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Les publications de l’UMR

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Ursuegui, S., Schneider, J. P., Imbs, C., Lauvoisard, F., Dudek, M., Mosser, M., and Wagner, A.

Expedient synthesis of trifunctional oligoethyleneglycol-amine linkers and their use in the preparation of PEG-based branched platforms, Org. Biomol. Chem., 2018, 16, 8579-8584.

We designed a convergent synthesis pathway that provides access to trifunctional oligoethyleneglycol-amine (OEG-amine) linkers. By applying the reductive coupling of a primary azide to bifunctional OEG-azide precursors, the corresponding symmetrical dialkylamine bearing two homo-functional end chain groups and a central nitrogen was obtained. These building blocks bear minimal structural perturbation compared to the native OEG backbone which makes them attractive for biomedical applications. The NMR investigations of the mechanism process reveal the formation of nitrile and imine intermediates which can react with the reduced free amine form. Additionally, these trifunctional OEG-amine linkers were employed in a coupling reaction to afford branched multifunctional PEG dendrons which are molecularly defined. These discrete PEG-based dendrons (n = 16, 18 and 36) could be useful for numerous applications where multivalency is required.

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Leriche, G., Chisholm, L., and Wagner, A.

Cleavable linkers in chemical biology, Bioorg. Med. Chem., 2012, 20, 571-582.

Interest in cleavable linkers is growing due to the rapid development and expansion of chemical biology. The chemical constrains imposed by the biological conditions cause significant challenges for organic chemists. In this review we will present an overview of the cleavable linkers used in chemical biology classified according to their cleavage conditions by enzymes, nucleophilic/basic reagents, reducing agents, photo-irradiation, electrophilic/acidic reagents, organometallic and metal reagents, oxidizing reagents.

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Bui The Thuong, M., Catala, C., Colas, C., Schaeffer, C., Van Dorsselaer, A., Mann, A., and Wagner, A.

Trimethoxyarene, a highly ionisable tag for reaction analysis by APPI/MS: exploration of heterocyclic synthesis, Eur. J. Org. Chem., 2012, 85-92.

A mass spectrometry (MS) method was developed to rapidly analyze crude reaction mixtures. This method relies on highly effective ionization by atmospheric pressure photoionization (APPI) of molecules with a prosthetic trimethoxyarene (TMOA) residue. In a crude reaction mixture, products resulting from the reaction of the TMOA‐labeled substrate will be selectively ionized to afford an easily readable mass spectrum. Interestingly, we noticed that TMOA‐labeled molecules were not fragmented and gave the preferred [M + H]+ ion peak. This APPI‐MS reaction mixture analysis method was used for the optimization of heterocycle synthesis. By comparing results obtained by APPI/MS, GC, and HPLC analysis, it appeared that a semi‐quantification could be achieved by integrating the MS peak intensities.

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Egea, P., Muller-Steffner, H., Kuhn, I., Cakir-Kiefer, C., Oppenheimer, N. J., Stroud, R. M., Kellenberger, E., and Schuber, F.

Insights into the mechanism of bovine CD38/NAD+glycohydrolase from the X-Ray structures of its Michaelis Complex and covalently-trapped intermediates, PLOS One, 2012, 7, 34918.

Bovine CD38/NAD+glycohydrolase (bCD38) catalyses the hydrolysis of NAD+ into nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose (cADPR). We solved the crystal structures of the mono N-glycosylated forms of the ecto-domain of bCD38 or the catalytic residue mutant Glu218Gln in their apo state or bound to aFNAD or rFNAD, two 2′-fluorinated analogs of NAD+. Both compounds behave as mechanism-based inhibitors, allowing the trapping of a reaction intermediate covalently linked to Glu218. Compared to the non-covalent (Michaelis) complex, the ligands adopt a more folded conformation in the covalent complexes. Altogether these crystallographic snapshots along the reaction pathway reveal the drastic conformational rearrangements undergone by the ligand during catalysis with the repositioning of its adenine ring from a solvent-exposed position stacked against Trp168 to a more buried position stacked against Trp181. This adenine flipping between conserved tryptophans is a prerequisite for the proper positioning of the N1 of the adenine ring to perform the nucleophilic attack on the C1′ of the ribofuranoside ring ultimately yielding cADPR. In all structures, however, the adenine ring adopts the most thermodynamically favorable anti conformation, explaining why cyclization, which requires a syn conformation, remains a rare alternate event in the reactions catalyzed by bCD38 (cADPR represents only 1% of the reaction products). In the Michaelis complex, the substrate is bound in a constrained conformation; the enzyme uses this ground-state destabilization, in addition to a hydrophobic environment and desolvation of the nicotinamide-ribosyl bond, to destabilize the scissile bond leading to the formation of a ribooxocarbenium ion intermediate. The Glu218 side chain stabilizes this reaction intermediate and plays another important role during catalysis by polarizing the 2′-OH of the substrate NAD+. Based on our structural analysis and data on active site mutants, we propose a detailed analysis of the catalytic mechanism.

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Leriche, G., Budin, G., Darwich, Z., Weltin, D., Mély, Y., Klymchenko, A. S., and Wagner, A.

A FRET-based probe with a chemically deactivatable quencher, Chem. Commun., 2012, 48, 3224-3226.

A new concept of a chemically deactivatable quencher is proposed for a FRET-based probe that turns-on its fluorescence by either an enzymatic cleavage or a chemical reagent (sodium dithionite). This concept allowed us to quantify the caspase-3 cleavage activity in solution and to reveal unreacted probes in cell experiments.

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Varenne, F., Bourdillon, M., Meyer, M., Lin, Y., Brellier, M., Baati, R., Charbonnière, L. J., Wagner, A., Doris, E., Taran, F., and Hagège, A.

Capillary electrophoresis–inductively coupled plasma-mass spectrometry hyphenation for the determination at the nanogram scale of metal affinities and binding constants of phosphorylated ligands, J. Chromatogr. A, 2012, 1229, 280–287.

A screening strategy based on hyphenated capillary electrophoresis and inductively coupled plasma mass spectrometry (CE–ICP-MS) was developed to classify phosphorylated ligands according to their europium(III) binding affinity in a hydro-organic medium (sodium formate, pH 3.7, H2O/MeOH 90:10, v/v). Taking advantage of the high sensibility of ICP-MS for detecting phosphorus, this method enabled to assess the affinity of a variety of phosphorylated compounds, including phosphine oxides, thiophosphines, phosphonates, and phosphinates, in less than 1 h and using less than 5 ng of substance. By varying the total europium concentration, complexation constants could be determined according to a sequential multiple run strategy, which proved to be in excellent agreement with the values obtained by UV–Vis absorption spectrophotometric titrations.

Dehuyser, L., Schaeffer, E., Chaloin, O., Mueller, C. G., Baati, R., and Wagner, A.

Synthesis of novel mannoside glycolipid conjugates for inhibition of HIV-1 trans-infection, Bioconjugate Chem., 2012, 23, 1731–1739.

Mannose-binding lectins, such as dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN), are expressed at the surface of human dendritic cells (DCs) that capture and transmit human immunodeficiency virus type-1 (HIV-1) to CD4+ cells. With the goal of reducing viral trans-infection by targeting DC-SIGN, we have designed a new class of mannoside glycolipid conjugates. We report the synthesis of amphiphiles composed of a mannose head, a hydrophilic linker essential for solubility in aqueous media, and a lipid chain of variable length. These conjugates presented unusual properties based on a cooperation between the mannoside head and the lipid chain, which enhanced the affinity and decreased the need for multivalency. With an optimal lipid length, they exhibited strong binding affinity for DC-SIGN (Kd in the micromolar range) as assessed by surface plasmon resonance. The most active molecules were branched trimannoside conjugates, able to inhibit the interaction of the HIV-1 envelope with DCs, and to drastically reduce trans-infection of HIV-1 mediated by DCs (IC50s in the low micromolar range). This new class of compounds may be of potential use for prevention of HIV-1 dissemination, and also of infection by other DC-SIGN-binding human pathogens.

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King, M., Baati, R., and Wagner, A.

New tetramethylthiepinium (TMTI) for copper-free click chemistry, Chem. Commun., 2012, 48, 9308-9309.

A new derivative of the strained 3,3,6,6-tetramethylthiacycloheptyne (TMTH) bearing a functional handle is reported. Following an optimized synthesis, the handle was introduced by mild alkylation of the sulphur atom. The resulting functionalized strained 4,5-didehydro-3,3,6,6-tetramethyl-2,3,6,7-tetrahydrothiepinium (TMTI) proved to be stable and underwent extremely fast [3+2] cycloaddition reaction with benzyl azide in both organic and aqueous solvents. The reaction was equally efficient in cell lysate and serum and therefore opens interesting prospects for chemical-biology applications.

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Lemau de Talance, V., Massinon, O., Baati, R., Wagner, A., Vincent, S. P.

First steps towards conformationally selective artificial lectins: the chair-boat discrimination by molecularly imprinted polymers, Chem. Commun., 2012, 48, 10684-10686.

A series of molecularly imprinted polymers (MIPs) were prepared in the presence of a synthetic galactoside locked in a 1,4B boat conformation. This study demonstrates that, depending on the polymerisation technique, an organic material can selectively bind a carbohydrate in a biologically relevant boat conformation.

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