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Accueil > Les équipes > Chemical Biology (ChemBio) > Publications

Publications

publié le , mis à jour le

2012


  • N. Dupre, C. Brazel, L. Fensterbank, M. Malacria, S. Thorimbert, B. Hasenknopf, et E. Lacôte, « Self-Buffering Hybrid Gold-Polyoxometalate Catalysts for the Catalytic Cyclization of Acid-Sensitive Substrates », Chemistry-a European Journal, vol. 18, nᵒ 41, p. 12962-12965.
    Mots-clés : allenes, asymmetric enamine catalysts, carbene nhc complexes, CHEMBIO, COS, Cycloisomerization, epoxidation, GOBS, Gold, Heterocycles, heteropoly compounds, highly efficient, Hydroamination, intercluster compound, MACO, organic-inorganic hybrid composites, oxidation, POLE 1, POLE 3, Polyoxometalates, polyoxotungstates, protonation, SUPRA.


  • L. Eloy, A. - S. Jarrousse, M. - L. Teyssot, A. Gautier, L. Morel, C. Jolivalt, T. Cresteil, et S. Roland, « Anticancer Activity of Silver–N-Heterocyclic Carbene Complexes: Caspase-Independent Induction of Apoptosis via Mitochondrial Apoptosis-Inducing Factor (AIF) », ChemMedChem, vol. 7, nᵒ 5, p. 805–814.
    Résumé : Fourteen silver(I) complexes bearing N-heterocyclic carbene (NHC) ligands were prepared and evaluated for anticancer activity. Some of these were found to exhibit potent antiproliferative activity toward several types of human cancer cell lines, including drug-resistant cell lines, with IC50 values in the nanomolar range. An initial investigation into the mechanism of cell death induced by this family of silver(I) complexes was carried out. Cell death was shown to result from the activation of apoptosis without involvement of primary necrosis. In HL60 cells, silver–NHCs induce depolarization of the mitochondrial membrane potential (ΔΨm) and likely allow the release of mitochondrial proteins to elicit early apoptosis. This effect is not related to the overproduction of reactive oxygen species (ROS). In addition, apoptosis is not associated with the activation of caspase-3, but is triggered by the translocation of apoptosis-inducing factor (AIF) and caspase-12 from mitochondria and the endoplasmic reticulum, respectively, into the nucleus to promote DNA fragmentation and ultimately cell death. No modification in cell-cycle distribution was observed, indicating that silver–NHCs are not genotoxic. Finally, the use of a fluorescent complex showed that silver–NHCs target mitochondria. Altogether, these results demonstrate that silver–NHCs induce cancer cell death independent of the caspase cascade via the mitochondrial AIF pathway.
    Mots-clés : apoptosis-inducing factor, cancer, Carbene ligands, CHEMBIO, GOBS, Heterocycles, mode of action, POLE 3, silver.


  • N. Fischer-Durand, M. Salmain, A. Vessières, et G. Jaouen, « A new bioorthogonal cross-linker with alkyne and hydrazide end groups for chemoselective ligation. Application to antibody labelling », Tetrahedron, vol. 68, nᵒ 47, p. 9638-9644.
    Résumé : We describe here the synthesis of the first bioorthogonal cross-linking reagent based on aminocaproic acid core with a hydrazide function at one end to react with glycoproteins and an alkyne group at the other end for Cu(I)-catalyzed click chemistry to azide-derivatized probes. As an application, this cross-linker was used to orthogonally conjugate profluorescent 3-azido-7-hydroxycoumarin to immunoglobulin G (IgG). An immunoassay showed that IgG was mostly not affected by the Cu(I)-catalyzed click chemistry conditions. Successful conjugations and retained immunoreactivity demonstrate the potential of this new bioorthogonal cross-linker in chemoselective ligation.
    Mots-clés : Bioorthogonal chemistry, CHEMBIO, Coumarin, Fluorescent label, Heterobifunctional cross-linker, Immunoglobulin G, POLE 3.

  • A. Garduno-Alva, M. Carmen Ortega-Alfaro, J. G. Lopez-Cortes, I. Chavez, J. Barroso-Flores, R. A. Toscano, H. Rudler, et C. Alvarez-Toledano, « Synthesis of new gamma-lactones from preactivated monosubstituted pyrazines and TMS-ketene acetals », Canadian Journal of Chemistry-Revue Canadienne De Chimie, vol. 90, nᵒ 5, p. 469-482.
    Résumé : The double addition of bis(trimethylsilyl) ketene acetals (1a-1b, R-1 = CH3, -(CH2)(5)-) to 2-substituted pyrazines promoted by triflic anhydride leads to gamma-lactones in a single step. A systematic study involving electron-withdrawing and electron-donating groups (R-2 = CN, COOMe, PhCH=CH, Cl, Me, OMe) in the pyrazine ring reveals a strong dependence of electronic effects on the regiochemistry of nucleophilic addition.
    Mots-clés : 1,1-bis(trimethylsilyloxy)ketene acetals, access, allylic acetates, Bis(trimethylsilyl)ketene acetals, CHEMBIO, cyclization, delta-lactones, double nucleophilic-addition, gamma-lactones, Heterocycles, N-activation, POLE 3, pyrazines, pyridines, Triflic anhydride, unsaturated carboxylic-acids.


  • M. Görmen, P. Pigeon, E. A. Hillard, A. Vessières, M. Huché, M. - A. Richard, M. J. McGlinchey, S. Top, et G. Jaouen, « Synthesis and Antiproliferative Effects of [3]Ferrocenophane Transposition Products and Pinacols Obtained from McMurry Cross-Coupling Reactions », Organometallics, vol. 31, nᵒ 16, p. 5856-5866.
    Résumé : We here report the synthesis and antiproliferative activities of two new series of ferrocenophanes obtained from McMurry cross-coupling reactions of [3]ferrocenophan-1-one with benzophenone, 4-hydroxybenzophenone, 4,4′-dihydroxybenzophenone, and 4,4′-diacetylaminobenzophenone. In addition to the main formation of olefins at reflux, tetrahedral transposition products, resulting from a pinacolic rearrangement, were also isolated in about 10% yields. Lowering the temperature of the reaction to 0 °C allowed the isolation of pinacols, which could be transformed into transposition compounds in good yields. Three ferrocenophane compounds have been characterized by X-ray crystallography: 1-(p-hydroxyphenyl)-1-phenyl-2-oxo[4]ferrocenophane (7b), 1,1-diphenyl-2-oxo[4]ferrocenophane (7c), and 1-hydroxy-1-[1-hydroxy-1-[3]ferrocenophanyl][3]ferrocenophane (12) crystallize in monoclinic P21/n, triclinic P1̅, and monoclinic P21/c space groups, respectively. The antiproliferative effects on hormone-independent breast cancer cells (MDA-MB-231) of the transposition compounds are generally lower than those of their corresponding butene analogues (IC50 values in micromolar versus nanomolar range). In contrast and quite surprisingly, the pinacol complexes are significantly cytotoxic (IC50 in the nanomolar range), among the most cytotoxic ferrocene compounds prepared so far. This antiproliferative activity may be linked to their oxidative cleavage.
    Mots-clés : CHEMBIO, POLE 3.


  • N. T. Huynh, C. Passirani, E. Allard-Vannier, L. Lemaire, J. Roux, E. Garcion, A. Vessieres, et J. - P. Benoit, « Administration-dependent efficacy of ferrociphenol lipid nanocapsules for the treatment of intracranial 9L rat gliosarcoma », International Journal of Pharmaceutics, vol. 423, nᵒ 1, p. 55-62.
    Résumé : The anti-tumour effect of ferrociphenol (FcdiOH)-loaded lipid nanocapsules (LNCs), with or without a DSPE-mPEG2000 coating, was evaluated on an orthotopic gliosarcoma model after administration by convection-enhanced delivery (CED) technique or by intra-carotid injection. No toxicity was observed by MRI nor by MRS in healthy rats receiving a CED injection of FcdiOH-LNCs (60 μL, 0.36 mg of FcdiOH/rat) when the pH and osmolarity had been adjusted to physiological values prior to injection. At this dose, the treatment by CED with FcdiOH-LNCs significantly increased the survival time of tumour-bearing rats in comparison with an untreated group (28.5 days vs 25 days, P = 0.0009) whereas DSPE-mPEG2000–FcdiOH-LNCs did not exhibit any efficacy with a median survival time of 24 days. After intra-carotid injection (400 μL, 2.4 mg of FcdiOH/rat), hyperosmolar DSPE-mPEG2000–FcdiOH-LNCs markedly increased the median survival time (up to 30 days, P = 0.0008) as compared to the control (20%). This was strengthened by their evidenced accumulation in the tumour zone and by the measure of the fluorescent brain surface obtained on brain slides for these DiI-labelled LNCs, being 3-fold higher than for the control. These results demonstrated that, depending upon the administration route used, the characteristics of LNC suspensions had to be carefully adapted.
    Mots-clés : Brain tumour, CHEMBIO, Convection-enhanced delivery (CED), DSPE-mPEG2000, Intra-carotid injection, PEGylated nanoparticles, POLE 3.


  • A. - L. Laine, N. T. Huynh, A. Clavreul, J. Balzeau, J. Béjaud, A. Vessieres, J. - P. Benoit, J. Eyer, et C. Passirani, « Brain tumour targeting strategies via coated ferrociphenol lipid nanocapsules. », European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, vol. 81, nᵒ 3, p. 690-693.
    Résumé : Abstract: In this study, a new active targeting strategy to favour ferrociphenol (FcdiOH) internalisation into brain tumour cells was developed by the use...
    Mots-clés : CHEMBIO, POLE 3.


  • P. Messina, E. Labbé, O. Buriez, E. A. Hillard, A. Vessières, D. Hamels, S. Top, G. Jaouen, Y. M. Frapart, D. Mansuy, et C. Amatore, « Deciphering the Activation Sequence of Ferrociphenol Anticancer Drug Candidates », Chemistry – A European Journal, vol. 18, nᵒ 21, p. 6581-6587.
    Résumé : The complete oxidation sequence of a model for ferrociphenols, a new class of anticancer drug candidate, is reported. Cyclic voltammetry was used to monitor the formation of oxidation intermediates on different timescales, thereby allowing the electrochemical characterization of both the short-lived and stable species obtained from the successive electron-transfer and deprotonation steps. The electrochemical preparation of the ferrocenium intermediate enabled a stepwise voltammetric determination of the stable oxidation compounds obtained upon addition of a base as well as the electron stoichiometry observed for the overall oxidation process. A mechanism has been established from the electrochemical data, which involves a base-promoted intramolecular electron transfer between the phenol and the ferrocenium cation. The resulting species is further oxidized then deprotonated to yield a stable quinone methide. To further characterize the transient species successively formed during the two-electron oxidation of the ferrociphenol to its quinone methide, EPR was used to monitor the fate of the paramagnetic species generated upon addition of imidazole to the electrogenerated ferrocenium. The study revealed the passage from an iron-centered to a carbon-centered radical, which is then oxidized to yield the quinone methide, namely, the species that interacts with proteins and so forth under biological conditions.
    Mots-clés : Antitumor agents, CHEMBIO, cyclic voltammetry, ferrociphenols, oxidation, POLE 3, Reaction mechanisms.


  • M. Roger, A. Clavreul, N. T. Huynh, C. Passirani, P. Schiller, A. Vessières, C. Montero-Menei, et P. Menei, « Ferrociphenol lipid nanocapsule delivery by mesenchymal stromal cells in brain tumor therapy », International Journal of Pharmaceutics, vol. 423, nᵒ 1, p. 63-68.
    Résumé : The prognosis of patients with malignant glioma remains extremely poor despite surgery and improvements in radio- and chemo-therapies. Thus, treatment strategies that specifically target these tumors have the potential to greatly improve therapeutic outcomes. “Marrow-isolated adult multilineage inducible” cells (MIAMI cells) are a subpopulation of mesenchymal stromal cells (MSCs) which possess the ability to migrate to brain tumors. We have previously shown that MIAMI cells were able to efficiently incorporate lipid nanocapsules (LNCs) without altering either their stem cell properties or their migration capacity. In this study, we assessed whether the cytotoxic effects of MIAMI cells loaded with LNCs containing an organometallic complex (ferrociphenol or Fc-diOH) could be used to treat brain tumors. The results showed that MIAMI cells internalized Fc-diOH-LNCs and that this internalization did not induce MIAMI cell death. Furthermore, Fc-diOH-LNC-loaded MIAMI cells produced a cytotoxic effect on U87MG glioma cells in vitro. This cytotoxic effect was validated in vivo after intratumoral injection of Fc-diOH-LNC-loaded MIAMI cells in a heterotopic U87MG glioma model in nude mice. These promising results open up a new field of treatment in which cellular vehicles and nanoparticles can be combined to treat brain tumors.
    Mots-clés : CHEMBIO, Glioma, Mesenchymal stromal cells, Nanocarriers, Organometallic compound, POLE 3.


  • B. Rudolf, M. Salmain, E. Fornal, et A. Rybarczyk-Pirek, « Metallocarbonyl complexes of bromo- and dibromomaleimide: synthesis and biochemical application », Applied Organometallic Chemistry, vol. 26, nᵒ 2, p. 80-85.
    Résumé : Bromomaleimides react with cysteine residues to form thiomaleimides that can be further cleaved with TCEP (tris(2-carboxyethyl)phosphine) to regenerate the cysteine derivatives. Herein we report the preparation of new organometallic Fe complexes containing monobromo and dibromo maleimide ligands. Both of these complexes were characterised by X-ray diffraction. Organometallic bromomaleimide derivatives were reacted with the thiol-containing biomolecules: cysteine ethyl ester hydrochloride, glutathione and papain. These cysteine-containing molecules underwent a substitution reaction with metallocarbonyl bromo- or dibromo maleimide complexes, followed by an addition reaction to the thio-maleimide double bond if thiol was added in excess. The metallocarbonyl mono-bromomaleimide complex was shown to inhibit the peptidase activity of the enzyme papain. The resulting papain–maleimide product could be cleaved by addition of TCEP to regenerate the catalytically active enzyme. Copyright © 2012 John Wiley & Sons, Ltd.
    Mots-clés : biometalloorganic chemistry, bromomaleimides, CHEMBIO, metallocarbonyl complexes, papain inhibitors, POLE 3.


  • M. Salmain, M. Ghasemi, S. Boujday, et C. - M. Pradier, « Elaboration of a reusable immunosensor for the detection of staphylococcal enterotoxin A (SEA) in milk with a quartz crystal microbalance

     », Sensors and Actuators B: Chemical, vol. 173, p. 148-156.
    Résumé : An immunosensor with quartz crystal microbalance (QCM) detection operating in flow-through mode was set up for assaying staphylococcal enterotoxin A (SEA) in model buffer medium and in milk. This biosensor is label-free and operates in the direct format. Each step of construction of the sensing layer comprising the capture anti-SEA antibody was investigated at the molecular level and optimized. The molecular layer was built using either amine- or acid-terminated thiols, with and without adding protein A to immobilize anti-SEA. The most efficient strategy to immobilize the antibody was selected on the basis of the biosensor's response to a standard solution of SEA. The optimized sensing layer was successfully used for the direct and fast (15 min) assay of SEA in phosphate buffer by QCM within a working range of 0.05-1 mg L−1 and a limit of detection of 0.02 mg L−1. Using a sandwich type assay, the response was amplified by a factor of 2 and consequently the lowest measurable concentration dropped down to 0.007 mg L−1 for a total assay time of 25 min. Furthermore, sensor regeneration was achieved in good conditions with low pH buffer releasing solution. Two levels of regeneration were reached, the first one, up to the binding protein level, necessitating the rebinding of anti-SEA. In this case the response of the regenerated sensor was 73% in the first cycle then stabilized at 60% of the primary response. For the second level, the capture antibody was cross-linked to the underlayer of protein A and no further grafting was needed. In this second case, the response of the regenerated sensor was 65% of the primary response. Eventually, the piezoelectric immunosensor was successfully applied to the direct assay of SEA spiked in real milk samples.
    Mots-clés : Biosensor, CHEMBIO, POLE 3, Polyclonal antibody, Protein A, Quartz crystal microbalance (QCM), Regeneration, Staphylococcal enterotoxin A.


  • G. Sava, G. Jaouen, E. A. Hillard, et A. Bergamo, « Targeted therapy vs. DNA-adduct formation-guided design: thoughts about the future of metal-based anticancer drugs », Dalton Transactions, vol. 41, nᵒ 27, p. 8226-8234.
    Résumé : The development of metal-based anticancer drugs is mainly governed by the experience accumulated with cisplatin and its analogues. The synthesis is focused on adding appropriate leaving and non-leaving groups to a transition metal in order to get more favorable DNA binding properties, and the biological activity is tested in vitro, always in a second step, looking for the cell line that is killed at the lowest drug concentration. This strategy seems unproductive today for the area of new drug development where the knowledge on cancer genomics is suggesting the use of targets selectively expressed, or overexpressed by cancer cells. These targets almost always are proteins, constituting membrane receptors or components of crucial biochemical pathways. Some data indicate that the antitumor activity of cisplatin might also be due to the interaction with protein targets. This critical review examines the possibilities for metal-based drugs to challenge tumors with innovative strategies, based on genomic approaches, capitalizing on the chemical experiences with metals in medicine and focusing on the nature of the ligands which are added to a metal depending on the selected tumor cells and on their molecular targets.
    Mots-clés : CHEMBIO, POLE 3.


  • Y. L. K. Tan, P. Pigeon, S. Top, E. Labbé, O. Buriez, E. A. Hillard, A. Vessières, C. Amatore, W. K. Leong, et G. Jaouen, « Ferrocenyl catechols: synthesis, oxidation chemistry and anti-proliferative effects on MDA-MB-231 breast cancer cells », Dalton Transactions, vol. 41, nᵒ 25, p. 7537-7549.
    Résumé : The synthesis and anti-tumoral properties of a series of compounds possessing a ferrocenyl group tethered to a catechol via a conjugated system is presented. On MDA-MB-231 breast cancer cell lines, the catechol compounds display a similar or greater anti-proliferative potency (IC50 values ranging from 0.48–1.21 μM) than their corresponding phenolic analogues (0.57–12.7 μM), with the highest activity found for species incorporating the [3]ferrocenophane motif. On the electrochemical timescale, phenolic compounds appear to oxidize to the quinone methide, while catechol moieties form the o-quinone by a similar mechanism. Chemical oxidation of selected compounds with Ag2O confirms this interpretation and demonstrates the probable involvement of such oxidative metabolites in the in vitro activity of these species.
    Mots-clés : CHEMBIO, POLE 3.


  • K. N. Tiwari, J. - P. Monserrat, A. Hequet, C. Ganem-Elbaz, T. Cresteil, G. Jaouen, A. Vessières, E. A. Hillard, et C. Jolivalt, « In vitro inhibitory properties of ferrocene-substituted chalcones and aurones on bacterial and human cell cultures », Dalton Transactions, vol. 41, nᵒ 21, p. 6451-6457.
    Résumé : Two series of ten chalcones and ten aurones, where ferrocene replaces the C ring and with diverse substituents on the A ring were synthesized. The compounds were tested against two antibiotic-sensitive bacterial strains, E. coli ATCC 25922 and S. aureus ATCC 25923, and two antibiotic-resistant strains, S. aureus SA-1199B and S. epidermidis IPF896. The unsubstituted compound and those with methoxy substitution showed an inhibitory effect on all bacterial strains at minimum inhibitory concentrations ranging between 2 and 32 mg L−1. For four of these compounds, the effect was bactericidal, as opposed to bacteriostatic. The corresponding organic aurones did not show growth inhibition, underscoring the role of the ferrocene group. The methoxy-substituted aurones and the unsubstituted aurone also showed low micromolar (IC50) activity against MRC-5 non-tumoral lung cells and MDA-MB-231 breast cancer cells, suggesting non-specific toxicity.
    Mots-clés : CHEMBIO, POLE 3.

  • V. Toum, G. Lhommet, et L. Dechoux, « Synthesis of Cyclohexa-1,3-dienamines by Formal [3+3] Cycloaddition », Synlett, nᵒ 16, p. 2349-2352.
    Résumé : Formal [3+3] cycloadditions of beta-carboxymethylenamino esters with acrolein derivatives give a range of cyclohexa-2,6-dicarboxymethyl-1,3-dienamines that are potential acceptordonor-acceptor systems.
    Mots-clés : acid chlorides, Aza-annulation, CHEMBIO, cyclization, cyclohexa-1,3-dienamines, derivatives, donor-acceptor systems, enamine chemistry, Heterocycles, imines, multicomponent reactions, POLE 3, [3+3] cycloaddition.

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