Nos tutelles

CNRS

Rechercher





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

Publications

publié le , mis à jour le

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)


  • 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.
    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, β-Lactoglobulin.


  • V. Scalcon, M. Salmain, A. Folda, S. Top, P. Pigeon, H. Z. S. Lee, G. Jaouen, A. Bindoli, A. Vessières, et M. P. Rigobello, « Tamoxifen-like metallocifens target thioredoxin system determining mitochondrial impairment leading to apoptosis in Jurkat cells », Metallomics.
    Résumé : Tamoxifen-like metallocifens (TLMs) of the group-8 metals (Fe, Ru, Os) show strong anti-proliferative activity on cancer cell lines resistant to apoptosis, owing to their unique redox properties. On the other hand, the thioredoxin system, which is involved in cellular redox balance, is often overexpressed in cancer cells, especially in tumour types resistant to standard chemotherapies. Therefore, we investigated the effect of these three TLMs on the thioredoxin system and evaluated the input of the metallocene unit by comparison with structurally related organic tamoxifens. In vitro, all three TLMs became strong inhibitors of the cytosolic (TrxR1) and mitochondrial (TrxR2) isoforms of thioredoxin reductase after enzymatic oxidation with HRP/H2O2 while none of the organic analogues was effective. In Jurkat cells, TLMs inhibited mainly TrxR2, resulting in accumulation of oxidized thioredoxin 2 and cell redox imbalance. Overproduction of ROS ensued in a strong decrease of mitochondrial membrane potential, translocation of cytochrome c to the cytosol and activation of caspase 3, thus leading to apoptosis. None of these events occurred with organic tamoxifens. The mitochondrial fraction of cells exposed to TLMs contained a high amount of the corresponding metal as quantified by ICP-OES. The lipophilic and cationic character associated with the singular redox properties of the TLMs could explain why they alter the mitochondrial function. These results provide new insights into the mechanism of action of tamoxifen-like metallocifens, underlying their prodrug behaviour and the pivotal role played by the metallocenic entity in their cytotoxic activity associated with induction of apoptosis.
    Mots-clés : CHEMBIO, POLE 3.
    Pièce jointe Full Text PDF 1.3 Mo (source)


  • 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.
    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, biotransformation, CHEMBIO, gentiopicroside, GOBS, natural product, POLE 3, secoiridoid, total synthesis..


  • 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.
    Résumé : We report the synthesis, characterization, and photophysical properties of two new cyclometalated half-sandwich iridium(III) complexes having the general formula [(η5-Cp*)Ir(ppy)Z]PF6 where η5-Cp* = pentamethylcyclopentadienyl and ppy = 2-phenyl-pyridine as C∧N-chelating ligand and Z = 3- or 4-pyridyl-BODIPY (BODIPY = 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene dye containing a 3- or 4-pyridyl group at the meso position). The molecular structure of both complexes has been determined by X-ray crystallography. The photophysical properties of the dyads were investigated and compared to the pyridyl-BODIPY precursors. Antiproliferative studies demonstrated that one of the compounds was highly active with submicromolar IC50 on a panel of cancer cell lines. The replacement of the chlorido ligand by the pyridyl-BODIPY increased the lipophilicity of the complexes and slowed down the hydrolysis rate, which in turn increased the cytotoxicity of the metallodrug candidate. For the first time, cell uptake of one of the dyads was monitored by living cell fluorescence imaging. Interestingly, extremely fast internalization was observed the rate of which was temperature-dependent.
    Mots-clés : CHEMBIO, POLE 3.

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.


  • 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 :

    ng> 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.


  • 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-ferrocifen 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.

    width="16" alt="Pièce jointe"/> Snapshot


  • 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, « Biofunctionalization 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.


  • 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.


  • R. D. Bethel et M. Y. Darensbourg, « The Bioorganometallic Chemistry of Hydrogenase », in Bioorganometallic Chemistry, G. Jaouen et M. Salmain, Éd. Wiley-VCH Verlag GmbH & Co. KGaA, p. 239-272.
    Résumé : A new subfield of bioorganometallic chemistry is evolving, which derives from hydrogenase enzymes: metalloproteins containing low-valent, first-row transition metals within metal–metal binding distance and stabilized by the most classical of organometallic ligands, carbon monoxide. The review of the structures, mechanisms, and synthetic analogs of the active sites of [NiFe]-, [FeFe]-, and [Fe]-hydrogenase enzymes recalls the discovery and characterization of such organometallics, well buried within proteins and required by some of the most ancient of organisms. Historically, the role of synthetic chemists in the study of enzymes has been largely directed toward providing structural and spectroscopic references for biochemists. The same is true with hydrogenases; however, with the obvious structures and reactivity in the active sites, organometallic chemists are moving forward with enzyme active site-inspired compounds that display catalytic function, both as small molecules in their own right and through incorporation into active enzymes. These are described in this chapter.
    Mots-clés : Biomimetic, biosynthesis, carbon monoxide, CHEMBIO, cyanide, hydrogenase, low-valent metal, POLE 3, transition metal hydride.

  • C. Brazel, N. Dupre, M. Malacria, B. Hasenknopf, E. Lacôte, et S. Thorimbert, « Intramolecular anion effect in polyoxometalate-based organocatalysts: reactivity enhancement and chirality transfer by a metal oxide-organic cation interaction. », Chemistry A European Journal, vol. 20, nᵒ 49, p. 16074-7.
    Résumé : An alpha1 -Dawson polyanion bearing a lateral side chain with a 4-aminopyridine end group was synthesized. This organopolyoxometalate catalyzes the addition of indenyl allyl silanes to cinnamoyl fluorides. The polyanionic framework influences the organocatalyst activity and selectivity. A moderate but nonzero chirality transfer from the chiral inorganic framework to the organic substrate was observed. 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Mots-clés : CHEMBIO, GOBS, MACO, POLE 1, POLE 3.

  • C. Bruyere, V. Mathieu, A. Vessieres, P. Pigeon, S. Top, G. Jaouen, et R. Kiss, « Ferrocifen derivatives that induce senescence in cancer cells: selected examples », Journal of Inorganic Biochemistry, vol. 141, p. 144-151.
    Résumé : Platinum coordination complexes represent an important class of anti-tumor agents. Due to recognized drawbacks, research into other types of metallodrugs has been diversified with the aim of finding new chemical entities with alternative mechanisms of action to overcome classical chemoresistance. P5 and DP1, two closely related ferrocenyl complexes bearing a similar ferrocenyl-ene-phenyl motif and displaying marked differences in their conformations and oxidation state versatility, were assayed in cancer cell models characterized by various sensitivities to pro-apoptotic stimuli. P5 and DP1 exert growth inhibitory effects between 0.5 and 10 mu M against glioma and melanoma cells including pluripotent stem-like cells. These effects are due, at least partly, to senescence induction with typical SA-beta-galactosidase staining and senescence-associated secretory phenotype (SASP) as measured by the secretion of IL-l alpha, IL-1 beta, IL-6, IL-8 and TNF-alpha. Regulation of these cytokines' secretion may be related to AP-1 and other transcription factors unrelated to senescence. An in vivo graft of B16F10 cells after in vitro pre-incubation with DP1 or P5 led to increased survival in mice. In conclusion, P5 and DP1 ferrocenyl complexes induce senescence in various cancer cell models associated with distinct sensitivity to pro-apoptotic stimuli. (C) 2014 Elsevier Inc. All rights reserved.
    Mots-clés : Anti-cancer effects, cellular senescence, CHEMBIO, chemotherapy, Cytokine, drug-resistance, Ferrocene, galectin-1, hydroxytamoxifen, in-vitro, Inhibition, lines, Metallodrug, POLE 3, Senescence, therapy.


  • s="csl-bib-body">
    J. de J. Cázares-Marinero, S. Top, et G. Jaouen, « Synthesis and characterization of new ferrocenyl compounds with different alkyl chain lengths and functional groups to target breast cancer cells », Journal of Organometallic Chemistry, vol. 751, p. 610-619.


  • J. de J. Cázares-Marinero, S. Top, A. Vessières, et G. Jaouen, « Synthesis and antiproliferative activity of hydroxyferrocifen hybrids against triple-negative breast cancer cells », Dalton Transactions, vol. 43, nᵒ 2, p. 817-830.

  • A. Chevalley, M. V. Cherrier, J. C. Fontecilla-Camps, M. Ghasemi, et M. Salmain, « Artificial metalloenzymes derived from bovine beta-lactoglobulin for the asymmetric transfer hydrogenation of an aryl ketone - synthesis, characterization and catalytic activity », Dalton Transactions, vol. 43, nᵒ 14, p. 5482-5489.
    Résumé : A series of diimines derived from saturated and unsaturated fatty acids and including a dipyridylamine (dpa) or a bispyridylmethane (bpm) scaffold as a chelating moiety were synthesized and characterized spectroscopically. Complexation by [LM(mu-Cl) Cl](2) (M = Ru, L = p-cymene; M = Rh, L = Cp*) afforded the monocationic, mononuclear complexes of general formula [LM(N boolean AND N)Cl]Cl with N boolean AND N being the diimine ligand. Unsurprisingly, these new complexes catalysed the transfer hydrogenation of an activated aromatic ketone, namely 2,2,2-trifluoroacetophenone (TFACP), in water at neutral pH and mild temperature in the presence of formate as a hydrogen donor. The catalytic activity of the complexes expressed as TOF was shown to depend not only on the metal (Ru or Rh) but also on the chelating entity (dpa or bpm) and the length and nature of the lipidic chain tethered to it. Incorporation of the complexes within bovine beta-lactoglobulin (beta LG) as the protein host was studied by circular dichroism and fluorescence spectroscopy and again noticeable differences were observed between the saturated and unsaturated fatty acid derivatives. Eventually, the ability of the protein hybrids to catalyse the transfer hydrogenation of TFACP was demonstrated. Good-to-quantitative conversions in the corresponding alcohol were reached within 72 h with the rhodium(III) hybrids and the best enantioselectivities (up to 32% ee for the (R)-enantiomer) were measured with the Rh(III) cofactors derived from palmitic and stearic acids once incorporated into the isoform A of beta LG.
    Mots-clés : aqueous-solution, aromatic ketones, binding site, biotin-avidin technology, CHEMBIO, directed evolution, enantioselective catalysis, fatty-acids, hybrid catalysts, parinaric acid, POLE 3, ruthenium complexes.

  • A. Citta, A. Folda, A. Bindoli, P. Pigeon, S. Top, A. Vessieres, M. Salmain, G. Jaouen, et M. P. Rigobello, « Evidence for Targeting Thioredoxin Reductases with Ferrocenyl Quinone Methides. A Possible Molecular Basis for the Antiproliferative Effect of Hydroxyferrocifens on Cancer Cells », Journal of Medicinal Chemistry, vol. 57, nᵒ 21, p. 8849-8859.
    Résumé : Many anticancer compounds are strong inhibitors of thioredoxin reductases (TrxRs), selenoenzymes involved in cellular redox regulation. This study examined the effect of two hydroxyferrocifens (1, FcOH; 2, FcOHTAM) and of their corresponding quinone methides (QMs), 1-QM, and 2-QM, on these enzymes. In vitro, both QMs were more potent TrxR inhibitors (IC50 2.5 mu M) than the hydroxyferrocifens (IC50 15 mu M). This inhibition was due to a Michael addition of the penultimate selenocysteine residue of TrxRs to the QMs. In Jurkat cancer cells, both 2 and 2-QM inhibited TrxRs in the same proportion, leading to accumulation of oxidized forms of thioredoxin, while 1 and 1-QM were scarcely effective. This difference of behavior was ascribed to the competitive conversion of 1-QM to an inactive indene in protic medium. This set of experiments confirms for the first time the role played by ferrocenyl quinone methides on several biological targets and gives a molecular basis for these effects. It also highlights differences in the mechanisms of action of 1 and 2 in cancer cells.
    Mots-clés : anticancer agents, breast-cancer, CHEMBIO, drug candidates, estrogen-receptor modulators, glutathione-peroxidase, gold compounds, heterocyclic carbene complexes, lipid nanocapsules, mitochondrial thioredoxin, POLE 3, redox regulation.


  • S. Clède, F. Lambert, R. Saint-Fort, M. - A. Plamont, H. Bertrand, A. Vessières, et C. Policar, « Influence of the Side-Chain Length on the Cellular Uptake and the Cytotoxicity of Rhenium Triscarbonyl Derivatives: A Bimodal Infrared and Luminescence Quantitative Study », Chemistry - A European Journal, vol. 20, nᵒ 28, p. 8714-8722.

  • A. C. de Oliveira, E. G. da Silva, D. D. Rocha, E. A. Hillard, P. Pigeon, G. Jaouen, F. A. R. Rodrigues, F. C. de Abreu, F. da R. Ferreira, M. O. F. Goulart, et L. V. Costa-Lotufo, « Molecular Mechanism of Action of 2-Ferrocenyl-1,1-diphenylbut-1-ene on HL-60 Leukemia Cells », ChemMedChem, vol. 9, nᵒ 11, p. 2580-2586.
    Résumé : The aim of this work was to investigate the mechanism of action of 2-ferrocenyl-1,1-diphenylbut-1-ene (1) on HL-60 human leukemia cells. While inactive against noncancerous cells, 1 provoked a concentration-dependent decrease in viable tumor cells, primarily via apoptosis, as evidenced by analysis of cell morphology, activation of caspases3 and 7, increased DNA fragmentation, and externalization of phosphatidylserine. Necrosis was observed only at the highest tested concentration (4M). Compound 1 interfered with the cell cycle, causing an accumulation of cells in the G(1)/G(0) phase. Interaction of 1 with dsDNA and ssDNA was observed by differential pulse voltammetry and confirmed by hyperchromicity in the UV/Vis spectra of dsDNA, with an interaction constant of 2x10(4)M(-1). Both the organic analogue 1,1,2-triphenylbut-1-ene (2) and ferrocene were inactive against cancer and noncancer cell lines and did not react with DNA. These results reinforce the idea that the hybrid strategy of conjugating ferrocene to the structure of tamoxifen derivatives is advantageous in finding new substances with antineoplastic activity.
    Mots-clés : Antitumor agents, Apoptosis, binding, bioelectrochemistry, breast-cancer cells, calf-thymus dna, CHEMBIO, electron-transfer, estrogen, Ferrocene, ferrocenes, growth, HL-60 cells, in-vitro, POLE 3, receptor, tumor-cells.

  • A. M. Debela, M. Ortiz, C. K. OSullivan, S. Thorimbert, et B. Hasenknopf, « Postfunctionalization of Keggin silicotungstates by general coupling procedures », Polyhedron, vol. 68, p. 131-137.
    Résumé : Tetrabutyl ammonium (TBA) salts of organotin derivatives of polyoxometalates (TBA)(5)[SiW11O39 {Sn(CH2)(2)COOH}] (1). (TBA)(4)[SiW11O39(Sn(CH2)(2)CO}] (2), (TBA)(5)[SiW11O39(Sn(CH2)(2)CONH(CH2)(3)N-3}] (3), TBA(5)[SiW11O39(Sn(CH2)(2)CONH(CH2)(3)(N3C2H)C10H9Fe}] (4) and an ammonium salt (NH4)(5)[SiW11O39 {Sn(CH2)(2)CONH(CH2)(3)N-3}](3') have been synthesized for the first time by adapting the organic functionalization strategies developed earlier for phosphotungstates. The products were characterized using FTIR, NMR, ESI MS, and electrochemical techniques. The Keggin silicotungstate is more nucleophilic than the Keggin phosphotungstate and displays reactivity previously known only for Dawson phosphotungstates. The methodology of CuAAC "click" reaction for silico- and phosphotungstates allows the coupling by a common protocol of diverse POMs with different redox properties, which is potentially useful for bioelectroanalytical applications with redox labels. (C) 2013 Elsevier Ltd. All rights reserved.
    Mots-clés : activation, CHEMBIO, chemistry, complexes, dawson-type polyoxotungstates, derivatives, Electrochemical study, formula, Functionalization, GOBS, Hybrid compound, Organic functionalization, organic-inorganic hybrids, POLE 3, polyoxometalate clusters, Polyoxometalates, reduction.

  • A. Ear, V. Toum, S. Thorimbert, et L. Dechoux, « Decarboxylative Knoevenagel-Type Reactions on Tetronamides: Synthesis of 5-Ylidene-4-Amino-2(5H)-Furanones », Synlett, vol. 25, nᵒ 12, p. 1713-1716.
    Résumé : A detailed account regarding the synthesis of 5-ylidene-2(5H)-furanones is given. The key step is a decarboxylative Knoevenagel-type reaction of tetronamides with various -functionalized aldehydes. The synthesis of protected basidalin is presented.
    Mots-clés : -enaminoesters, 4-amino-2(5H)-furanones, basidalin, carboxylic-acids, CHEMBIO, facile synthesis, Knoevenagel-Doebner reaction, okadaic acid, POLE 3, polysubstituted pyrroles, practical synthesis, ring transformation, stereoselective-synthesis, tetronamides, thermal rearrangement, unsaturated-acids, vinylogous urethane approach.


  • M. El Arbi, J. Théolier, P. Pigeon, K. Jellali, F. Trigui, S. Top, S. Aifa, I. Fliss, G. Jaouen, et R. Hammami, « Antibacterial properties and mode of action of new triaryl butene citrate compounds », European Journal of Medicinal Chemistry, vol. 76, p. 408-413.


  • G. Jaouen, S. Top, et M. J. McGlinchey, « The Biological Target Potential of Organometallic Steroids », in Bioorganometallic Chemistry, G. Jaouen et M. Salmain, Éd. Wiley-VCH Verlag GmbH & Co. KGaA, p. 43-84.
    Résumé : The discovery of the superfamily of nuclear receptors, represented first by the estrogen receptor (ERα) identified by E.V. Jensen in 1958, caused a veritable revolution in biology. Its repercussions are still with us, in the chemistry of steroids, synthetic selective steroid receptor modulators, and endocrine disruptors. These small molecules, including the group of steroids we will focus on here, can be linked to major diseases (e.g., cancers, osteoporosis, and diabetes), as well as issues relating to fertility and conception, birth control, and environmental diseases. After a brief description of the mechanism of action of the nuclear receptors we will address the issue of the organometallic versions of molecules that can potentially target these receptors, as well as their biological advantages. We have shown via radioactive labeling that certain organometallic hormone complexes have good targeting ability for nuclear receptors. The reversible binding of these complexes with specific receptors as well as the case of irreversible inhibition of estrogen receptors that can sometimes be obtained using carefully selected organometallic moieties will be discussed in this chapter. This work introduces the approach using SERMs, SARMs, and so on, which due to their large numbers are only touched on here. A section gives more complete details of organometallic radiopharmaceuticals, mostly steroidal. In broader strokes the current renaissance underway in the area of organometallic steroids is discussed with emphasis on biological aspects where known. Finally, some directions are indicated concerning new organometallic bioprobes obtained with SERMs and other endocrine disruptors that make new types of analysis possible. This combined with endocrine modulators possessing an additional organometallic function, for example of the redox type, points to a future that looks to be rich in promise.
    Mots-clés : CHEMBIO, Ferrocene, nuclear receptors, POLE 3, radiopharmaceuticals, SERM, steroid hormones.


  • A. - L. Lainé, A. Clavreul, A. Rousseau, C. Tétaud, A. Vessieres, E. Garcion, G. Jaouen, L. Aubert, M. Guilbert, J. - P. Benoit, R. - A. Toillon, et C. Passirani, « Inhibition of ectopic glioma tumor growth by a potent ferrocenyl drug loaded into stealth lipid nanocapsules », Nanomedicine: Nanotechnology, Biology and Medicine, vol. 10, nᵒ 8, p. 1667-1677.
    Résumé : In this work, a novel ferrocenyl complex (ansa-FcdiOH) was assessed for brain tumor therapy through stealth lipid nanocapsules (LNCs). Stealth LNCs, prepared according to a one-step process, showed rapid uptake by cancer cells and extended blood circulation time. The ferrocenyl complex was successfully encapsulated into these LNCs measuring 40 nm with a high loading capacity (6.4%). In vitro studies showed a potent anticancer effect of ansa-FcdiOH on 9L cells with a low IC50 value (0.1 μM) associated with an oxidative stress and a dose-dependent alteration of the cell cycle. Repeated intravenous injections of stealth ansa-FcdiOH LNCs in ectopic glioma bearing rats induced a significant tumor growth inhibition, supported by a reduced number of proliferative cells in tumors compared to control group. Additionally, no liver damage was observed in treated animals. These results indicated that stealth ansa-FcdiOH LNCs might be considered as a potential new approach for cancer chemotherapy. From the Clinical Editor In this study, a novel ferrocenyl complex was assessed for brain tumor therapy through stealth lipid nanocapsules, demonstrating no liver damage, and superior tumor volume reduction compared to saline and stealth lipid nanocapsules alone in an ectopic glioma model.
    Mots-clés : ansa-FcdiOH, Cell cycle, CHEMBIO, EPR effect, Nanomedicine, POLE 3.

0 | 50

--- Exporter la sélection au format