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

Publications

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2018


  • M. Ben Haddada, M. Salmain, et S. Boujday, « Gold colloid-nanostructured surfaces for enhanced piezoelectric immunosensing of staphylococcal enterotoxin A », SENSORS AND ACTUATORS B-CHEMICAL, vol. 255, nᵒ 2, p. 1604-1613, mars 2018.


  • B. Bertrand, K. Passador, C. Goze, F. Denat, E. Bodio, et M. Salmain, « Metal-based BODIPY derivatives as multimodal tools for life sciences », Coordination Chemistry Reviews, vol. 358, p. 108-124, mars 2018.
    Résumé : Nowadays, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene – better known as BODIPY – is at the forefront of fluorophores for life sciences. Indeed, its high brightness, its tunable excitation and emission wavelengths along with its high chemical and photochemical stability draw more and more the interest of researchers. In the last decade, chemists have taken advantage of the versatility of the synthesis of BODIPY to design sophisticated objects. This review focuses on the different recent studies dealing with the conception of metal-based-BODIPY derivatives for medical purposes. More precisely, emphasis is put on the use of BODIPY derivatives for the elaboration of BODIPY-based theranostics, multimodal imaging probes, and photodynamic therapy sensitizers.
    Mots-clés : Bimodal imaging, BODIPY, CHEMBIO, Fluorescence, Metal-based drugs, Photodynamic therapy, POLE 3, Theranostics.


  • N. Chahin, L. A. Uribe, A. M. Debela, S. Thorimbert, B. Hasenknopf, M. Ortiz, I. Katakis, et C. K. O'Sullivan, « Electrochemical primer extension based on polyoxometalate electroactive labels for multiplexed detection of single nucleotide polymorphisms », Biosensors and Bioelectronics, vol. 117, p. 201-206, oct. 2018.
    Résumé : Polyoxymetalates (POMs) ([SiW11O39{Sn(CH2)2CO)}]4- and [P2W17O61{Sn(CH2)2CO)}]6-) were used to modify dideoxynucleotides (ddNTPs) through amide bond formation, and applied to the multiplexed detection of single nucleotide polymorphisms (SNPs) in an electrochemical primer extension reaction. Each gold electrode of an array was functionalised with a short single stranded thiolated DNA probe, specifically designed to extend with the POM-ddNTP at the SNP site to be interrogated. The system was applied to the simultaneous detection of 4 SNPs within a single stranded 103-mer model target generated using asymmetric PCR, highlighting the potential of POM-ddNTPs for targeted, multiplexed SNP detection. The four DNA bases were successfully labelled with both ([SiW11O39{Sn(CH2)2CO)}]4- and [P2W17O61{Sn(CH2)2CO)}]6-), and [SiW11O39{Sn(CH2)2CO)}]4- demonstrated to be the more suitable due to its single oxidation peak, which provides an unequivocal signal. The POM-ddNTP enzymatically incorporated to the DNA anchored to the surface was visualised by AFM using gold coated mica. The developed assay has been demonstrated to be highly reproducible, simple to carry out and with very low non-specific background signals. Future work will focus on applying the developed platform to the detection of SNPs associated with rifampicin resistance in real samples from patients suffering from tuberculosis.
    Mots-clés : CHEMBIO, Electrochemical primer extension reaction (éPEX), Multiplexed electrochemical detection, POLE 3, Polyoxometalate-labelled ddNTPs, SNP detection.


  • L. Chang, N. Klipfel, L. Dechoux, et S. Thorimbert, « A solvent-free, base-catalyzed domino reaction towards trifluoromethylated benzenes from bio-based methyl coumalate », Green Chemistry, vol. 20, nᵒ 7, p. 1491-1498, 2018.
    Résumé : A novel, efficient, and environmentally compatible method for CF3-substituted benzene production is reported. It sources a bio-based feedstock, employs tBuOK as a catalyst, and is solvent-free. This regioselective approach provides various trifluoromethyl benzenes in good to excellent yields, without any extra oxidant or special care. CO2 and water are the only byproducts of this process, and the reaction conditions can scale up to gram quantities. The transformation involves an unprecedented tBuOK-catalyzed domino process, and features Michael addition/6[small pi]-electrocyclic ring opening/[1,5]-H shift/carba-6[small pi]-electrocyclic ring closure/decarboxylative aromatization reactions.
    Mots-clés : CHEMBIO, POLE 3.


  • de Jesús Cázares-Marinero José, Przybylski Cédric, et Salmain Michèle, « Proteins as Macromolecular Ligands for Metal-Catalysed Asymmetric Transfer Hydrogenation of Ketones in Aqueous Medium », European Journal of Inorganic Chemistry, vol. 2018, nᵒ 12, p. 1383-1393, janv. 2018.
    Résumé : Biohybrid catalysts resulting from the dative anchoring of half-sandwich organometallic complexes [M(arene)(H2O)x(Cl)y]n+ (M = RuII, arene = ?6-benzene, p-cymene or mesitylene; M = IrIII, RhIII, arene = ?5-Cp*; x = 1?3, y = 0?2, n = 0?2) to bovine beta-lactoglobulin (?LG) or hen egg white lysozyme showed unprecedented behaviour. These constructs were shown to catalyse the asymmetric transfer hydrogenation of aryl ketones in water with sodium formate as hydrogen donor at a much faster rate than the complexes alone. Full conversion of the benchmark substrate 2,2,2-trifluoroacetophenone was reached with an ee of 86?% for the most selective biohybrid. Surprisingly, even the crude biohybrid gave a good ee despite the presence of non-protein-bound metal species in the reaction medium. Other aryl ketones were reduced in the same way, and the highest ee was obtained for ortho-substituted acetophenone derivatives. Furthermore, treatment of ?LG with dimethyl pyrocarbonate resulted in a noticeable decrease of the activity and selectivity of the biohybrid, indicating that the sole accessible histidine residue (His146) was probably involved in the coordination and activation of Ru(benzene). This work underscores that protein scaffolds are efficient chiral ligands for asymmetric catalysis. The use of sodium formate instead of dihydrogen makes this approach safe, inexpensive and environmentally friendly.
    Mots-clés : Artificial metalloenzymes, Asymmetric catalysis, CHEMBIO, Hydrogenation, Mass spectrometry, POLE 3, Ruthenium.
    Note Note
    <p>doi: 10.1002/ejic.201701359</p>


  • J. Elloumi-Mseddi, S. Mnif, N. Akacha, B. Hakim, P. Pigeon, G. Jaouen, S. Top, et S. Aifa, « Selective cytotoxicity of arene tricarbonylchromium towards tumour cell lines », Journal of Organometallic Chemistry, vol. 862, p. 7-12, 2018.
    Mots-clés : 50% inhibitory concentration, CHEMBIO, Cytotoxicity, Inorganic chromium (VI), Organometallics, POLE 3, Tricarbonylchromium, Tumour cell lines.


  • R. Karim, E. Lepeltier, L. Esnault, P. Pigeon, L. Lemaire, C. Lépinoux-Chambaud, N. Clere, G. Jaouen, J. Eyer, G. Piel, et C. Passirani, « Enhanced and preferential internalization of lipid nanocapsules into human glioblastoma cells: effect of a surface-functionalizing NFL peptide », Nanoscale, vol. 10, nᵒ 28, p. 13485-13501, 2018.
    Résumé : Increasing intracellular drug concentration using nanocarriers can be a potential strategy to improve efficacy against glioblastoma (GBM). Here, the fluorescent-labelled NFL-TBS·40-63 peptide (fluoNFL) concentration on a lipid nanocapsule (LNC) was studied to enhance nanovector internalization into human GBM cells. LNC surface-functionalization with various fluoNFL concentrations was performed by adsorption. LNC size and surface charge altered gradually with increasing peptide concentration, but their complement protein consumption remained low. Desorption of fluoNFL from the LNC surface was found to be slow. Furthermore, it was observed that the rate and extent of LNC internalization in the U87MG human glioblastoma cells were dependent on the surface-functionalizing fluoNFL concentration. In addition, we showed that the uptake of fluoNFL-functionalized LNCs was preferential towards U87MG cells compared to healthy human astrocytes. The fluoNFL-functionalized LNC internalization into the U87MG cells was energy-dependent and occurred possibly by macropinocytosis and clathrin-mediated and caveolin-mediated endocytosis. A new ferrocifen-type molecule (FcTriOH), as a potent anticancer candidate, was then encapsulated in the LNCs and the functionalization improved its in vitro efficacy compared to other tested formulations against U87MG cells. In the preliminary study, on subcutaneous human GBM tumor model in nude mice, a significant reduction of relative tumor volume was observed at one week after the second intravenous injection with FcTriOH-loaded LNCs. These results showed that enhancing NFL peptide concentration on the LNC surface is a promising approach for increased and preferential nanocarrier internalization into human GBM cells, and the FcTriOH-loaded LNCs are a promising therapy approach for GBM. ER
    Mots-clés : CHEMBIO, POLE3.


  • Ortiz Mayreli, Debela Ahmed M., Méthivier Christophe, Thorimbert Serge, Hasenknopf Bernold, et O'Sullivan Ciara K., « Stable Carboxylate-Terminated Gold Surfaces Produced by Spontaneous Grafting of an Alkyltin Compound », Chemistry – A European Journal, 2018.
    Résumé : Abstract Self-assembled monolayers formed by chemisorption of thiolated molecules on gold surfaces are widely applied for biosensing. Moreover, and due to the low stability of thiol?gold chemistry, contributions to the functionalisation of gold substrates with linkers that provide a more stable platform for the immobilisation of electroactive or biological molecules are highly appreciated. Herein, it is demonstrated that a carboxylated organotin compound can be successfully grafted onto gold substrates to form a highly stable organic layer with reactivity for subsequent binding to an aminated molecule. A battery of techniques were used to characterise the surface chemistry. The grafted layer was used to anchor aminoferrocene and subjected to both thermostability tests and long-term stability studies over a period of one year, demonstrating thermostability up to 90?°C and storage stability for at least 12?months at 4?°C protected from light. The stable surface tethering of molecules on gold substrates can be exploited in a plethora of applications, including molecular techniques, such as solid-phase amplification and solid-phase melting curve analysis, that require elevated temperature stability, as well as biosensors, which require long-term storage stability.
    Mots-clés : biosensors, CHEMBIO, electrochemistry, gold, POLE 3, surface chemistry, tin.
    Note Note
    <p>doi: 10.1002/chem.201801854</p>


  • Y. Wang, F. Heinemann, S. Top, A. Dazzi, C. Policar, L. Henry, F. Lambert, G. Jaouen, M. Salmain, et A. Vessieres, « Ferrocifens labelled with an infrared rhenium tricarbonyl tag: synthesis, antiproliferative activity, quantification and nano IR mapping in cancer cells », Dalton Transactions, 2018.
    Résumé : Antiproliferative activities of several members of the ferrocifen family, both in vitro and in vivo, are well documented although their precise location in cancer cells has not yet been elucidated. However, two different infrared imaging techniques have been used to map the non-cytotoxic cyrhetrenyl analogue of ferrociphenol in a single cell. This observation prompted us to tag two ferrocifens with a cyrhetrenyl unit [CpRe(CO)3; Cp = η5-cyclopentadienyl] by grafting it, via an ester bond, either to one of the phenols (4, 5) or to the hydroxypropyl chain (6). Complexes 4–6 retained a high cytotoxicity on breast cancer cells (MDA-MB-231) with IC50 values in the range 0.32–2.5 μM. Transmission IR spectroscopy was used to quantify the amount of cyrhetrenyl tag present in cells incubated with 5 or 6. The results show that after a 1-hour incubation of cells at 37 °C, complexes 5 and 6 are mainly present within cells while only a limited percentage, quantified by ICP-OES, remained in the incubation medium. AFM-IR spectroscopy, a technique coupling infrared irradiation with near-field AFM detection, was used to map the cyrhetrenyl unit in a single MDA-MB-231 cell, incubated at 37 °C for 1 hour with 10 μM of 6. The results show that signal distribution of the characteristic band of the Re(CO)3 entity at 1950 cm−1 matched those of amide and phosphate, thus indicating a location of the complex mainly in the cell nucl
    Mots-clés : CHEMBIO, POLE 3.

2017



  • M. Beaupérin, D. Polat, F. Roudesly, S. Top, A. Vessières, J. Oble, G. Jaouen, et G. Poli, « Approach to ferrocenyl-podophyllotoxin analogs and their evaluation as anti-tumor agents », Journal of Organometallic Chemistry, vol. 839, p. 83-90.
    Résumé : Podophyllotoxin is a natural product endowed of a high antimitotic activity and a high affinity for tubulin. Its action results in the cessation of cell division, inducing cell death. However, its high toxicity restrains its use as drug. To overcome this drawback, several chemical modifications of the native podophyllotoxin have been made. However, to date, no reports have so far been directed toward incorporation of a metallocene moiety. The search for new organometallic drugs is a central field in drug discovery, including the domain of cancer therapy. In particular, metallocenyl moieties are known to increase or decrease, depending on the degree of conjugation in the organometallic motif, the selectivity of drugs toward cancer cells. The conjugate organometallic compound reduces the damage of healthy tissues, yet permitting the selective desired antimitotic and cytotoxic effects of the active principle. We report here the synthesis of ferrocene-containing podophyllotoxin analogs and preliminary antiproliferative tests.
    Mots-clés : Antitumor agent, Bioorganometallic chemistry, CHEMBIO, Ferrocene, Multi-step synthesis, Palladium, Podophyllotoxin, POLE 1, POLE 3, ROCS.


  • L. Chang, K. Plevová, S. Thorimbert, et L. Dechoux, « Preparation of Substituted 2H-Pyrans via a Cascade Reaction from Methyl Coumalate and Activated Methylene Nucleophiles », The Journal of Organic Chemistry, vol. 82, nᵒ 10, p. 5499-5505.
    Résumé : The reaction of methyl coumalate with a wide range of methylene active compounds, such as keto-esters or keto-sulfones and cyclic or acyclic diketones, afforded more than 30 2,3,5,6-tetrasubstituted 2H-pyrans. The reaction proceeds via a cascade reaction involving a Michael addition-6π-electrocyclic ring opening-proton transfer and 6π electrocyclization, in which a variety of functional groups were tolerated.
    Mots-clés : CHEMBIO, POLE 3.


  • M. Gormen, P. Pigeon, Y. Wang, A. Vessières, S. Top, F. Martial, C. Gros, M. J. McGlinchey, et G. Jaouen, « Side-Chain Effects on the 1-(Bis-aryl-methylidene)-[3]ferrocenophane Skeleton: Antiproliferative Activity against TNBC Cancer Cells and Comparison with the Acyclic Ferrocifen Series », European Journal of Inorganic Chemistry, vol. 2017, nᵒ 2, p. 454-465.
    Résumé : As part of our ongoing study of the toxicity of compounds derived from 1,1-bis(4-hydroxyphenyl)-2-ferrocenylbut-1-ene, we have recently shown that closely analogous [3]ferrocenophane complexes have an in vitro toxicity level substantially higher than that of their ferrocene counterparts, particularly in the case of mono- and diphenol complexes. In this study we have examined whether the presence of a dimethylamino chain, analogous to the chain in hydroxytamoxifen, is capable of producing in the ferrocenophane series the same antiestrogenic effect observed for OH-Tam and Fc-OH-Tam. To this end, we have synthesized and characterized new complexes bearing various side-chains [O(CH2)3NMe2, O(CH2)3piperidine, O(CH2)3pyrrolidine, NHCO(CH2)2NMe2] and studied the biochemical properties of those complexes possessing appropriate solubility. The results revealed that the new complexes of [3]ferrocenophane have very strong antiproliferative effects; one of the compounds bearing an NHCO(CH2)2NMe2 chain has an IC50 value of 0.05 ± 0.02 µm for MDA-MB-231 breast cancer cells. All the complexes showed affinity for the estradiol receptor. At the low (nanomolar range) concentrations at which the estrogenic/antiestrogenic effect is expressed in these molecules, the presence of an amino-substituted side-chain does not induce in the [3]ferrocenophane series the antiestrogenic effect observed with OH-Tam and Fc-OH-Tam. However, this effect has been found for the complex with a slightly longer chain [O(CH2)4NMe2].
    Mots-clés : Antitumor agents, Bioorganometallic chemistry, CHEMBIO, Ferrocene, POLE 3, substituent effects, Toxicity.


  • L. Le Falher, A. Mumtaz, A. Nina Diogo, S. Thorimbert, et C. Botuha, « Chemoselective Access to π-Conjugated Heterocycles by Stille and Sonogashira Reactions on 2-Substituted 4H-Pyrido[e][1,3]oxazin-4-ones », European Journal of Organic Chemistry, vol. 2017, nᵒ 4, p. 827-832.
    Résumé : Site-selective PdII-catalyzed cross-coupling reactions of 2-substituted-4H-pyrido[e][1,3]oxazin-4-ones were developed. C4- and C5-alkynylated pyridooxazinones were thus obtained through Sonogashira coupling, whereas the efficient incorporation of (hetero)aryl and ethenyl substituents at the C5 position was achieved by Stille coupling. Finally, an example of one-pot sequential multiple Sonogashira reactions with different alkynes was realized. The strategy developed herein provides rapid access to polyfunctionalized precursors with extended π-conjugation for further application as fluorescent materials.
    Mots-clés : CHEMBIO, cross-coupling, Fluorescent probes, heterocycles, homogeneous catalysis, Palladium, POLE 3.
    Pièce jointe Full Text PDF 995.6 ko (source)


  • C. K. O'Sullivan, M. Ortiz, A. , M. Debela, M. Svobodova, S. Thorimbert, D. Lesage, R. Cole, et B. Hasenknopf, « PCR Incorporation of Polyoxometalate Modified Deoxynucleotide Triphosphates and Their Application in Molecular Electrochemical Sensing of Yersinia pestis », Chemistry – A European Journal, vol. 23, nᵒ 44, p. 10597–10603.
    Résumé : Redox-labeled nucleotides are of increasing interest for the fabrication of next generation molecular tools and should meet requirements of being thermally stable, sensitive, and compatible with polymerase-mediated incorporation whilst also being electrochemically discriminable. The synthesis and characterization of Keggin and Dawson polyoxometalate-deoxynucleotide (POM-dNTP) bioconjugates linked through 7-deaza-modified purines is described. The modified POM-dNTPs were used for polymerase based amplification of a DNA sequence specific for Yersinia pestis and the amplified DNA detected via an electrochemical DNA sensor. This highlights the potential of polyoxometalates as thermally stable, sensitive and polymerase-compatible redox labels for exploitation in bioanalytical applications.
    Mots-clés : Biosensor, CHEMBIO, CSOB, Electroanalytical Chemistry, GOBS, Labelled nucleotides, PCR, POLE 3, Polyoxometalates.
    Pièce jointe Full Text PDF 1.3 Mo (source)

  • P. Pigeon, Y. Wang, S. Top, F. Najlaoui, M. C. G. Alvarez, J. Bignon, M. J. McGlinchey, et G. Jaouen, « A New Series of Succinimido-ferrociphenols and Related Heterocyclic Species Induce Strong Antiproliferative Effects, Especially against Ovarian Cancer Cells Resistant to Cisplatin », JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, nᵒ 20, p. 8358-8368, nov. 2017.


  • L. Pocquet, N. Vologdin, G. F. Mangiatordi, I. Ciofini, O. Nicolotti, S. Thorimbert, et M. Salmain, « Supramolecular Anchoring of NCN-Pincer Palladium Complexes into a β-Barrel Protein Host: Molecular-Docking and Reactivity Insights », European Journal of Inorganic Chemistry, vol. 2017, nᵒ 30, p. 3622-3634, août 2017.
    Résumé : Several prochiral NCN-pincer complexes of palladium(II), with hemilabile ligands and a long aliphatic chain, were synthesized and characterized spectroscopically. In some of the complexes, the presence of two different substituents on the N donor atoms made them stereogenic, so that they were isolated as a mixture of diastereoisomers, which could be differentiated by 1H NMR spectroscopy. Binding of some of these complexes to bovine β-lactoglobin by insertion within its inner cavity was theoretically investigated by molecular-docking simulations and was experimentally confirmed by CD spectroscopy. Adjunction of H-bond donor substituents on the ligand framework gave more-stable supramolecular protein–complex assemblies. These constructs were shown to catalyze aldol condensation reactions in aqueous media, affording, in some cases, the less-favorable cis product. Since the corresponding complexes exclusively gave the trans product in the absence of β-lactoglobulin, this unusual diastereoselectivity was ensued by the second sphere of coordination brought by the protein host.
    Mots-clés : Aldol reactions, CHEMBIO, Docking, Metalloenzymes, Palladium, POLE 3, β-Lactoglobulin.

  • V. Scalcon, A. Folda, M. Salmain, G. Jaouen, A. Bindoli, A. Vessieres, et M. P. Rigobello, « Inhibition of the mitochondrial thioredoxin system by three metal-organic tamoxifen derivatives determines a redox imbalance inducing apoptosis in Jurkat cells », FREE RADICAL BIOLOGY AND MEDICINE, vol. 108, nᵒ 1, p. S14-S15, août 2017.
    Mots-clés : CHEMBIO, POLE 4.
    Note Note
    <p>OCC World Congress / Annual SFRR-E Conference, Berlin, GERMANY, JUN 21-23, 2017</p>

  • V. Scalcon, M. Salmain, A. Folda, S. Top, P. Pigeon, H. Z. S. Lee, G. Jaouen, A. Bindoli, A. Vessieres, et M. P. Rigobello, « Tamoxifen-like metallocifens target the thioredoxin system determining mitochondrial impairment leading to apoptosis in Jurkat cells », METALLOMICS, vol. 9, nᵒ 7, p. 949-959, août 2017.


  • Y. Wang, P. Pigeon, M. J. McGlinchey, S. Top, et G. Jaouen, « Synthesis and antiproliferative evaluation of novel hydroxypropyl-ferrociphenol derivatives, resulting from the modification of hydroxyl groups », Journal of Organometallic Chemistry, vol. 829, p. 108-115.
    Résumé : As previously reported, the ferrocenyl derivative HO(CH2)3C(Fc) = C(C6H4OH)2 (2) shows an excellent cytotoxic effect against MDA-MB-231 (TNBC) cancer cell lines. Building on an analysis of this molecular framework, a series of novel hydroxypropyl-ferrociphenol derivatives with modified terminal hydroxyl groups were synthesized, and their antiproliferative activities against MDA-MB-231 cell lines were evaluated. Biological results showed that compound 8, whose terminal hydroxyl was protected by acetylation, exhibited the greatest cytotoxic effect among this series of hydroxypropyl derivatives. Furthermore, the impact of acetyl as a protecting group on the cytotoxicity of hydroxypropyl-ferrociphenol compounds by incorporating it at alkyl or phenyl hydroxyl positions of the core structure has been studied. Several of the compounds presented in this study revealed lipophilicity more suitable for formulation in lipid nanocapsules (LNCs) for subsequent in vivo studies. They also inhibit the cancer cell growth of MDA-MB-231 at a submicromolar IC50 value, providing an interesting potential for further development as innovative anticancer agents.
    Mots-clés : anticancer agents, CHEMBIO, ferrocifen, mda-mb-231, organometallics, POLE 3, quinone methides.


  • S. Wu, L. Yang, W. Sun, L. Si, S. Xiao, Q. Wang, L. Dechoux, S. Thorimbert, M. Sollogoub, D. Zhou, et Y. Zhang, « Design, synthesis and biological evaluation of gentiopicroside derivatives as potential antiviral inhibitors », European Journal of Medicinal Chemistry, vol. 130, p. 308-319.
    Résumé : Based on classical drug design theory, a novel series of gentiopicroside derivatives was designed and synthesized. All synthesized compounds were then biologically evaluated for their inhibition of influenza virus and anti-HCV activity in vitro. Some of the gentiopicroside derivatives, such as 11a, 13d and 16 showed interesting anti-influenza virus activity with IC50 at 39.5 μM, 45.2 μM and 44.0 μM, respectively. However, no significant anti-HCV activity was found for all of gentiopicroside derivatives. The preliminary results indicate that modification of the sugar moiety on gentiopicroside was helpful for enhancing the anti-influenza activities. Our works demonstrate the importance of secoiridoid natural products as new leads in the development of potential antiviral inhibitors.
    Mots-clés : Anti-influenza virus, antiviral agents, CHEMBIO, Gentiopicroside derivatives, GOBS, Natural product, POLE 3, Secoiridoid.


  • S. Wu, N. Yaoyao, Y. Zhao, W. Sun, S. Thorimbert, L. Dechoux, M. Sollogoub, et Y. Zhang, « Research Progress of Natural Product Gentiopicroside - a Secoiridoid Compound », Mini-Reviews in Medicinal Chemistry, vol. 17, nᵒ 1, p. 62-77, 2017.
    Résumé : Gentiopicroside is a secoiridoid compound isolated from Gentiana lutea which is called Qin Jiao in Chinese. It is one of the most common herbal medicines used in China. In this article, we review the pharmacological and biological activity (antiviral, anti-inflammatory, analgesia, antihepatotoxic and choleretic), as well as biotransformation of the gentiopicroside. In addition, attempt towards the total synthesis of gentiopicroside is also presented.
    Mots-clés : Biological activity, CHEMBIO, gentiopicroside, GOBS, natural product, POLE 3.


  • J. M. Zimbron, K. Passador, B. Gatin-Fraudet, C. - M. Bachelet, D. Plażuk, L. - M. Chamoreau, C. Botuha, S. Thorimbert, et M. Salmain, « Synthesis, Photophysical Properties, and Living Cell Imaging of Theranostic Half-Sandwich Iridium–4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) Dyads », Organometallics, vol. 36, p. 3435-3442, juin 2017.

2016



  • M. E. Arbi, K. Jalléli, F. Trigui, P. Pigeon, M. Görmen, S. Top, S. Aifa, I. Fliss, G. Jaouen, et R. Hammami, « Efficacy of a novel ferrocenyl diaryl butene citrate compound as a biocide for preventing healthcare-associated infections », MedChemCom, vol. 7, nᵒ 5, p. 948-954.
    Résumé : The antiseptic and disinfectant potential of a formulation containing the tamoxifen analogue 1,1-bis[4-(3-dimethylaminopropoxy)phenyl]-2-ferrocenyl-but-1-ene citrate was assessed according to European standards and pharmacopeia in comparison with a commercial antiseptic product containing hexamidine diisethionate, chlorhexidine digluconate and chlorocresol as active ingredients. The formulation met the phase 1 requirement of reducing by 5 cycles the counts of microorganisms frequently involved in healthcare-associated infections, namely Escherichia coli ATCC 10536, Pseudomonas aeruginosa ATCC 15442, Staphylococcus aureus ATCC 6538, Enterococcus hirae ATCC 10541 and Candida albicans ATCC 10231. It also killed a clinical isolate of Acinetobacter baumannii which is highly resistant to antibiotics and antiseptics. In phase 2/step 2 tests, it reduced the counts of E. coli ATCC 10536 by 4 log cycles within 60 seconds on hands (standard EN 1499). The novel formula is a potent biocide, and this demonstration could lead to the development of a new commercial antiseptic.
    Mots-clés : CHEMBIO, POLE 3.


  • M. Beauperin, S. Top, M. - A. Richard, D. Plażuk, P. Pigeon, S. Toma, V. Poláčková, et G. Jaouen, « The length of the bridging chain in ansa-metallocenes influences their antiproliferative activity against triple negative breast cancer cells (TNBC) », Dalton Transactions, vol. 45, nᵒ 33, p. 13126-13134.
    Résumé : In order to examine whether the length of the bridging chain in ansa-ferrocenes affects their antiproliferative activity against MDA-MB-231 triple negative breast cancer cell lines (TNBC), we synthesized derivatives of the type 1-[bis-(4-hydroxyphenyl)]methylidene-[n]ferrocenophane and 1-[(4-hydroxyphenyl)-phenyl]methylidene-[n]ferrocenophane with n = 3, 4, 5. We found that the derivatives of [3]ferrocenophane, the compounds with the shortest bridging chains, are the most active. IC50 values were 0.09 ± 0.01, 2.41 ± 0.10, and 1.85 ± 0.25 μM for the dihydroxyphenyl derivatives, with n = 3, 4, 5, respectively. These differences can be explained in terms of modification of the key metabolites (radical versus quinone methides) within the ansa series depending on the length of the bridging chain. The derivative of [5]ferrocenophane, possessing two –[bis-(4-hydroxyphenyl)]methylidene groups, was also prepared. Surprisingly, this relatively large molecule is also active (IC50 = 2.7 ± 0.3 μM). Two ruthenocenophane analogs were also synthesized. These ruthenium compounds are practically inactive against MDA-MB-231 cells. The unusual chemistry of these different compounds is discussed in terms of elucidating the mechanism underlying their diverse antiproliferative activity, and their specific advantages are evaluated.
    Mots-clés : CHEMBIO, POLE 3.


  • M. Ben Haddada, M. Hübner, S. Casale, D. Knopp, R. Niessner, M. Salmain, et S. Boujday, « Gold Nanoparticles Assembly on Silicon and Gold Surfaces: Mechanism, Stability and Efficiency in Diclofenac Biosensing », Journal of Physical Chemistry C, vol. 120, nᵒ 51, p. 29302–29311, 2016.


  • A. M. Debela, S. Thorimbert, B. Hasenknopf, C. K. O'Sullivan, et M. Ortiz, « Electrochemical primer extension for the detection of single nucleotide polymorphisms in the cardiomyopathy associated MYH7 gene », Chemical Communications, vol. 52, nᵒ 4, p. 757-759.
    Résumé : We report the labelling of dideoxy nucleotides (ddNTPs) for use in electrochemical array based primer extension for the detection of single nucleotide polymorphisms (SNPs). The results confirm the extension of the immobilised primers for each of the four ddNTPs, representing a significant advance in achieving a cost-effective platform for screening of disease-specific SNPs.
    Mots-clés : CHEMBIO, GOBS, POLE 3.


  • R. Mokhtari, A. Adkhis, O. Berradj, F. Michaud, Y. Rousselin, et S. Top, « Synthesis, spectroscopic, and X-ray structural study of aqua-bis(thymine-N 1 ,N 4 )-ethylenediamine copper(II)dihydrate [Cu(Thy) 2 (en)(H 2 O)].2H 2 O », Inorganic and Nano-Metal Chemistry, vol. 47, nᵒ 6, p. 841 - 844, mai 2016.


  • K. Plevová, L. Chang, E. Martin, Q. Llopis, L. Dechoux, et S. Thorimbert, « Regio- and Stereoselective Preparation of β,γ-Unsaturated Carboxylic Acids by One-Pot Sequential Double 1,6-Addition of Grignard Reagents to Methyl Coumalate », Advanced Synthesis & Catalysis, vol. 358, nᵒ 20, p. 3293-3297.
    Résumé : An efficient regio- and stereoselective metal-catalyzed addition of two Grignard reagents (homo-coupling, 2 RMgX or hetero-coupling, R1MgX+R2MgX) to methyl coumalate (methyl 2-oxo-2H-pyran-5-carboxylate) is described. This synthetic approach opens the access to a wide variety of functionalized β,γ-unsaturated carboxylic acids in a modular way. Control of the chemo- and stereoselectivity of this one-pot procedure is discussed.
    Mots-clés : 6-π electrocyclic ring opening, CHEMBIO, double 1,6-conjugate addition, Grignard reagents, metal catalysis, POLE 3, unsaturated acids.


  • B. Rudolf, A. Kubicka, M. Salmain, M. Palusiak, A. J. Rybarczyk-Pirek, et S. Wojtulewski, « Synthesis and characterization of new M(II) carbonyl complexes (M = Fe or Ru) including an η1-N-maleimidato ligand. Reactivity studies with biological thiols », Journal of Organometallic Chemistry, vol. 801, p. 101-110.
    Résumé : Herein we report the preparation and characterization of the iron and ruthenium organometallic maleimides (η5-Cp*)Fe(CO)2(η1-maleimidato) (Cp* = pentamethyl cyclopentadienyl) and (η5-Cp)Ru(CO)2(η1-maleimidato). The molecular structure of the ruthenium complex was confirmed by X-ray diffraction study. The reactivity of the metallocarbonyl maleimide derivatives toward biologically meaningful thiols, namely cysteine ethyl ester hydrochloride, glutathione (GSH) and human serum albumin (HSA) was investigated. To get better insight into the reaction mechanism, kinetic studies of the reaction with GSH and HSA were performed as well as quantum-chemical calculations and QTAIM analysis. We found out that the reactivity of the organometallic maleimides towards thiols depended on: 1) the metal present in the structure, 2) the nature of the capping aromatic ligand due to differences in electron donating capabilities and steric demands and 3) additional interactions like hydrogen bonding in (η5-Cp*)Fe(CO)2(η1-maleimidato) and carbonyl … carbonyl interactions in (η5-Cp)Ru(CO)2(η1-maleimidato).
    Mots-clés : Bioorganometallic chemistry, CHEMBIO, cysteine thiols, Maleimides, Metal carbonyls, Organometallic, POLE 3.


  • V. Scalcon, A. Citta, A. Folda, A. Bindoli, M. Salmain, I. Ciofini, S. Blanchard, J. de Jésús Cázares-Marinero, Y. Wang, P. Pigeon, G. Jaouen, A. Vessières, et M. P. Rigobello, « Enzymatic oxidation of ansa-ferrocifen leads to strong and selective thioredoxin reductase inhibition in vitro », Journal of Inorganic Biochemistry, vol. 165, p. 146-151.
    Résumé : This paper reports the inhibitory effect on the cytosolic thioredoxin reductase (TrxR1) in vitro by the ansa-ferrocife

    n derivative (ansa-FcdiOH, 1). We found that 1 decreased only slightly enzyme activity (IC50 = 8 μM), while 1*, the species generated by enzymatic oxidation by the HRP (horseradish peroxidase)/H2O2 mixture, strongly inhibited TrxR1 (IC50 = 0.15 μM). At the same concentrations, neither 1 nor 1* had effect on glutathione reductase (GR). The most potent TrxR1 inhibitor did not appear to be the corresponding quinone methide as it was the case for ferrocifens of the acyclic series, or the stabilized carbocation as in the osmocifen series, but rather the quinone methide radical. This hypothesis was confirmed by ab-initio calculations of the species generated by oxidation of 1 and by EPR spectroscopy. BIAM (biotin-conjugated iodoacetamide) assay showed that 1* targeted both cysteine and selenocysteine of the C-terminal redox center of TrxR1.
    Mots-clés : Ansa-ferrocifen, CHEMBIO, E-POM, Enzymatic oxidation, Ferrocene, POLE 2, POLE 3, Quinone methide radical, Thioredoxin reductase.


  • V. Scalcon, S. Top, H. Z. S. Lee, A. Citta, A. Folda, A. Bindoli, W. K. Leong, M. Salmain, A. Vessières, G. Jaouen, et M. P. Rigobello, « Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells », Journal of Inorganic Biochemistry, vol. 160, p. 296-304.
    Résumé : The synthesis and the biological effects of two ferrocifen analogs in the osmium series, namely the monophenolic complex 1, the tamoxifen-like complex 2 and their oxidized quinone methide (QM) derivatives, 1-QM and 2-QM, are reported. Inhibition of purified thioredoxin reductase (TrxR) is observed with 1 and 2 only after their enzymatic oxidation by the hydrogen peroxide/horseradish peroxidase (H2O2/HRP) system with IC50 of 2.4 and 1.2 μM respectively. However, this inhibition is larger than that obtained with the corresponding quinone methides (IC50 = 5.4 μM for 1-QM and 3.6 μM for 2-QM). The UV–Vis spectra of 1 or 2 incubated in the presence of H2O2/HRP show that the species generated is not a quinone methide, but probably the corresponding cation. In Jurkat cells, 2 shows high toxicity (IC50 = 7.4 μM), while 1 is less effective (IC50 = 42 μM). Interestingly, a significant inhibition of TrxR activity is observed in cells incubated with 2 (about 70% inhibition with 15 μM) while the inhibition induced by 1 is much weaker (about 30% inhibition with 50 μM). This strong inhibition of TrxR by 2 leads to accumulation of thioredoxin and peroxiredoxin 3 in oxidized form and to a decrease of the mitochondrial membrane potential (MMP). These results show that cytotoxicity of the osmocifens depends on their oxidation within the cell and that inhibition of thioredoxin reductase by oxidized species is a key factor in rationalizing the cytotoxicity of these complexes on Jurkat cells.
    Mots-clés : CHEMBIO, Jurkat cancer cells, Osmocene, Osmocenyl-tamoxifen, POLE 3, ROS, Thioredoxin reductase.


  • P. Srivastava, M. Ghasemi, N. Ray, A. Sarkar, J. Kocabova, S. Lachmanova, M. Hromadova, S. Boujday, S. Cauteruccio, P. Thakare, E. Licandro, C. Fosse, et M. Salmain, « Fischer carbene mediated covalent grafting of a peptide nucleic acid on gold surfaces and IR optical detection of DNA hybridization with a transition metalcarbonyl label », Applied Surface Science, vol. 385, p. 47-55.
    Résumé : Amine-reactive surfaces comprising N-hydroxysuccinimide ester groups as well as much more unusual Fischer alkoxymetallocarbene groups were generated on gold-coated surfaces via self-assembled monolayers of carboxy- and azido-terminated thiolates, respectively. These functions were further used to immobilize homothymine peptide nucleic acid (PNA) decamer in a covalent fashion involving the primary amine located at its N-terminus. These stepwise processes were monitored by polarization modulation reflection – absorption infrared spectroscopy (PM-RAIRS) that gave useful information on the molecular composition of the organic layers. PNA grafting and hybridization with complementary DNA strand were successfully transduced by quartz crystal microbalance (QCM) measurements. Unfortunately, attempts to transduce the hybridization optically by IR in a label-free fashion were inconclusive. Therefore we undertook to introduce an IR reporter group, namely a transition metalcarbonyl (TMC) entity at the 5′ terminus of complementary DNA. Evidence for the formation of PNA-DNA heteroduplex was brought by the presence of ν(CO) bands in the 2000 cm−1 region of the IR spectrum of the gold surface owing to the metalcarbonyl label.
    Mots-clés : 11-mercaptoundecanoic acid, 4-methylbenzylhydrylamine, AFM, atomic force microscopy, Azide-alkyne cycloaddition, CHEMBIO, diisopropylethylamine, DIPEA, Fischer-type carbene complex, Genosensor, hexafluoroisopropanol, HFIP, MBHA, MUA, N, N', N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate, nanoshaving, NS, ODN, oligonucleotide, PBS, Peptide nucleic acid, phosphate buffered saline, PM-RAIRS, PNA, polarization-modulation reflection-absorption infrared spectroscopy, POLE 3, qcm-d, quartz crystal microbalance with dissipation, SAM, SEA, Self-assembled monolayer, single strand DNA, ssDNA, Staphylococcal enterotoxin A, tapping mode, TEA, TM, TMC, transition metalcarbonyl, triethylamine, TSTU.


  • Y. Wang, M. - A. Richard, S. Top, P. M. Dansette, P. Pigeon, A. Vessières, D. Mansuy, et G. Jaouen, « Ferrocenyl Quinone Methide–Thiol Adducts as New Antiproliferative Agents: Synthesis, Metabolic Formation from Ferrociphenols, and Oxidative Transformation », Angewandte Chemie International Edition, vol. 128, nᵒ 35, p. 10587-10590.
    Résumé : Ferrociphenols (FCs) and their oxidized, electrophilic quinone methide metabolites (FC-QMs) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC-QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC-SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC-SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC-QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC-SR-QM. These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs, and also open the way to a new series of organometallic antitumor compounds.
    Mots-clés : CHEMBIO, Glutathion, Lebermikrosome, Michael-Addition, Organometallverbindungen, POLE 3, Tumortherapeutika.

2015


  • « Creating artificial metalloenzymes », Adjacent Digital Politics. [Online]. Available: http://www.adjacentgovernment.co.uk/research-science-innovation-news/creating-artificial-metalloenzymes/14182/.
    Résumé : Dr Michèle Salmain from Université Pierre et Marie Curie, Paris gives an overview of the process involved in creating artificial enzymes
    Mots-clés : CHEMBIO, POLE 3.

  • A. Clavreul, A. Montagu, A. - L. Laine, C. Tetaud, N. Lautram, F. Franconi, C. Passirani, A. Vessieres, C. N. Montero-Menei, et P. Menei, « Targeting and treatment of glioblastomas with human mesenchymal stem cells carrying ferrociphenol lipid nanocapsules », International Journal of Nanomedicine, vol. 10, p. 1259-1271.
    Résumé : Recently developed drug delivery nanosystems, such as lipid nanocapsules (LNCs), hold great promise for the treatment of glioblastomas (GBs). In this study, we used a sub-population of human mesenchymal stem cells, "marrow-isolated adult multilineage inducible" (MIAMI) cells, which have endogenous tumor-homing activity, to deliver LNCs containing an organometallic complex (ferrociphenol or Fc-diOH), in the orthotopic U87MG GB model. We determined the optimal dose of Fc-diOH-LNCs that can be carried by MIAMI cells and compared the efficacy of Fc-diOH-LNC-loaded MIAMI cells with that of the free-standing Fc-diOH-LNC system. We showed that MIAMI cells entrapped an optimal dose of about 20 pg Fc-diOH per cell, with no effect on cell viability or migration capacity. The survival of U87MG-bearing mice was longer after the intratumoral injection of Fc-diOH-LNC-loaded MIAMI cells than after the injection of Fc-diOH-LNCs alone. The greater effect of the Fc-diOH-LNC-loaded MIAMI cells may be accounted for by their peritumoral distribution and a longer residence time of the drug within the tumor. These results confirm the potential of combinations of stem cell therapy and nanotechnology to improve the local tissue distribution of anticancer drugs in GB.
    Mots-clés : adjuvant temozolomide, anticancer drug, CHEMBIO, delivery vehicle, drug delivery, gene-therapy, glioblastoma, inducible miami cells, malignant glioma, mesenchymal stem cells, model, nanoparticle, nanoparticles, POLE 3, rat glioma, targeting, trial.


  • A. M. Debela, M. Ortiz, V. Beni, S. Thorimbert, D. Lesage, R. B. Cole, C. K. O'Sullivan, et B. Hasenknopf, « Biofunctionalizat

    ion of Polyoxometalates with DNA Primers, Their Use in the Polymerase Chain Reaction (PCR) and Electrochemical Detection of PCR Products », Chemistry – A European Journal, vol. 21, nᵒ 49, p. 17721-17727.
    Résumé : The bioconjugation of polyoxometalates (POMs), which are inorganic metal oxido clusters, to DNA strands to obtain functional labeled DNA primers and their potential use in electrochemical detection have been investigated. Activated monooxoacylated polyoxotungstates [SiW11O39{Sn(CH2)2CO}]8− and [P2W17O61{Sn(CH2)2CO}]6− have been used to link to a 5′-NH2 terminated 21-mer DNA forward primer through amide coupling. The functionalized primer was characterized by using a battery of techniques, including electrophoresis, mass spectrometry, as well as IR and Raman spectroscopy. The functionality of the POM-labeled primers was demonstrated through hybridization with a surface-immobilized probe. Finally, the labeled primers were successfully used in the polymerase chain reaction (PCR) and the PCR products were characterized by using electrophoresis.
    Mots-clés : CHEMBIO, CSOB, DNA, DNA Primers, Electrochemistry, GOBS, Nucleic Acid Hybridization, POLE 3, polymerase chain reaction, Polyoxometalates, Redox chemistry, Tungsten Compounds.

  • G. Jaouen, P. Pigeon, et S. Top, « Metallocene Derivatives with Anticancer Activity », U.S. Patent WO/2015/063201.
    Mots-clés : CHEMBIO, Metallocene Derivatives with Anticancer Activity, POLE 3.


  • G. Jaouen, A. Vessières, et S. Top, « Ferrocifen type anti cancer drugs », Chemical Society Reviews, vol. 44, nᵒ 24, p. 8802-8817.
    Résumé : Despite current developments in therapeutics focusing on biotechnologically-oriented species, the unflagging utility of small molecules or peptides in medicine is still producing strong results. In 2014 for example, of the 41 new medicines authorized for sale, 33 belonged to the category of small molecules, while in 2013 they represented 24 of 27, according to the FDA. This can be explained as the result of recent forays into new or long-neglected areas of chemistry. Medicinal organometallic chemistry can provide us with an antimalarial against resistant parasitic strains, as attested by the phase II clinical development of ferroquine, with a new framework for conceptual advances based on three-dimensional space-filling, and with redox or indeed catalytic intracellular properties. In this context, bioferrocene species with antiproliferative potential have for several years been the subject of sustained effort, based on some initial successes and on the nature of ferrocene as a stable aromatic, with low toxicity, low cost, and possessing reversible redox properties. We show here the different antitumoral approaches offered by ferrocifen derivatives, originally simple derivatives of tamoxifen, which over the course of their development have proved to possess remarkable structural and mechanistic diversity. These entities act via various targets, some of which have been identified, that are triggered according to the concentration of the products. They also act according to the nature of the cancer cells and their functionality, by mechanistic pathways that can operate either synergistically or not, in successive, concomitant or sequential ways, depending for example on newly identified signaling pathways inducing senescence or apoptosis. Here we present a first attempt to rationalize the behavior of these entities with various anticancer targets.
    Mots-clés : CHEMBIO, POLE 3.


  • L. Le Falher, O. Ben Ayad, O. Ziyaret, C. Botuha, S. Thorimbert, et F. Slowinski, « Preparation of Halogen-Containing 4H-Pyrido[e][1,3]oxazin-4-ones and Their Transformation into 2-Hydroxypyridinyl-Substituted 1,2,4-Oxadiazoles and 1,2,4-Triazoles », European Journal of Organic Chemistry, vol. 2015, nᵒ 17, p. 3830-3840.
    Résumé : A complete study on the preparation of original halogen-containing 4H-pyrido[e][1,3]oxazin-4-ones and their transformation into 1,2,4-oxadiazoles and 1,2,4-triazoles is presented. Starting from pyridyl-imide sodium salts, the efficiency of the intramolecular O-arylation was studied on three series of compounds, with different fluoro-, chloro-, and bromophenyl substituents at the C-2 position. The final halogenated compounds are of interest as new synthons for future functionalisation. We also present the discovery of a new, rapid, and complementary access to 2-substituted 4H-benzo[e][1,3]oxazinones. Finally, the one-step transformation of some of these pyrido-oxazinones into the corresponding hydroxypyridyl-substituted 1,2,4-oxadiazoles and 1,2,4-triazoles was explored, and the regioselectivity of the reaction was proved by X-ray crystallography.
    Mots-clés : aromatic substitution, CHEMBIO, cyclization, microwave chemistry, molecular diversity, nitrogen heterocycles, POLE 3.


  • H. Z. S. Lee, O. Buriez, F. Chau, E. Labbé, R. Ganguly, C. Amatore, G. Jaouen, A. Vessières, W. K. Leong, et S. Top, « Synthesis, Characterization, and Biological Properties of Osmium-Based Tamoxifen Derivatives – Comparison with Their Homologues in the Iron and Ruthenium Series », European Journal of Inorganic Chemistry, vol. 2015, nᵒ 25, p. 4217-4226.
    Résumé : Three osmium analogues 3a–3c of hydroxytamoxifen were prepared. The antiproliferative effects of these complexes were measured against two breast cancer cell lines (MCF-7 and MDA-MB-231) and compared with those of their homologues of ferrocene (1a–1c) and ruthenocene (2a–2c). The tamoxifen-like complexes 2c and 3c derived from osmium and ruthenium show good cytotoxicities against the two cell lines (IC50 values between 2 and 3 μM), albeit lower than those of ferrocifen 1c (IC50 between 0.5 and 0.8 μM). These complexes induce senescence of the cells at low concentration (0.5 μM). The mono- and diphenol complexes of osmium and ruthenium show little cytotoxicity against the two cell lines (2a, 2b, 3a, 3b; IC50 ≈ 30 μM), whereas the iron analogues show high cytotoxicity (1a and 1b; IC50 = 0.6–1.1 μM against MDA-MB-231). Further studies show that the cytotoxicity of the tamoxifen-like complexes of ruthenium and osmium is multifactorial and is partly due to the presence of the amino chain. Added to this is an effect of the metal center that could be due to a difference in the rate of formation, solubility, and stability of the corresponding quinone methides or to a difference in the acidity of the phenol protons. This work reveals the differences in the mechanisms of action that exist among the complexes of these three metallocenes. The uniqueness of the ferrocene complexes is underlined, but the cytotoxicity of the tamoxifen-like complexes of osmium and ruthenium is also demonstrated.
    Mots-clés : Antitumor ­agents, CHEMBIO, Drug design, ferrocifen, Metallocenes, Osmium, POLE 3, Ruthenium.


  • N. Madern, N. Queyriaux, A. Chevalley, M. Ghasemi, O. Nicolotti, I. Ciofini, G. F. Mangiatord, et M. Salmain, « Piano-stool d6-rhodium(III) complexes of chelating pyridine-based ligands and their papain bioconjugates for the catalysis of transfer hydrogenation of aryl ketones in aqueous medium », Journal of Molecular Catalysis B Enzymatic, vol. 122, p. 314-322.
    Résumé : Two half-sandwich d6-rhodium(III) complexes of the general formula [(η5-Cp*)Rh(N^N)Cl]Cl where N^N is a phenanthroline or a bispyridine methane derivative carrying a thiol-targeting maleimide or...
    Mots-clés : CHEMBIO, POLE 3.


  • D. Mercier, M. Ben Haddada, M. Huebner, D. Knopp, R. Niessner, M. Salmain, A. Proust, et S. Boujday, « Polyoxometalate nanostructured gold surfaces for sensitive biosensing of benzo[a]pyrene », Sensors and Actuators B: Chemical, vol. 209, p. 770-774.
    Mots-clés : arrays, Benzo[a]pyrene, Biosensor, carbon, CHEMBIO, E-POM, efficiency, immobilization, immunosensors, nanoparticles, Nanostructuration, plasmon resonance, POLE 2, POLE 3, pole3, polycyclic aromatic-hydrocarbons, Polyoxometalate, qcm-d, quartz-crystal microbalance.

  • F. Najlaoui, P. Pigeon, Z. Abdelkafi, S. Leclerc, P. Durand, M. E. Ayeb, N. Marrakchi, A. Rhouma, G. Jaouen, et S. Gibaud, « Phthalimido-ferrocidiphenol cyclodextrin complexes: Characterization and anticancer activity », International Journal of Pharmaceutics, vol. 491, nᵒ 1-2, p. 323-334.
    Résumé : Several ferrocenyl analogues of tamoxifen have already showed strong antiproliferative activity in experimental glioma models. Nevertheless, these compounds are very poorly soluble in water and an adapted formulation is needed. In this work, we have tailored and optimized methylated cyclodextrin soluble complexes of phthalimido-ferrocidiphenol for the first time. The complexes were characterized, and the optimized formulation was tested for in vitro efficacy and cell proliferation assays on U87, human glioblastoma cancer cells. Molecular modeling can provide accurate information about the inclusion process. The inclusion of all the moieties at the same time (i.e., ferrocene, phthalimidylpropyl, 2 phenols) is not possible due to the steric hindrance of the 1:4 system. The 1:3 systems are possible but do not seem very relevant. However, various 1:2 and 1:1 complexes are mostly present in aqueous solutions. Some experiments have confirmed our hypothesis. First, interactions between the phenol, phthalimidylpropyl and ferrocenyl groups have been observed in our NMR experiments. Second, the inclusion of phthalimidylpropyl was detected by UV-vis spectrophotometry with an apparent 1:1 interaction, which was observed through the Benesi-Hildebrand method. The complex is readily soluble in water and keeps its pharmacological activity against U87 tumor cells (IC50=0.028 ± 0.007 μM vs. 0.018 ± 0.003 μM for PhtFerr).
    Mots-clés : anticancer drug, Antineoplastic Agents, Cell Line, Tumor, cell proliferation, CHEMBIO, Chemistry, Pharmaceutical, Cyclodextrin, Cyclodextrins, Drug design, Drug Screening Assays, Antitumor, Ferrocene, Ferrous Compounds, Glioma, Hemolysis, humans, In Vitro Techniques, Methylation, Models, Molecular, Organometallic, Phthalimides, POLE 3, Solubility.

  • M. - A. Richard, D. Hamels, P. Pigeon, S. Top, P. M. Dansette, H. Z. S. Lee, A. Vessieres, D. Mansuy, et G. Jaouen, « Oxidative Metabolism of Ferrocene Analogues of Tamoxifen: Characterization and Antiproliferative Activities of the Metabolites », Chemmedchem, vol. 10, nᵒ 6, p. 981-990.
    Résumé : Ferrociphenols have been found to have high antiproliferative activity against estrogen-independent breast cancer cells. The rat and human liver microsome-mediated metabolism of three compounds of the ferrocifen (FC) family, 1,1-bis(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC1), 1-(4-hydroxyphenyl)-1-(phenyl)-2-ferrocenyl-but-1-ene (FC2), and 1-[4-(3-dimethylaminopropoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC3), was studied. Three main metabolite classes were identified: quinone methides (QMs) deriving from two-electron oxidation of FCs, cyclic indene products (CPs) deriving from acid-catalyzed cyclization of QMs, and allylic alcohols (AAs) deriving from hydroxylation of FCs. These metabolites are generated by cytochromes P450 (P450s), as shown by experiments with either N-benzylimidazole as a P450 inhibitor or recombinant human P450s. Such P450-dependent oxidation of the phenol function and hydroxylation of the allylic CH2 group of FCs leads to the formation of QM and AA metabolites, respectively. Some of the new ferrociphenols obtained in this study were found to exhibit remarkable antiproliferative effects toward MDA-MB-231 hormone-independent breast cancer cells.
    Mots-clés : bioactivation, breast cancer, breast-cancer, cancer cell-lines, CHEMBIO, derivatives, drug candidates, ferrocifen, in-vitro, indene metabolites, liver microsomes, P450-dependent oxidation, POLE 3, quinone methides, receptor modulators serms, toremifene.


  • N. B. de Souza, A. C. C. Aguiar, A. C. de Oliveira, S. Top, P. Pigeon, G. Jaouen, M. O. F. Goulart, et A. U. Krettli, « Antiplasmodial activity of iron(II) and ruthenium(II) organometallic complexes against Plasmodium falciparum blood parasites », Memórias do Instituto Oswaldo Cruz, vol. 110, nᵒ 8, p. 981-988.


  • Y. Wang, P. Pigeon, S. Top, M. J. McGlinchey, et G. Jaouen, « Organometallic Antitumor Compounds: Ferrocifens as Precursors to Quinone Methides », Angewandte Chemie International Edition, vol. 54, nᵒ 35, p. 10230-10233.
    Résumé : The synthesis and chemical oxidation profile of a new generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular, the hydroxypropyl derivative HO(CH2)3C(Fc)=C(C6H4OH)2 (3 b) exhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA-MB-231 TNBC, with IC50 values of 0.07 and 0.11 μM, respectively. Chemical oxidation of 3 b yielded an unprecedented tetrahydrofuran-substituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH3CH2-C(Fc)=C(C6H4OH)2 merely formed a vinyl QM. The ferrocenyl group in 3 b plays a key role, not only as an intramolecular reversible redox “antenna”, but also as a stabilized carbenium ion “modulator”. The presence of the oxygen heterocycle in 3 b-QM enhances its stability and leads to a unique chemical oxidation profile, thus revealing crucial clues for deciphering its mechanism of action in vivo.
    Mots-clés : Antitumor agents, CHEMBIO, drug discovery, Ferrocene, metabolism, POLE 3, quinones.


  • S. Wu, Y. Zhang, J. Agarwal, E. Mathieu, S. Thorimbert, et L. Dechoux, « Studies towards the synthesis of secoiridoids », Tetrahedron, vol. 71, nᵒ 40, p. 7663-7669.
    Résumé : A new approach to secoiridoids, based on the synthesis of the key functionalized intermediates 4 and 5, is presented. These compounds were tested in formal [3+3] cycloadditions. Acyl-chloride 15 was transformed into enol α,β-unsaturated ester 16, which was involved in a N-heterocyclic carbene rearrangement to give an advanced precursor 17 in the total synthesis of secoiridoids.
    Mots-clés : CHEMBIO, Gentiopicroside, GOBS, N-heterocyclic-carbenes, organocatalysis, POLE 3, Secoiridoids, [3+3] Cycloadditions.


  • W. - J. Xuan, C. Botuha, B. Hasenknopf, et S. Thorimbert, « Chiral Dawson-Type Hybrid Polyoxometalate Catalyzes Enantioselective Diels–Alder Reactions », Chemistry – A European Journal, vol. 21, nᵒ 46, p. 16512-16516.
    Résumé : Can achiral organocatalysts linked to chiral polyanionic metal oxide clusters provide good selectivity in enantioselective CC bond formations? The answer to this question is investigated by developing a new active hybrid polyoxometalate-based catalyst for asymmetric Diels–Alder reaction. Chirality transfer from the chiral anionic polyoxometalate to the covalently linked achiral imidazolidinone allows Diels–Alder cycloaddition products to be obtained with good yields and high enantioselectivities when using cyclopentadiene and acrylaldehydes as partners.
    Mots-clés : CHEMBIO, chirality, cycloaddition, Diels–Alder reaction, GOBS, organocatalysis, POLE 3, Polyoxometalates.

2014


  • J. Agarwal, O. Bayounes, S. Thorimbert, et L. Dechoux, « Stereoselective synthesis of conjugated alpha-Z/gamma-E and alpha-Z/gamma-Z dienoic acids. Kinetic torquoselectivity versus thermodynamic control », Rsc Advances, vol. 4, nᵒ 6, p. 2772-2775.
    Résumé : The stereoselective synthesis of conjugated (alpha-Z/gamma-E)-(alpha-Z/gamma-Z)-dienoic acids 4 and 4' is described. It is based on the regio- and stereoselective addition of Grignard reagents to methylcoumalate. The origin of the stereocontrol is discussed.
    Mots-clés : 2h-pyran-2-ones, analogs, CHEMBIO, cross-coupling reactions, derivatives, dft, POLE 3, pyrane, stereospecific synthesis, unit.

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