A.; Lesur, D.; Wadouachi, A.; Pilard, F.; Mulengi, J. K.
Mediterranean Journal of Chemistry 2014, 3, 935-946.
A novel glucoconjugate of the peptidic fragment of cryptophycin-24 was prepd. through the replacement of the leucic acid residue with L-leucine and the functionalisation of tyrosine residue with glucose. Those modifications lead to a novel protected tripeptide fragment of cryptophycin-24.
The Synthesis of an Aziridinyl Analogue of Unit A of Cryptophycin-1
Mezrai, A.; Drici, W.; Lesur, D.; Mulengi, J.; Wadouachi, A.; Pilard, F.
Lett. Org. Chem. 2014, 11, 259-267.
A novel analog of unit A of cryptophycin-1 was prepd. starting from com. trans-cinnamaldehyde. The modifications introduced into the new structure related to the replacement of the epoxide with an aziridine moiety, and the inclusion of the 1,3-enone moiety into an arom. ester frame through the synthesis of a key arom. ketone. Asymmetry was induced during the later steps of the synthetic pathway. The optical purity of compds. was monitored by chiral HPLC and polarimetric measurements.
Efficient synthesis of glycosylamines in solventless conditions promoted by mechanical milling
Lingome, C. E.; Pourceau, G.; Gobert-Deveaux, V.; Wadouachi, A.
RSC Advances 2014, 4, 36350.
A mecanosynthesis of glycosylamines under solventless conditions was established. This environmentally friendly approach optimized with L-rhamnose, was investigated using a variety of amines and other carbohydrates. High reaction yields and simple work-up allow the clean and fast synthesis of a variety of glycosylamines and glycosyl-(di)-amines.
Pyrolysis reaction of squaric acid: A one-step method for producing expanded foam of mesoporous carbon
Leclere, M.; Lejeune, M.; Dupont, L.; Barres, A.-L.; Renault, S.; Dolhem, F.; Poizot, P.
Mater. Lett. 2014, 137, 233-236.
A template-free approach is described for the synthesis of expanded foams of mesoporous carbon exhibiting high surface areas ranging from 550 to 1100 m2.g-1. The procedure is based on the exceptional carbonization reaction that occurs with squaric acid (H2C4O4), a strained four-membered carbocycle belonging to the oxocarbon acids. Indeed the pyrolysis reaction proceeds just above 300 °C through an amazing one-step and sharp exothermic phenomenon coupled with a wt. loss of 90%, thereby promoting a porous structure. This massive gas release behaves also as a "fluid" template during the carbon prodn., which explains the formation of expanded foams. This particular thermal behavior seems related to the phase transition that occurs in H2C4O4 crystals at Tc=121 °C. Below Tc the planar squaric acid mols. exhibit a fully ordered structure in a monoclinic system whereas for T>Tc the structure undergoes a disordered tetragonal structure where all C-O bonds of squaric acid become statistically equiv. in a perfect square, making a discrete thermal decompn. reaction possible.
Scalable asymmetric synthesis of a key fragment of Bcl-2/Bcl-xLinhibitors
Laclef, S.; Taillier, C.; Penloup, C.; Viger, A.; Brière, J.-F.; Hardouin, C.; Levacher, V.
RSC Adv. 2014, 4, 39817.
The asym. synthesis of a 1,3-diamine building block for the elaboration of Bcl-2 and Bcl-xL protein inhibitors is described through two key steps: (1) a highly diastereoselective aza-Reformatsky reaction, and (2) a chemoselective amination under Mitsunobu conditions. This synthetic sequence was also demonstrated to be successfully amenable to a large-scale synthesis.
Synthesis of 1,2:4,5-Di-O-(3,3-pentylidene) arabitol via Kinetic Acetal Formation
KonradHohlfeld; SolenJosse; SylvainPicon; Bruno, L.
Carbohydrate Chemistry 2014, 231-238.
The synthesis of 1,2:4,5-Di-O-(3,3-pentylidene) arabitol via kinetic acetal formation is presented.
A convenient procedure for the synthesis of chiral 6,7-dihydroxy-1-phenylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones
Kacem, Y.; Hassine, B. B.
Tetrahedron: Asymmetry 2014, 25, 252-257.
The cyclocondensation reactions between l-α-amino acid phenylhydrazides and 2,3-O-isopropylidene-l-erythruronolactone in the presence of a catalytic amount of p-toluenesulfonic acid afforded diastereomerically pure (3S,6R,7R,7aS)-3-substituted-6,7-isopropylidenedioxy-1-phenylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones, which were converted by acidic hydrolysis with MeOH–HCl into their corresponding optically active (3S,6R,7R,7aS)-3-substituted-6,7-dihydroxy-1-phenylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones in good yields.
N-cadherin/wnt interaction controls bone marrow mesenchymal cell fate and bone mass during aging
Hay, E.; Dieudonne, F. X.; Saidak, Z.; Marty, C.; Brun, J.; Da Nascimento, S.; Sonnet, P.; Marie, P. J.
J. Cell. Physiol. 2014, 229, 1765-75.
Age-related bone loss is characterized by reduced osteoblastogenesis and excessive bone marrow adipogenesis. The mechanisms governing bone marrow mesenchymal stromal cell (BMSC) differentiation into adipocytes or osteoblasts during aging are unknown. We show here that overexpressing N-cadherin (Cadh2) in osteoblasts increased BMSC adipocyte differentiation and reduced osteoblast differentiation in young transgenic (Tg) mice whereas this phenotype was fully reversed with aging. The reversed phenotype with age was associated with enhanced Wnt5a and Wnt10b expression in osteoblasts and a concomitant increase in BMSC osteogenic differentiation. Consistent with this mechanism, conditioned media from young wild type osteoblasts inhibited adipogenesis and promoted osteoblast differentiation in BMSC from old Cadh2 Tg mice, and this response was abolished by Wnt5a and Wnt10b silencing. Transplantation of BMSC from old Cadh2 Tg mice into young Tg recipients increased Wnt5a and Wnt10b expression and rescued BMSC osteogenic differentiation. In senescent osteopenic mice, blocking the CADH2-Wnt interaction using an antagonist peptide increased Wnt5a and Wnt10b expression, bone formation, and bone mass. The data indicate that Cadh2/Wnt interaction in osteoblasts regulates BMSC lineage determination, bone formation, and bone mass and suggest a therapeutic target for promoting bone formation in the aging skeleton.
Chapter 11 Anionic oligosaccharides: synthesis and applications
Grand, E.; Kovensky, J.; Pourceau, G.; Toumieux, S.; Wadouachi, A.
Carbohydrate Chemistry: Volume 40 2014, 40, 195-235.
Voltage Gain in Lithiated Enolate-Based Organic Cathode Materials by Isomeric Effect
Gottis, S.; Barres, A.-L.; Dolhem, F.; Poizot, P.
ACS Appl. Mater. Interfaces 2014, 6, 10870-10876.
Li-ion batteries (LIBs) appear nowadays as flagship technol. able to power an increasing range of applications starting from small portable electronic devices to advanced elec. vehicles. Over the past 2 decades, the discoveries of new metal-based host structures, together with substantial tech. developments, have considerably improved their electrochem. performance, particularly in terms of energy d. To further promote electrochem. storage systems while limiting the demand on metal-based raw materials, a possible parallel research to inorg.-based batteries consists in developing efficient and low-polluting org. electrode materials. For a long time, this class of redox-active materials was disregarded mainly due to stability issues but, in recent years, progress was made demonstrating that orgs. undeniably exhibit considerable assets. From the ongoing research aiming at elaborating lithiated org. cathode materials, the authors report herein on a chem. approach that takes advantage of the pos. potential shift when switching from para to ortho-position in the dihydroxyterephthaloyl system. In practice, dilithium (2,3-dilithium-oxy)-terephthalate compd. (Li4C8H2O6) was 1st produced through an eco-friendly synthesis scheme based on CO2 sequestration, then characterized, and finally tested electrochem. as lithiated cathode material vs. Li. This new org. salt shows promising electrochem. performance, notably fast kinetics, good cycling stability and above all an av. operating potential of 2.85 V vs. Li+/Li0 (i.e., +300 mV in comparison with its para-regioisomer), verifying the relevance of the followed strategy.
Anti-biofilm activity: a function of Klebsiella pneumoniae capsular polysaccharide
Goncalves Mdos, S.; Delattre, C.; Balestrino, D.; Charbonnel, N.; Elboutachfaiti, R.; Wadouachi, A.; Badel, S.; Bernardi, T.; Michaud, P.; Forestier, C.
PLoS One 2014, 9, e99995.
Competition and cooperation phenomena occur within highly interactive biofilm communities and several non-biocides molecules produced by microorganisms have been described as impairing biofilm formation. In this study, we investigated the anti-biofilm capacities of an ubiquitous and biofilm producing bacterium, Klebsiella pneumoniae. Cell-free supernatant from K. pneumoniae planktonic cultures showed anti-biofilm effects on most Gram positive bacteria tested but also encompassed some Gram negative bacilli. The anti-biofilm non-bactericidal activity was further investigated on Staphylococcus epidermidis, by determining the biofilm biomass, microscopic observations and agglutination measurement through a magnetic bead-mediated agglutination test. Cell-free extracts from K. pneumoniae biofilm (supernatant and acellular matrix) also showed an influence, although to a lesser extend. Chemical analyses indicated that the active molecule was a high molecular weight polysaccharide composed of five monosaccharides: galactose, glucose, rhamnose, glucuronic acid and glucosamine and the main following sugar linkage residues [--> 2)-alpha-L-Rhap-(1 -->]; [--> 4)-alpha-L-Rhap-(1 -->]; [alpha-D-Galp-(1 -->]; [--> 2,3)-alpha-D-Galp-(1 -->]; [--> 3)-beta-D-Galp-(1 -->] and, [--> 4)-beta-D-GlcAp-(1 -->]. Characterization of this molecule indicated that this component was more likely capsular polysaccharide (CPS) and precoating of abiotic surfaces with CPS extracts from different serotypes impaired the bacteria-surface interactions. Thus the CPS of Klebsiella would exhibit a pleiotropic activity during biofilm formation, both stimulating the initial adhesion and maturation steps as previously described, but also repelling potential competitors.
Diesterification of 3-[(β-Cyclodextrinyl)succinamido]propane-1,2-diol Catalysed by Lipase: Diastereoselectivity or Tridimensional Substrate Specificity?
Gervaise, C.; Bonnet, V.; Nolay, F.; Cezard, C.; Stasik, I.; Sarazin, C.; Djedaini-Pilard, F.
Eur. J. Org. Chem. 2014, 2014, 6200-6209.
The transesterification of 3-[(β-cyclodextrinyl)succinamido]propane-1,2-diol with fatty esters catalyzed by immobilized lipase from Mucor miehei occurred with very different conversions of the two diastereoisomers [(R)- or (S)-amidopropanediol]. The highest conversion obsd. with the (S)-amidopropanediol can be related to either lipase diastereoselectivity or substrate specificity. To investigate the diastereoselectivity of the lipase, diastereoisomers of the methylated β-cyclodextrin were replaced by methylated glucopyranoside or methylleucine. No discrimination of the diastereoisomers by lipase was obsd. Mol. modeling was performed to assess the lipase selectivity towards the two diastereoisomers. It was found that the (R)-amidopropanediol is stabilized by hydrogen bonding with the cyclodextrin rim resulting in less reactive hydroxy groups.
Microwave-Assisted Extraction of Herbacetin Diglucoside from Flax (Linum usitatissimum L.) Seed Cakes and Its Quantification using an RP-HPLC-UV System
Fliniaux, O.; Corbin, C.; Ramsay, A.; Renouard, S.; Beejmohun, V.; Doussot, J.; Falguières, A.; Ferroud, C.; Lamblin, F.; Lainé, E.; Roscher, A.; Grand, E.; Mesnard, F.; Hano, C.
Molecules 2014, 19, 3025.
Flax (Linum usitatissimum L.) seeds are widely used for oil extraction and the cold-pressed flaxseed (or linseed) cakes obtained during this process constitute a valuable by-product. The flavonol herbacetin diglucoside (HDG) has been previously reported as a constituent of the flaxseed lignan macromolecule linked through ester bonds to the linker molecule hydroxymethylglutaric acid. In this context, the development and validation of a new approach using microwave-assisted extraction (MAE) of HDG from flaxseed cakes followed by quantification with a reverse-phase HPLC system with UV detection was purposed. The experimental parameters affecting the HDG extraction yield, such as microwave power, extraction time and sodium hydroxide concentration, from the lignan macromolecule were optimized. A maximum HDG concentration of 5.76 mg/g DW in flaxseed cakes was measured following an irradiation time of 6 min, for a microwave power of 150 W using a direct extraction in 0.1 M NaOH in 70% (v/v) aqueous methanol. The optimized method was proven to be rapid and reliable in terms of precision, repeatability, stability and accuracy for the extraction of HDG. Comparison with a conventional extraction method demonstrated that MAE is more effective and less time-consuming.
Interface stability of a TiO(2)/3-methoxypropionitrile-based electrolyte: first evidence for solid electrolyte interphase formation and implications
Flasque, M.; Van Nhien, A. N.; Swiatowska, J.; Seyeux, A.; Davoisne, C.; Sauvage, F.
ChemPhysChem 2014, 15, 1126-37.
We report an in-depth study focusing on the stability of a benchmark electrolyte composition based on a low-volatile 3-methoxypropionitrile (MPN) solvent employed in dye-sensitized solar cells. In the presence of TiO2, the semi-conductor surface plays a catalytic role in the thermal degradation of the electrolyte, which induces, among other effects, the nucleation and growth of a uniform solid electrolyte interphase (SEI) layer that wraps TiO2. On the basis of our actual understanding, we argue that SEI formation is responsible for triiodide depletion in the electrolyte during ageing and also has a simultaneous impact on TiO2 optoelectronic properties through the onset of a visible-light absorption tail, energy modification of intraband trap states, and the induction of an increase in both electron lifetime and transport time in TiO2. In-depth characterization of this layer by using XPS and ToF-SIMS indicates that the chemical composition of this SEI results from solvent and additive degradation, that is, iodide, sulfur, cyano, nitrogen, carbon, and imidazolium rings. The SEI thickness, its content, and the concentration profile strongly vary depending on the ageing conditions. The outcome of this new finding is discussed in comparison with literature observations and stresses the difficulties in reaching long-term stability at 85 degrees C by using MPN-based electrolytes unless new interfacial engineering is accomplished to impede pinholes between dye molecules on TiO2.
Synthesis and antibacterial activity of catecholate-ciprofloxacin conjugates
Fardeau, S.; Dassonville-Klimpt, A.; Audic, N.; Sasaki, A.; Pillon, M.; Baudrin, E.; Mullie, C.; Sonnet, P.
Bioorg. Med. Chem. 2014, 22, 4049-4060.
The development of an efficient route to obtain artificial siderophore-antibiotic conjugates active against Gram-neg. bacteria is crucial. Herein, a practical access to triscatecholate enterobactin analogs linked to the ciprofloxacin along with their antibacterial evaluation are described. Two series of conjugates were obtained with and without a piperazine linker which is known to improve the pharmacokinetics profile of a drug. A monocatecholate-ciprofloxacin conjugate was also synthesized and evaluated. The antibacterial activities against Pseudomonas aeruginosa for some conjugates are related to the iron concn. in the culture medium and seem to depend on the bacterial iron uptake systems.
5-O-caffeoylshikimic acid from Solanum somalense leaves: advantage of centrifugal partition chromatography over conventional column chromatography
Chideh, S.; Pilard, S.; Attoumbre, J.; Saguez, R.; Hassan-Abdallah, A.; Cailleu, D.; Wadouachi, A.; Baltora-Rosset, S.
J. Sep. Sci. 2014, 37, 2331-9.
Solanum somalense leaves, used in Djibouti for their medicinal properties, were extracted by MeOH. Because of the high polyphenol and flavonoid contents of the extract, respectively, determined at 80.80 +/- 2.13 mg gallic acid equivalent/g dry weight and 24.4 +/- 1.01 mg quercetin equivalent/g dry weight, the isolation and purification of the main polyphenols were carried out by silica gel column chromatography and centrifugal partition chromatography. Column chromatography led to 11 enriched fractions requiring further purification, while centrifugal partition chromatography allowed the easy recovery of the main compound of the extract. In a solvent system composed of CHCl3/MeOH/H2O (9.5:10:5), 21.8 mg of this compound at 97% purity was obtained leading to a yield of 2.63%. Its structure was established as 5-O-caffeoylshikimic acid by mass spectrometry and NMR spectroscopy. This work shows that S. somalense leaves contain very high level of 5-O-caffeoylshikimic acid (0.74% dry weight), making it a potential source of production of this secondary metabolite that is not commonly found in nature but could be partly responsible of the medicinal properties of S. somalense leaves.
Synthesis of divalent ligands of β-thio-and β-N-galactopyranosides and related lactosides and their evaluation as substrates and inhibitors of Trypanosoma cruzi trans-sialidase
Cano, M. E.; Agusti, R.; Cagnoni, A. J.; Tesoriero, M. F.; Kovensky, J.; Uhrig, M. L.; de Lederkremer, R. M.
Beilstein J. Org. Chem. 2014, 10, 3073-3086.
In this work we describe the synthesis of mono- and divalent beta-N- and beta-S-galactopyranosides and related lactosides built on sugar scaffolds and their evaluation as substrates and inhibitors of the Trypanosoma cruzi trans-sialidase (TcTS). This enzyme catalyzes the transfer of sialic acid from an oligosaccharidic donor in the host, to parasite betaGalp terminal units and it has been demonstrated that it plays an important role in the infection. Herein, the enzyme was also tested as a tool for the chemoenzymatic synthesis of sialic acid containing glycoclusters. The transfer reaction of sialic acid was performed using a recombinant TcTS and 3'-sialyllactose as sialic acid donor, in the presence of the acceptor having betaGalp non reducing ends. The products were analyzed by high performance anion exchange chromatography with pulse amperometric detection (HPAEC-PAD). The ability of the different S-linked and N-linked glycosides to inhibit the sialic acid transfer reaction from 3'-sialyllactose to the natural substrate N-acetyllactosamine, was also studied. Most of the substrates behaved as good acceptors and moderate competitive inhibitors. A di-N-lactoside showed to be the strongest competitive inhibitor among the compounds tested (70% inhibition at equimolar concentration). The usefulness of the enzymatic trans-sialylation for the preparation of sialylated ligands was assessed by performing a preparative sialylation of a divalent substrate, which afforded the monosialylated compound as main product, together with the disialylated glycocluster.
Design and Synthesis of Hydrolytically Stable Multivalent Ligands Bearing Thiodigalactoside Analogues for Peanut Lectin and Human Galectin-3 Binding
Cagnoni, A. J.; Kovensky, J.; Uhrig, M. L.
J. Org. Chem. 2014, 79, 6456-6467.
Herein, we describe the design and synthesis of a novel family of hydrolytically stable glycoclusters bearing thiodigalactoside (TDG) analogues as recognition elements of β-galactoside binding lectins. The TDG analogue was synthesized by thioglycosylation of a 6-S-acetyl-α-d-glucosyl bromide with the isothiouronium salt of 2,3,4,6-tetra-O-acetyl-β-d-galactose. Further propargylation of the TDG analogue allowed the coupling to azido-functionalized oligosaccharide scaffolds through copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) under microwave activation. The final mono-, di-, and tetravalent ligands were resistant to enzymatic hydrolisis by Escherichia coli β-galactosidase. Binding affinities to peanut agglutinin and human galectin-3 were measured by isothermal titration calorimetry which showed Ka constants in the micromolar range as well as a multivalent effect. Monovalent ligand exhibited a binding affinity higher than that of thiodigalactoside. Docking studies performed with a model ligand on both β-galactoside binding lectins showed additional interactions between the triazole ring and lectin amino acid residues, suggesting a positive effect of this aromatic residue on the biological activity.
Mechanistic studies of highly regioselective decarboxylative-prenyl migration reactions of prenyloxycarbonyl-diketo-dioxinones
Anderson, K.; Laclef, S.; Barrett, A. G. M.
Tetrahedron 2014, 70, 5569-5579.
Mechanistic studies of tandem regioselective decarboxylation, prenyl transfer, and aromatization reactions of prenyl dioxinone diketo-carboxylates to provide 3-prenyl-resorcylate derivs. are described. Studies of the effects of concn. and the base employed as well as the results of cross-over expts. were all found to be consistent with the reaction proceeding largely via an intermol. reaction pathway.