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- Agents pour l’imagerie moléculaire
- Enzymes et régulateurs
- Glycochimie
- Outils synthétiques
- Stimulants de la croissance des plantes


Agents pour l’imagerie moléculaire




Pollet, R. ; Bonnet, C. S. ; Retailleau, P. ; Durand, P. ; Tóth, É., Inorg. Chem. 2017, 56, 4317-4323.

Proton Exchange in a Paramagnetic Chemical Exchange Saturation Transfer Agent from Experimental Studies and ab Initio Metadynamics Simulation. The proton-exchange process between water and a carbamate has been studied experimentally and theoretically in a lanthanide-based paramagnetic chemical exchange saturation transfer agent endowed with potential multimodality detection capabilities (optical imaging, or T1 MRI for the Gd(III) analogue). In addition to an in-depth structural analysis by a combined approach (using X-ray crystallography, NMR, and molecular dynamics), our ab initio simulation in aqueous solution sheds light on the reaction mechanism for this proton exchange, which involves structural Grotthuss diffusion.

DOI : 10.1021/acs.inorgchem.6b02773




He J., Bonnet C. S., Eliseeva S. V., Lacerda S., Chauvin T., Retailleau P., Szeremeta F., Badet B., Petoud S., Tóth É., Durand P., J. Am. Chem. Soc. 2016, 138, 2913-2916.

Prototypes of Lanthanide(III) Agents Responsive to Enzymatic Activities in Three Complementary Imaging Modalities : Visible/Near-Infrared Luminescence, PARACEST‑, and T1‑MRI. We report first prototypes of responsive lanthanide(III) complexes that can be monitored independently in three complementary imaging modalities. Through the appropriate choice of lanthanide(III) cations, the same reactive ligand can be used to form complexes providing detection by (i) visible (Tb3+) and near-infrared (Yb3+) luminescence, (ii) PARACEST- (Tb3+, Yb3+), or (iii) T1-weighted (Gd3+) MRI. The use of lanthanide(III) ions of different natures for these imaging modalities induces only a minor change in the structure of complexes that are therefore expected to have a single biodistribution and cytotoxicity.

DOI : 10.1021/jacs.5b12084




Fugier, E. ; Dumont, A. ; Malleron, A. ; Poquet, E. ; Pons, J. M. ; Baron, A. ; Vauzeilles, B. ; Dukan, S., PLoS One 2015, 10 (6).

Rapid and Specific Enrichment of Culturable Gram Negative Bacteria Using Non-Lethal Copper-Free Click Chemistry Coupled with Magnetic Beads Separation. Currently, identification of pathogenic bacteria present at very low concentration requires a preliminary culture-based enrichment step. Many research efforts focus on the possibility to shorten this pre-enrichment step which is needed to reach the minimal number of cells that allows efficient identification. Rapid microbiological controls are a real public health issue and are required in food processing, water quality assessment or clinical pathology. Thus, the development of new methods for faster detection and isolation of pathogenic culturable bacteria is necessary. Here we describe a specific enrichment technique for culturable Gram negative bacteria, based on non-lethal click chemistry and the use of magnetic beads that allows fast detection and isolation. The assimilation and incorporation of an analog of Kdo, an essential component of lipopolysaccharides, possessing a bio-orthogonal azido function (Kdo-N-3), allow functionalization of almost all Gram negative bacteria at the membrane level. Detection can be realized through strain-promoted azide-cyclooctyne cycloaddition, an example of click chemistry, which interestingly does not affect bacterial growth. Using E. coli as an example of Gram negative bacterium, we demonstrate the excellent specificity of the technique to detect culturable E. coli among bacterial mixtures also containing either dead E. coli, or live B. subtilis (as a model of microorganism not containing Kdo). Finally, in order to specifically isolate and concentrate culturable E. coli cells, we performed separation using magnetic beads in combination with click chemistry. This work highlights the efficiency of our technique to rapidly enrich and concentrate culturable Gram negative bacteria among other microorganisms that do not possess Kdo within their cell envelope.

DOI : 10.1371/journal.pone.0127700




Mas Pons, J. ; Dumont, A. ; Sautejeau, G. ; Fugier, E. ; Baron, A. ; Dukan, S. ; Vauzeilles, B., Angew. Chem. Int. Ed., 2014, 53(5), pp. 1275-1278.

Identification of living Legionella pneumophila using species-specific metabolic lipopolysaccharide labeling.Legionella pneumophila is a pathogenic bacterium involved in regular outbreaks characterized by a relatively high fatality rate and an important societal impact. Frequent monitoring of the presence of this bacterium in environmental water samples is necessary to prevent these epidemic events, but the traditional culture-based detection and identification method requires up to 10 days. Reported herein is a method allowing identification of Legionella pneumophila by metabolic lipopolysaccharide labeling which targets, for the first time, a precursor to monosaccharides that are specifically present within the O-antigen of the bacterium. This new approach allows easy detection of living Legionella pneumophila, while other Legionella species are not labeled.

DOI : 10.1002/anie.201309072




Chauvin, T. ; Torres, S. ; Rosseto, R. ; Kotek, J. ; Badet, B. ; Durand, P. ; Tóth, É., Chemistry – A European Journal 2012, 18 (5), 1408-1418.

Lanthanide(III) Complexes That Contain a Self-Immolative Arm : Potential Enzyme Responsive Contrast Agents for Magnetic Resonance Imaging. Enzyme-responsive MRI-contrast agents containing a “self-immolative” benzylcarbamate moiety that links the MRI-reporter lanthanide complex to a specific enzyme substrate have been developed. The enzymatic cleavage initiates an electronic cascade reaction that leads to a structural change in the LnIII complex, with a concomitant response in its MRI-contrast-enhancing properties. We synthesized and investigated a series of Gd3+ and Yb3+ complexes, including those bearing a self-immolative arm and a sugar unit as selective substrates for β-galactosidase ; we synthesized complex LnL1, its NH2 amine derivatives formed after enzymatic cleavage, LnL2, and two model compounds, LnL3 and LnL4. All of the Gd3+ complexes synthesized have a single inner-sphere water molecule. The relaxivity change upon enzymatic cleavage is limited (3.68 vs. 3.15 mM−1 s−1 for complexes GdL1 and GdL2, respectively ; 37 °C, 60 MHz), which prevents application of this system as an enzyme-responsive T1 relaxation agent. Variable-temperature 17O NMR spectroscopy and 1H  NMRD (nuclear magnetic relaxation dispersion) analysis were used to assess the parameters that determine proton relaxivity for the Gd3+ complexes, including the water-exchange rate (kex298, varies in the range 1.5–3.9×106 s−1). Following the enzymatic reaction, the chelates contain an exocyclic amine that is not protonated at physiological pH, as deduced from pH-potentiometric measurements (log KH=5.12(±0.01) and 5.99(±0.01) for GdL2 and GdL3, respectively). The Yb3+ analogues show a PARACEST effect after enzymatic cleavage that can be exploited for the specific detection of enzymatic activity. The proton-exchange rates were determined at various pH values for the amine derivatives by using the dependency of the CEST effect on concentration, saturation time, and saturation power. A concentration-independent analysis of the saturation-power-dependency data was also applied. All these different methods showed that the exchange rate of the amine protons of the YbIII complexes decreases with increasing pH value (for YbL3, kex=1300 s−1 at pH 8.4 vs. 6000 s−1 at pH 6.4), thereby resulting in a diminution of the observed CEST effect.

DOI : 10.1002/chem.201101779




Enzymes et régulateurs


Benito-Cambra, M. ; Gareil, P. ; Badet, B. ; Badet-Denisot, M. A. ; Delaunay, N., First investigations for the characterization of glucosamine-6-phosphate synthase by capillary electrophoresis. J. Chromatogr. B 2018, 1072, 130-135.

First investigations for the characterization of glucosamine-6-phosphate synthase by capillary electrophoresis.The enzyme glucosamine-6-phosphate synthase (GlmS) is an important point of metabolic control in biosynthesis of amino sugar-containing macromolecules and is therefore a potential target in order to design antibacterial and antifungal drugs. It has two oligomerization states, which are the active dimer and the inactive hexamer. For the first time, the potential of CE to separate and quantify the two forms was studied. After incubating GlmS with the D-glucosamine 6-phosphate (G1cN6P) inhibitor, an electrolyte based on sodium phosphate at pH 7.2 and an ionic strength of 100 mM plus G1cN6P (either 2 or 20 mM) allowed the hexamer-dimer separation. However, the displacement of the dimer/hexamer equilibrium during the analysis time prevented any improvement of the resolution when varying the effective separation length or the temperature of the analysis. Therefore, the use of a short-end CE method allowed the decrease in the analysis time to about 1 min. Some parameters such as the temperature and the time of incubation and the ratio of the inhibitor and enzyme concentrations were studied. Then, it was also possible to test, very rapidly and with a very small amount, some molecules having an inhibition potential for the GlmS enzyme (arabinose-5-phosphate oxime, 2-amino-2-deoxy-D-glucitol 6-phosphate, and glucose-6-phosphate).

DOI : 10.1016/j.jchromb.2017.11.015



Gaucher-Wieczorek, F. ; Guerineau, V. ; Touboul, D. ; Thetiot-Laurent, S. ; Pelissier, F. ; Badet-Denisot, M.-A. ; Badet, B. ; Durand, P., Anal. Biochem. 2014, 458, 61-65.

Evaluation of synthase and hemisynthase activities of glucosamine-6-phosphate synthase by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.TGlucosamine-6-phosphate synthase (GlmS, EC 2.6.1.16) catalyzes the first and rate-limiting step in the hexosamine biosynthetic pathway, leading to the synthesis of uridine-5’-diphospho-N-acetyl-d-glucosamine, the major building block for the edification of peptidoglycan in bacteria, chitin in fungi, and glycoproteins in mammals. This bisubstrate enzyme converts d-fructose-6-phosphate (Fru-6P) and l-glutamine (Gln) into d-glucosamine-6-phosphate (GlcN-6P) and l-glutamate (Glu), respectively. We previously demonstrated that matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) allows determination of the kinetic parameters of the synthase activity. We propose here to refine the experimental protocol to quantify Glu and GlcN-6P, allowing determination of both hemisynthase and synthase parameters from a single assay kinetic experiment, while avoiding interferences encountered in other assays. It is the first time that MALDI-MS is used to survey the activity of a bisubstrate enzyme.

DOI : 10.1016/j.ab.2014.04.033




Assrir, N. ; Richez, C. ; Durand, P. ; Guittet, E. ; Badet, B. ; Lescop, E. ; Badet-Denisot, M.-A., Biochimie 2014, 97, 39-48.

Mapping the UDP-N-acetylglucosamine regulatory site of human glucosamine-6P synthase by saturation-transfer difference NMR and site-directed mutagenesis.The enzyme glucosamine-6P Synthase (Gfat, l-glutamine:d-fructose-6P amidotransferase) is involved in the hexosamine biosynthetic pathway and catalyzes the formation of glucosamine-6P from the substrates d-fructose-6-phosphate and l-glutamine. In eukaryotic cells, Gfat is inhibited by UDPGlcNAc, the end product of the biochemical pathway. In this work we present the dissection of the binding and inhibition properties of this feedback inhibitor and of its fragments by a combination of STD-NMR experiments and inhibition measurements on the wild type human enzyme (hGfat) as well as on site-directed mutants. We demonstrate that the UDPGlcNAc binding site is located in the isomerase domain of hGfat. Two amino acid residues (G445 and G461) located at the bottom of the binding site are identified to play a key role in the specificity of UDPGlcNAc inhibition of hGfat activity vs its bacterial Escherichia coli counterpart. We also show that UDPGlcNAc subcomponents have distinct features : the nucleotidic moiety is entirely responsible for binding whereas the N-acetyl group is mandatory for inhibition but not for binding, and the sugar moiety acts as a linker between the nucleotidic and N-acetyl groups. Combining these structural recognition determinants therefore appears as a promising strategy to selectively inhibit hGfat, which may for example help reduce complications in diabetes.

DOI : 10.1074/jbc.M112.380378




Mouilleron, S. ; Badet-Denisot, M.-A. ; Pecqueur, L. ; Madiona, K. ; Assrir, N. ; Badet, B. ; Golinelli-Pimpaneau, B., J. Biol. Chem. 2012, 287, 34533-34546.

Structural Basis for Morpheein-type Allosteric Regulation of Escherichia coli Glucosamine-6-phosphate Synthase EQUILIBRIUM BETWEEN INACTIVE HEXAMER AND ACTIVE DIMER.The amino-terminal cysteine of glucosamine-6-phosphate synthase (GlmS) acts as a nucleophile to release and transfer ammonia from glutamine to fructose 6-phosphate through a channel. The crystal structure of the C1A mutant of Escherichia coli GlmS, solved at 2.5 A resolution, is organized as a hexamer, where the glutaminase domains adopt an inactive conformation. Although the wild-type enzyme is active as a dimer, size exclusion chromatography, dynamic and quasi-elastic light scattering, native polyacrylamide gel electrophoresis, and ultracentrifugation data show that the dimer is in equilibrium with a hexameric state, in vitro and in cellulo. The previously determined structures of the wild-type enzyme, alone or in complex with glucosamine 6-phosphate, are also consistent with a hexameric assembly that is catalytically inactive because the ammonia channel is not formed. The shift of the equilibrium toward the hexameric form in the presence of cyclic glucosamine 6-phosphate, together with the decrease of the specific activity with increasing enzyme concentration, strongly supports product inhibition through hexamer stabilization. Altogether, our data allow us to propose a morpheein model, in which the active dimer can rearrange into a transiently stable form, which has the propensity to form an inactive hexamer. This would account for a physiologically relevant allosteric regulation of E. coli GlmS. Finally, in addition to cyclic glucose 6-phosphate bound at the active site, the hexameric organization of E. coli GlmS enables the binding of another linear sugar molecule. Targeting this sugar-binding site to stabilize the inactive hexameric state is therefore suggested for the development of specific antibacterial inhibitors.

DOI : 10.1016/j.biochi.2013.09.011



Glycochimie



Xolin, A. ; Losa, R. ; Kaid, A. ; Tresse, C. ; Beau, J.-M. ; Boyer, F.-D. ; Norsikian, S., Org. Biomol. Chem. 2018, 16, 325-335.

Stereocontrolled glycoside synthesis by activation of glycosyl sulfone donors with scandium(iii) triflate. The activation of aryl glycosyl sulfone donors has been achieved using scandium(iii) triflate and has led to the selective preparation of [small alpha]-mannosides resulting from a post-glycosylation anomerization.

DOI : 10.1039/C7OB02792C




Berthelot, N. ; Brossay, A. ; Gasciolli, V. ; Bono, J.-J. ; Baron, A. ; Beau, J.-M. ; Urban, D. ; Boyer, F.-D. ; Vauzeilles, B., Org. Biomol. Chem. 2017, 15, 7802-7812.

Synthesis of lipo-chitooligosaccharide analogues and their interaction with LYR3, a high affinity binding protein for Nod factors and Myc-LCOs. Lipo-chitotetrasaccharide analogues where one central GlcNAc residue was replaced by a triazole unit have been synthesized from a derivative obtained by chitin depolymerization and a functionalized N-acetyl-glucosamine via the copper-catalyzed azide-alkyne cycloaddition. Their evaluation in a binding assay using LYR3, a putative lipo-chitooligosaccharide receptor in Medicago truncatula, shows a complete loss of binding.

DOI : 10.1039/C7OB01201B




Xolin, A. ; Norsikian, S. ; Boyer, F.-D. ; Beau, J.-M., Eur. J. Org. Chem. 2016, 3408-3418.

Iron(III)-Triflate-Catalyzed Multiple Glycosylations with Peracetylated β-d-Glucosamine. Direct multiple glycosylations of thioaryl and propargyl mannopyranosides with peracetylated β-d-glucosamine have been carried out using catalytic iron(III) triflate as a promoter in the presence of 2,4,6-tri-tert-butylpyrimidine under microwave irradiation. This has led to the one-step formation of various oligosaccharides with mannose at the branching point. Subsequent direct introduction of a linker through copper-catalyzed azide–alkyne cycloaddition with the propargyl branched glycan and final deprotection gave rapid access to N-glycan mimetics.

DOI : 110.1002/ejoc.201600457




Gillard, L. ; Tran, A.-T. ; Boyer, F.-D. ; Beau, J.-M., Eur. J. Org. Chem. 2016, 1103-1109.

Chitooligosaccharide Synthesis Using an Ionic Tag. An environmentally improved synthesis of the N-differentiated chitotetrasaccharide CO-IV-(NH2), a key intermediate for the preparation of lipochitooligosaccharides and the TMG-chitotriomycin, is reported based on a chromatography-free ionic-liquid tagging approach. The method involves the glycosylation of ionic-liquid-tagged acceptors with thioglucosamine donors leading to the stereoselective formation of β-(1[RIGHTWARDS ARROW]4)-linked glucosamine-containing oligomers.

DOI : 10.1002/ejoc.201501476




Xolin, A. ; Stevenin, A. ; Pucheault, M. ; Norsikian, S. ; Boyer, F.-D. ; Beau, J.-M., Org. Chem. Front. 2014, 1 (8), 992-1000.

Glycosylation with N-acetyl glycosamine donors using catalytic iron(iii) triflate : from microwave batch chemistry to a scalable continuous-flow process. Efficient and highly selective glycosylation reactions of peracetylated β-D-N-acetyl gluco- and galactosamine are described using catalytic iron(III) triflate under microwave conditions or in a continuous flow process. Simple β-glycosides and β-(1 → 6), β-(1 → 2) and β-(1 → 3) linked disaccharides bearing various protecting groups were obtained in high yields. Insights into the glycosylation mechanism are discussed.

DOI : 10.1039/c4qo00183d




Despras, G. ; Urban, D. ; Vauzeilles, B. ; Beau, J.-M., J.-M., Chem. Commun. 2014, 50 (9), 1067-1069.

One-pot synthesis of D-glucosamine and chitobiosyl building blocks catalyzed by triflic acid on molecular sieves. Combining triflic acid-catalyzed acetalation, benzylation, reductive ring opening of benzylidene acetal and glycosylation in one-pot transformations leads to a wide range of D-glucosamine building blocks for assembling oligomers.

DOI : 10.1039/c3cc48078j




Beau, J.-M. ; Bourdreux, Y. ; Boyer, F.-D. ; Norsikian, S. ; Urban, D. ; Doisneau, G. ; Vauzeilles, B. ; Gouasmat, A. ; Lemetais, A. ; Mathieu, A. ; Soule, J.-F. ; Stevenin, A. ; Xolin, A., Carbohydrate Chemistry : Volume 40, The Royal Society of Chemistry : 2014 ; Vol. 40, pp 118-139.

Recent results in synthetic glycochemistry with iron salts at Orsay-Gif. The synthesis of novel carbohydrates and carbohydrate mimetics continues to be a major challenge for organic chemists, not least because of the incresingly interdiscipliniary nature of carbohydrate science. Covering both chemical and biological science related to the particular volume topic, this series demonstrates the interdisciplinary nature of modern carbohydrate research, and will be of great benefit to any researcher who wishes to learn about the latest developments in the carbohydrate field.

DOI : 10.1039/9781849739986-00118




Despras, G. ; Alix, A. ; Urban, D. ; Vauzeilles, B. ; Beau, J.-M., Angew. Chem., Int. Ed. 2014, 53, 11912-11916.

From Chitin to Bioactive Chitooligosaccharides and Conjugates : Access to Lipochitooligosaccharides and the TMG-chitotriomycin. The direct and chemoselective N-transacylation of peracetylated chitooligosaccharides (COSs), readily obtained from chitin, to give per-N-trifluoroacetyl derivatives offers an attractive route to size-defined COSs and derived glycoconjugates. It involves the use of various acceptor building blocks and trifluoromethyl oxazoline dimer donors prepared with efficiency and highly reactive in 1,2-trans glycosylation reactions. This method was applied to the preparation of the important symbiotic glycolipids which are highly active on plants and to the TMG-chitotriomycin, a potent and specific inhibitor of insect, fungal, and bacterial N-acetylglucosaminidases.

DOI : 10.1002/anie.201406802




Gillard, L. ; Stevenin, A. ; Schmitz-Afonso, I. ; Vauzeilles, B. ; Boyer, F.-D. ; Beau, Eur. J. Org. Chem. 2013, 2013 (32), 7382-7390.

Synthesis of the Fungal Lipo-Chitooligosaccharide Myc-IV (C16:0, S), Symbiotic Signal of Arbuscular Mycorrhiza. A new synthesis of the fungal lipo-chitooligosaccharide Myc-IV (C16:0, S), which was recently reported to be a major symbiotic signalling molecule in arbuscular mycorrhiza, is described. Key steps include the oxidative cleavage of a 4,6-O-benzylidene acetal to prepare a disaccharidic glycosyl acceptor, and stereoselective glycosylations with 2-methyl-5-tert-butylphenyl thioglycosyl donors.

DOI : 10.1002/ejoc.201301015




Norsikian, S. ; Soulé, J.-F. ; Cannillo, A. ; Guillot, R. ; Tran Huu Dau, M.-E. ; Beau, J.-M., Org. Lett. 2012, 14 (2), 544-547.

Remarkable Stereoselectivity in Intramolecular Borono-Mannich Reactions : Synthesis of Conduramines. An unprecedented intramolecular Petasis condensation provides a novel approach to biologically important conduramines. The compounds are produced with an exclusive anti stereoselectivity for the newly created β-amino alcohol motif. The stereochemical outcome of the reaction is opposite to the one usually observed in the intermolecular reaction.

DOI : 10.1021/ol203162s




Outils synthétiques



Jeanne-Julien, L. ; Masson, G. ; Astier, E. ; Genta-Jouve, G. ; Servajean, V. ; Beau, J.-M. ; Norsikian, S. ; Roulland, E., Org. Lett. 2017, 19 (15), 4006-4009.

Synthesis of a Tiacumicin B Protected Aglycone. Our study of the synthesis of the aglycone of tiacumicin B is discussed here. We imagined two possible strategies featuring a main retrosynthetic disconnection between C13 and C14. The first strategy was based on Suzuki–Miyaura cross-coupling of 1,1-dichloro-1-alkenes, but the failure of this pathway led us to use a Pd/Cu-dual-catalyzed cross-coupling of alkynes with allenes that had never been implemented before in a total synthesis context. We used density functional theory calculations to guide our strategic choices concerning a [2.3]-Wittig rearrangement step and the final ring-size selective Yamaguchi macrolactonization. This led to two syntheses of the aglycone of tiacumicin B, with one of last generation delivering ultimately an adequately protected and glycosylation-ready aglycone.

DOI : 10.1021/acs.orglett.7b01744




Norsikian, S. ; Beretta, M. ; Cannillo, A. ; Martin, A. ; Retailleau, P. ; Beau, J.-M., Chem. Commun. 2015, 51 (49), 9991-9994.

Synthesis of enantioenriched 1,2-trans-diamines using the borono-Mannich reaction with N-protected alpha-amino aldehydes.The three-component Petasis borono-Mannich reaction starting with easily accessible N-protected α-amino aldehydes produces efficiently and diastereoselectively 1,2-trans-diamines with an enantiomeric excess of up to 98%.

DOI : 10.1039/c5cc01716e




Cannillo, A. ; Norsikian, S. ; Tran Huu Dau, M. E. ; Retailleau, P. ; Iorga, B. I. ; Beau, J. M., Chem. Eur. J. 2014, 20 (38), 12133-43. DOI 10.1002/chem.201402965

From enantiopure hydroxyaldehydes to complex heterocyclic scaffolds : development of domino petasis/diels-alder and cross-metathesis/michael addition reactions.One-step assembly of hexahydroisoindole scaffolds by a sequence of Petasis and Diels–Alder reactions is described. This easy and fast entry to functionalized polycyclic structures can be pursued by further transformations, which include additional ring closure by a cross-metathesis/Michael addition domino sequence (see scheme).

DOI : 10.1039/c4qo00183d




Norsikian, S. ; Soulé, J.-F. ; Cannillo, A. ; Guillot, R. ; Tran Huu Dau, M.-E. ; Beau, J.-M., Org. Lett. 2012, 14 (2), 544-547.

Remarkable Stereoselectivity in Intramolecular Borono-Mannich Reactions : Synthesis of Conduramines. An unprecedented intramolecular Petasis condensation provides a novel approach to biologically important conduramines. The compounds are produced with an exclusive anti stereoselectivity for the newly created β-amino alcohol motif. The stereochemical outcome of the reaction is opposite to the one usually observed in the intermolecular reaction.

DOI : 10.1021/ol203162s




Soulé, J.-F. ; Mathieu, A. ; Norsikian, S. ; Beau, J.-M., Org. Lett. 2010, 12 (22), 5322-5325.

Coupling the Petasis Condensation to an Iron(III) Chloride-Promoted Cascade Provides a Short Synthesis of Relenza Congeners.Iron(III) chloride hexahydrate promotes a cascade of transformations on a Petasis condensation product that sets up the right dihydropyran precursors of valuable Relenza congeners.

DOI : 10.1021/ol102326b




Chang, C.-W. ; Norsikian, S. ; Guillot, R. ; Beau, J.-M., Eur. J. Org. Chem. 2010, 2010 (12), 2280-2294.

Regio- and Stereocontrolled Palladium-Catalyzed Allylic Substitution on N-Acetylneuraminic Acid Derivatives.A process for highly effective regio- and stereoselective palladium-catalyzed allylic substitution of 2,3-unsaturated derivatives of N-acetylneuraminic acid (Neu5Ac2en) has been developed. We show that the efficiency of the allylation reaction depends on suitable protecting groups on the starting material and that, with sodium malonate anion as a nucleophile, the regioselectivity can be fine-tuned by the nature of the ligands associated with the palladium complex. These results are explained by the stoichiometric preparation and study of the highly probable complexes involved in the catalytic reaction. Reactions of this type were also applied to other nucleophiles for the construction of C–C, C–N, and C–O bonds, leading to the major formation of the C-4 regioisomers. The selective transformation of some of the substitution products provided easy access to a variety of modified sialic acid derivatives that might serve as useful sialyl building blocks for biological research.

DOI : 10.1002/ejoc.200901452




Gaucher-Wieczorek, F. S. ; Maillard, L. T. ; Badet, B. ; Durand, P., J. Comb. Chem. 2010, 12 (5), 655-658.

Fluorous Tagged N-Hydroxy Phthalimide for the Parallel Synthesis of O-Aryloxyamines.The parallel synthesis of O-aryloxyamines remains an unfulfilled need in the field of medicinal chemistry and fragment-based approaches. To fill this gap a solution-phase two-step process based on (1) a copper-catalyzed cross-coupling of aryl boronic acids with a fluorous tagged N-hydroxyphthalimide, and (2) a supported aminolysis was designed and optimized using Taguchi’s method. A library of O-aryloxyamines was synthesized in high yields with high purity and diversity.

DOI : 10.1021/cc100098v




Stimulants de la croissance des plantes



Boutet-Mercey, S. ; Perreau, F. ; Roux, A. ; Clavé, G. ; Pillot, J.-P. ; Schmitz-Afonso, I. ; Touboul, D. ; Mouille, G. ; Rameau, C. ; Boyer, F.-D., Phytochem. Anal. 2018, 29 (1), 59-68.

Method for Strigolactone Quantification by Ultra High-Performance Liquid Chromatography – Electrospray Ionisation Tandem Mass Spectrometry Using Novel Deuterium Labelled Standards.Introduction Strigolactones (SLs) are important plant hormones. They are difficult to analyse because they occur in very small concentrations especially in comparison with other plant hormones and other substances can interfere with their detection. Objective To develop a procedure for the extraction, purification and quantification of SLs from plant roots. Methodology Samples were prepared by extraction of plant root tissues with ethyl acetate. Then the extracts were further purified with silica column chromatography. The natural SLs in the final extracts were quantified using novel deuterium labelled SLs. The results of the methodology were compared with those of the procedure of Yoneyama and coworkers. Results This procedure required about 1-g root samples to detect and quantify simultaneously the SLs (orobanchyl acetate and fabacyl acetate) concentration with high reliability. Conclusion A method was developed for determining endogenous fabacyl acetate and orobanchyl acetate in plant tissue based on novel deuterium labelled standards. A method of orobanchol quantification using a synthetic SL GR24 as internal standard was proposed.

DOI : 10.1002/pca.2714




Berthelot, N. ; Brossay, A. ; Gasciolli, V. ; Bono, J.-J. ; Baron, A. ; Beau, J.-M. ; Urban, D. ; Boyer, F.-D. ; Vauzeilles, B., Org. Biomol. Chem. 2017, 15, 7802-7812.

Synthesis of lipo-chitooligosaccharide analogues and their interaction with LYR3, a high affinity binding protein for Nod factors and Myc-LCOs. Lipo-chitotetrasaccharide analogues where one central GlcNAc residue was replaced by a triazole unit have been synthesized from a derivative obtained by chitin depolymerization and a functionalized N-acetyl-glucosamine via the copper-catalyzed azide-alkyne cycloaddition. Their evaluation in a binding assay using LYR3, a putative lipo-chitooligosaccharide receptor in Medicago truncatula, shows a complete loss of binding.

DOI : 10.1039/C7OB01201B




de Saint Germain, A. ; Clave, G. ; Badet-Denisot, M.-A. ; Pillot, J.-P. ; Cornu, D. ; Le Caer, J.-P. ; Burger, M. ; Pelissier, F. ; Retailleau, P. ; Turnbull, C. ; Bonhomme, S. ; Chory, J. ; Rameau, C. ; Boyer, F.-D., Nat Chem Biol 2016, 12 (10), 787-794.

An histidine covalent receptor and butenolide complex mediates strigolactone perception. Strigolactone plant hormones control plant architecture and are key players in both symbiotic and parasitic interactions. They contain an ABC tricyclic lactone connected to a butenolide group, the D ring. The DWARF14 (D14) strigolactone receptor belongs to the superfamily of alpha/beta-hydrolases, and is known to hydrolyze the bond between the ABC lactone and the D ring. Here we characterized the binding and catalytic functions of RAMOSUS3 (RMS3), the pea (Pisum sativum) ortholog of rice (Oryza sativa) D14 strigolactone receptor. Using new profluorescent probes with strigolactone-like bioactivity, we found that RMS3 acts as a single-turnover enzyme that explains its apparent low enzymatic rate. We demonstrated the formation of a covalent RMS3-D-ring complex, essential for bioactivity, in which the D ring was attached to histidine 247 of the catalytic triad. These results reveal an undescribed mechanism of plant hormone reception in which the receptor performs an irreversible enzymatic reaction to generate its own ligand.

DOI : 10.1038/nchembio.2147




Lopez-Obando, M. ; Ligerot, Y. ; Bonhomme, S. ; Boyer, F. D. ; Rameau, C. : Development 2015, 142, 3615-3619.

Strigolactone biosynthesis and signaling in plant development. Strigolactones (SLs), first identified for their role in parasitic and symbiotic interactions in the rhizosphere, constitute the most recently discovered group of plant hormones. They are best known for their role in shoot branching but, more recently, roles for SLs in other aspects of plant development have emerged. In the last five years, insights into the SL biosynthetic pathway have also been revealed and several key components of the SL signaling pathway have been identified. Here, and in the accompanying poster, we summarize our current understanding of the SL pathway and discuss how this pathway regulates plant development.

DOI : 10.1242/dev.120006




Chambon, R. ; Despras, G. ; Brossay, A. ; Vauzeilles, B. ; Urban, D. ; Beau, J. M. ; Armand, S. ; Cottaz, S. ; Fort, S., Green Chem. 2015, 17 (7), 3923-3930.

Efficient chemoenzymatic synthesis of lipo-chitin oligosaccharides as plant growth promoters.Lipo-chitin oligosaccharides (Nod and Myc LCOs) are molecules involved in symbiotic phenomena in the plant kingdom. They play a major role in the process of atmospheric nitrogen fixation and mineral soil nutrients uptake both in legumes and in non-legumes, and are active at extremely low concentrations down to the nano- and even picomolar range. These compounds contain various substitutions along the oligosaccharide backbone of the molecule including an essential fatty acid on the non-reducing unit and are considered as environmentally-friendly fertilizers. Currently, chemical synthesis cannot produce precursors of Nod and Myc LCOs at a large scale and an in vitro chemoenzymatic pathway is presented here as a new and efficient method for preparing quantities of these high-value oligosaccharides. VC1280 (Vibrio cholerae) is a chitin deacetylase (CD) capable of regioselectively cleaving an acetate from the non-reducing penultimate N-acetyl-d-glucosaminyl (GlcNAc) unit of chitin oligosaccharides (COs). This provides a free amino group which can be further N-acylated with a fatty-acid chain to give analogues of LCOs. Alternatively, the non-reducing GlcNAc unit can be removed by [small beta]-N-acetylglucosaminidase treatment, followed by N-acylation to give natural LCOs. VC1280 CD was produced in the periplasm of E. coli. Under the conditions used, 120 mg of the pure enzyme was recovered from 1 L of culture medium. For the first time, in vitro production of a library of natural LCOs as well as their analogues has been carried out at a preparative scale from biosourced chitin oligosaccharides constituting an approach of major interest for sustainable agriculture.

DOI : 10.1039/C5GC00623F




Boyer, F.-D. ; de Saint Germain, A. ; Pouvreau, J.-B. ; Clave, G. ; Pillot, J.-P. ; Roux, A. ; Rasmussen, A. ; Depuydt, S. ; Lauressergues, D. ; Frey, N. F. D. ; Heugebaert, T. S. A. ; Stevens, C. V. ; Geelen, D. ; Goormachtig, S. ; Rameau, C., Mol. Plant 2014, 7 (4), 675-690.

New Strigolactone Analogs as Plant Hormones with Low Activities in the Rhizosphere. Strigolactones (SLs) are known not only as plant hormones, but also as rhizosphere signals for establishing symbiotic and parasitic interactions. The design of new specific SL analogs is a challenging goal in understanding the basic plant biology and is also useful to control plant architectures without favoring the development of parasitic plants. Two different molecules (23 (3-methyl-GR24), 31 (thia-3-methyl-debranone-like molecule)) already described, and a new one (AR36), for which the synthesis is presented, are biologically compared with the well-known GR24 and the recently identified CISA-1. These different structures emphasize the wide range of parts attached to the D-ring for the bioactivity as a plant hormone. These new compounds possess a common dimethylbutenolide motif but their structure varies in the ABC part of the molecules : 23 has the same ABC part as GR24, while 31 and AR36 carry, respectively, an aromatic ring and an acyclic carbon chain. Detailed information is given for the bioactivity of such derivatives in strigolactone synthesis or in perception mutant plants (pea rms1 and rms4, Arabidopsis max2 and, max4) for different hormonal functions along with their action in the rhizosphere on arbuscular mycorrhizal hyphal growth and parasitic weed germination.

DOI : 10.1093/mp/sst163




Despras, G. ; Alix, A. ; Urban, D. ; Vauzeilles, B. ; Beau, J.-M., Angew. Chem., Int. Ed. 2014, 53, 11912-11916.

From Chitin to Bioactive Chitooligosaccharides and Conjugates : Access to Lipochitooligosaccharides and the TMG-chitotriomycin. The direct and chemoselective N-transacylation of peracetylated chitooligosaccharides (COSs), readily obtained from chitin, to give per-N-trifluoroacetyl derivatives offers an attractive route to size-defined COSs and derived glycoconjugates. It involves the use of various acceptor building blocks and trifluoromethyl oxazoline dimer donors prepared with efficiency and highly reactive in 1,2-trans glycosylation reactions. This method was applied to the preparation of the important symbiotic glycolipids which are highly active on plants and to the TMG-chitotriomycin, a potent and specific inhibitor of insect, fungal, and bacterial N-acetylglucosaminidases.

DOI : 10.1002/anie.201406802




de Saint Germain, A. ; Bonhomme, S. ; Boyer, F.-D. ; Rameau, C., Curr. Opin. Plant Biol. 2013, 16 (5), 583-589.

Novel insights into strigolactone distribution and signalling. Strigolactones (SLs), a group of small carotenoid-derived molecules, were first known for their function in the rhizosphere in both symbiotic and parasitic interactions. Most of the progress for deciphering SL biosynthesis and signalling pathways comes from the use of high branching mutants identified in several species demonstrating that SLs also play a hormonal role in plant development. How SLs are perceived by the different organisms on which they show bioactivity is a current major challenge for the growing SL research community. These molecules very likely predate the colonization of land by plants and represent a fascinating example of signalling molecules involved in key innovations during plant evolution.

DOI : 10.1016/j.pbi.2013.06.007




Fliegmann, J. ; Canova, S. ; Lachaud, C. ; Uhlenbroich, S. ; Gasciolli, V. ; Pichereaux, C. ; Rossignol, M. ; Rosenberg, C. ; Cumener, M. ; Pitorre, D. ; Lefebvre, B. ; Gough, C. ; Samain, E. ; Fort, S. b. ; Driguez, H. ; Vauzeilles, B. ; Beau, J.-M. ; Nurisso, A. ; Imberty, A. ; Cullimore, J. ; Bono, J.-J., Curr. ACS Chem. Biol. 2013, 8 (9), 1900-1906.

Lipo-chitooligosaccharidic Symbiotic Signals Are Recognized by LysM Receptor-Like Kinase LYR3 in the Legume Medicago truncatula. While chitooligosaccharides (COs) derived from fungal chitin are potent elicitors of defense reactions, structurally related signals produced by certain bacteria and fungi, called lipo-chitooligosaccharides (LCOs), play important roles in the establishment of symbioses with plants. Understanding how plants distinguish between friend and foe through the perception of these signals is a major challenge. We report the synthesis of a range of COs and LCOs, including photoactivatable probes, to characterize a membrane protein from the legume Medicago truncatula. By coupling photoaffinity labeling experiments with proteomics and transcriptomics, we identified the likely LCO-binding protein as LYR3, a lysin motif receptor-like kinase (LysM-RLK). LYR3, expressed heterologously, exhibits high-affinity binding to LCOs but not COs. Homology modeling, based on the Arabidopsis CO-binding LysM-RLK AtCERK1, suggests that LYR3 could accommodate the LCO in a conserved binding site. The identification of LYR3 opens up ways for the molecular characterization of LCO/CO discrimination.

DOI : 10.1021/cb400369u




Chen, V. X. ; Boyer, F.-D. ; Rameau, C. ; Pillot, J.-P. ; Vors, J.-P. ; Beau, J.-M., Chem. Eur. J., 2013, 19(15), pp. 4849-4857

New Synthesis of A-Ring Aromatic Strigolactone Analogues and Their Evaluation as Plant Hormones in Pea (Pisum sativum). A new general access to A-ring aromatic strigolactones, a new class of plant hormones, has been developed. The key transformations include in sequence ring-closing metathesis, enzymatic kinetic resolution and a radical cyclization with atom transfer to install the tricyclic ABC-ring system. The activity as plant hormones for the inhibition of shoot branching in pea of various analogues synthesized by this strategy is reported.

DOI : 10.1002/chem.201203585




Gillard, L. ; Stevenin, A. ; Schmitz-Afonso, I. ; Vauzeilles, B. ; Boyer, F.-D. ; Beau, Eur. J. Org. Chem. 2013, 2013 (32), 7382-7390.

Synthesis of the Fungal Lipo-Chitooligosaccharide Myc-IV (C16:0, S), Symbiotic Signal of Arbuscular Mycorrhiza. A new synthesis of the fungal lipo-chitooligosaccharide Myc-IV (C16:0, S), which was recently reported to be a major symbiotic signalling molecule in arbuscular mycorrhiza, is described. Key steps include the oxidative cleavage of a 4,6-O-benzylidene acetal to prepare a disaccharidic glycosyl acceptor, and stereoselective glycosylations with 2-methyl-5-tert-butylphenyl thioglycosyl donors.

DOI : 10.1002/ejoc.201301015




Boyer, F.-D. ; Germain, A. d. S. ; Pillot, J.-P. ; Pouvreau, J.-B. ; Chen, V. X. ; Ramos, S. ; Stevenin, A. ; Simier, P. ; Delavault, P. ; Beau, J.-M. ; Rameau, C., Plant Physiol. 2012, 159 (4), 1524-1544.

Structure-Activity Relationship Studies of Strigolactone-Related Molecules for Branching Inhibition in Garden Pea : Molecule Design for Shoot Branching. Initially known for their role in the rhizosphere in stimulating the seed germination of parasitic weeds such as the Striga and Orobanche species, and later as host recognition signals for arbuscular mycorrhizal fungi, strigolactones (SLs) were recently rediscovered as a new class of plant hormones involved in the control of shoot branching in plants. Herein, we report the synthesis of new SL analogs and, to our knowledge, the first study of SL structure-activity relationships for their hormonal activity in garden pea (Pisum sativum). Comparisons with their action for the germination of broomrape (Phelipanche ramosa) are also presented. The pea rms1 SL-deficient mutant was used in a SL bioassay based on axillary bud length after direct SL application on the bud. This assay was compared with an assay where SLs were fed via the roots using hydroponics and with a molecular assay in which transcript levels of BRANCHED1, the pea homolog of the maize TEOSINTE BRANCHED1 gene were quantified in axillary buds only 6 h after application of SLs. We have demonstrated that the presence of a Michael acceptor and a methylbutenolide or dimethylbutenolide motif in the same molecule is essential. It was established that the more active analog 23 with a dimethylbutenolide as the D-ring could be used to control the plant architecture without strongly favoring the germination of P. ramosa seeds. Bold numerals refer to numbers of compounds.

DOI : 10.1104/pp.112.195826




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