Françoise Nepveu

University of Toulouse, Tolosa de Llenguadoc, Midi-Pyrénées, France

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Publications (90)232.83 Total impact

  • Françoise Nepveu, Ennaji Najahi, Alexis Valentin
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    ABSTRACT: The search for antimalarial compounds continues to be an area of intensive investigation in medicinal chemistry. This review presents the structural variations around the indolone-N-oxide core. From these pharmacomodulation studies, new antiplasmodial agents with various structures have emerged. Most of the molecules generated from reduced forms of the indolone scaffold have led to compounds with antiplasmodial properties. These results confirm the importance of the redox reversibility of the bioreducible N=C bond in these series to obtain antimalarial activities.
    Current topics in medicinal chemistry. 08/2014;
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    ABSTRACT: We recently showed that the indolone-N-oxides can be promising candidates for the treatment of chloroquine-resistant malaria. However, the in vivo assays have been hampered by the very poor aqueous solubility of these compounds resulting in poor and variable activity. Here, we describe the preparation, characterization and in vivo evaluation of biodegradable albumin-bound indolone-N-oxide nanoparticles. Nanoparticles were prepared by precipitation followed by high-pressure homogenization and characterized by photon correlation spectroscopy, transmission electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The process was optimized to yield nanoparticles of controllable diameter with narrow size distribution suitable for intravenous administration, which guarantees direct drug contact with parasitized erythrocytes. Stable nanoparticles showed greatly enhanced dissolution rate (complete drug release within 30min compared to 1.5% of pure drug) preserving the rapid antimalarial activity. The formulation achieved complete cure of Plasmodium berghei-infected mice at 25mg/kg with parasitemia inhibition (99.1%) comparable to that of artesunate and chloroquine and was remarkably more effective in prolonging survival time and inhibiting recrudescence. In 'humanized' mice infected with Plasmodium falciparum, the same dose proved to be highly effective: with parasitemia reduced by 97.5% and the mean survival time prolonged. This formulation can help advance the preclinical trials of indolone-N-oxides. Albumin-bound nanoparticles represent a new strategic approach to use this most abundant plasma protein to target malaria-infected erythrocytes.
    International Journal of Pharmaceutics 01/2014; · 3.99 Impact Factor
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    ABSTRACT: A series of 2-aryl-3H-indol-3-ones was synthesized via deoxygenation of indolone-N-oxides and was evaluated for in vitro activity against chloroquine-resistant strains of Plasmodium falciparum.
    European journal of medicinal chemistry 01/2014; 78:269–274. · 3.27 Impact Factor
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    ABSTRACT: A synthesis of new pyrimidinones by two different methods utilizing microwave (MW) irradiation is described.
    Chinese Chemical Letters 01/2014; · 1.18 Impact Factor
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    ABSTRACT: A series of original amino-indolone-N-oxides was synthesized via the nitro-alkyne cycloisomerization of o-alkynylnitrobenzenes and was evaluated for in vitro activity against chloroquine-resistant strains of Plasmodium falciparum.
    European journal of medicinal chemistry 01/2014; 76:369–375. · 3.27 Impact Factor
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    ABSTRACT: Uncatalyzed racemization processes in atropisomeric diphenyl-like frameworks are classically described as the result of the rotation around the pivotal single bond linking two planar frameworks. Severe constraints leading to more or less distorted transition states account for the experimental barrier to atropenantiomerization. In 1988, one of us hypothesized that in N-aryl-2(1H)-pyrimidin-(thi)ones, a ring-opening/ ring-closure process was contributing to the observed racemization process accounting for the lower barriers in the sulphur analogues than in oxygen analogues. Now a series of six novel 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidinones 5a-f and two 6-amino-5-cyano-4-p-tolyl-1-substituted-2(1H)-pyrimidinethiones 6a-b were synthesized and characterized through spectroscopic and X-ray diffraction studies. Semi-preparative HPLC chiral separation was achieved and enantiomerization barriers were obtained by thermal racemization. The rotational barriers of 6-amino-5-cyano-1-o-tolyl-4-p-tolyl-2(1H)-pyrimidinone (5b) and 6-amino-5-cyano-1-(naphthalen-1-yl)-4-p-tolyl-2(1H)-pyrimidinone (5e) were found to be 120.3 and 125.1 kJ.mol-1 (n-BuOH, 117 DegC), respectively and those of the corresponding thiones were 116.8 and 109.6 kJ.mol-1 (EtOH, 78 DegC), respectively. DFT calculations of the rotational barriers clearly ruled out the classical rotation around the pivotal bond with distorted transition states in the case of the sulphur derivatives. Instead, the ranking of the experimental barriers (sulphur versus oxygen, and O-tolyl versus 1-naphthyl in both series) were nicely reproduced by calculations when the rotation occurred via a ring-opened form in N-aryl-2(1H)-pyrimidinethiones.
    The Journal of Organic Chemistry 12/2013; · 4.56 Impact Factor
  • Françoise Nepveu, Francesco Turrini
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    ABSTRACT: Targeting the redox metabolism of Plasmodium falciparum to create a fatal overload of oxidative stress is a route to explore the discovery of new antimalarial drugs. There are three main possibilities to target the redox metabolism of P. falciparum at the erythrocytic stage: selective targeting and inhibition of a redox P. falciparum protein or enzyme; oxidant drugs targeting essential parasite components and heme by-products; and redox cycler drugs targeting the parasitized red blood cell. Oxidants and redox cycler agents, with or without specific targets, may disrupt the fragile parasitized erythrocyte redox-dependent architecture given that: redox equilibrium plays a vital role at the erythrocytic stage; P. falciparum possesses major NADPH-dependent redox systems, such as glutathione and thioredoxin ones; and the protein-NADPH-dependent phosphorylation-dephosphorylation process is involved in building new permeation pathways and channels for the nutrient-waste import-export traffic of the parasite.
    Future medicinal chemistry 10/2013; 5(16):1993-2006. · 3.31 Impact Factor
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    ABSTRACT: Copper-amyloid-β ROS production: Copper ions (red sphere, see picture) have been found to accumulate in amyloid-β plaques and play a role in the generation of reactive oxygen species (ROS) within this context. Mass spectrometry studies were able to detail the sites of oxidation damage and shed new light on the mechanism of ROS production, important for the understanding of the pathogenicity of amyloid-β peptides.
    Angewandte Chemie International Edition 09/2013; · 11.34 Impact Factor
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    ABSTRACT: ETHNOPHARMACOLOGICAL RELEVANCE: Crinum latifolium L. (CL) leaf extracts have been traditionally used in Vietnam and are now used all over the world for the treatment of prostate cancer. However, the precise cellular mechanisms of the action of CL extracts remain unclear. AIM OF THE STUDY: To examine the effects of CL samples on the anti-tumour activity of peritoneal murine macrophages. MATERIALS AND METHODS: The properties of three extracts (aqueous, flavonoid, alkaloid), one fraction (alkaloid), and one pure compound (6-hydroxycrinamidine) obtained from CL, were studied i) for redox capacities (DPPH and bleaching beta-carotene assays), ii) on murine peritoneal macrophages (MTT assay) and on lymphoma EL4-luc2 cells (luciferine assay) for cytotoxicity, iii) on macrophage polarization (production of ROS and gene expression by PCR), and iv) on the tumoricidal functions of murine peritoneal macrophages (lymphoma cytotoxicity by co-culture with syngeneic macrophages). RESULTS: The total flavonoid extract with a high antioxidant activity (IC50=107.36mg/L, DPPH assay) showed an inhibitory action on cancer cells. Alkaloid extracts inhibited the proliferation of lymphoma cells either by directly acting on tumour cells or by activating of the tumoricidal functions of syngeneic macrophages. The aqueous extract induced mRNA expression of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin 6 (IL-6) indicating differentiation of macrophages into pro-inflammatory M1 polarized macrophages. The total flavonoid, alkaloid extracts and an alkaloid fraction induced the expression of the formyl peptide receptor (FPR) on the surface of the polarized macrophages that could lead to the activation of macrophages towards the M1 phenotype. Aqueous and flavonoid extracts enhanced NADPH quinine oxido-reductase 1 (NQO1) mRNA expression in polarized macrophages which could play an important role in cancer chemoprevention. All the samples studied were non-toxic to normal living cells and the pure alkaloid tested, 6-hydroxycrinamidine, was not active in any of the models investigated. CONCLUSIONS: Our results indicate that CL extracts and alkaloid fraction (but not pure 6-hydroxycrinamidine) inhibit the proliferation of lymphoma cells in multiple pathways. Our results are in accordance with traditional usage and encourage further studies and in vivo assays.
    Journal of ethnopharmacology 06/2013; · 2.32 Impact Factor
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    ABSTRACT: Circulating blood monocytes belong to the first line of defense against pathogens and inflammation. Monocytes can be divided into three populations defined by the expression of the cell surface molecules, CD 14 and CD 16. The CD 14(++) CD 16(-) cells, called "classical" monocytes, represent 85% to 95% of the total monocytes in a healthy person whereas CD 14(-) CD 16(+), called "proinflammatory" monocytes, are found in greater numbers in the blood of patients with acute inflammation and infectious diseases. This increase in the concentration of proinflammatory monocytes can be a good indicator of an infectious state. This study presents an immunosensor based on impedance detection for specific cell trapping of classical and proinflammatory monocytes. The grafting of specific antibodies (CD 14 or CD 16) was based on the use of mixed SAM associated with protein G. Each step of the functionalization was characterized by electrochemical methods, quartz crystal microbalance and atomic force microscopy. Faradaic electrochemical impedance spectroscopy and voltametric analysis confirmed the success of the modification process with a surface coverage reaching 92% for the antibody layer. The increase in the deposited mass at each step of the modification process confirmed this results revealing that one protein G in two was bound to an antibody. The cell trapping capacity, evaluated by the variation in the film resistance using non-faradaic impedance spectroscopy revealed that the cell trapping is selective, depending on the specific antibody grafted and quantitative with the range of detection being 1000 to 30,000 infected cells. This range of detection is consistent with the application targeted.
    Biosensors & bioelectronics 05/2013; 49C:305-311. · 5.43 Impact Factor
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    ABSTRACT: Indolone-N-oxides (INODs) are bioreducible and possess remarkable anti-malarial activities in the low nanomolar range in vitro against different Plasmodium falciparum (P. falciparum) strains and in vivo. INODs have an original mechanism of action: they damage the host cell membrane without affecting non-parasitized erythrocytes. These molecules produce a redox signal which activates SYK tyrosine kinases and induces a hyperphosphorylation of AE1 (band 3, erythrocyte membrane protein). The present work aimed to understand the early stages of the biochemical interactions of these compounds with some erythrocyte components from which the redox signal could originate. The interactions were studied in a biomimetic model and compared with those of chloroquine and artemisinin. The results showed that INODs i) do not enter the coordination sphere of the metal in the heme iron complex as does chloroquine; ii) do not generate iron-dependent radicals as does artemisinin; iii) generate stable free radical adducts after reduction at one electron; iv) cannot trap free radicals after reduction. These results confirm that the bioactivity of INODs does not lie in their spin-trapping properties but rather in their pro-oxidant character. This property may be the initiator of the redox signal which activates SYK tyrosine kinases.
    Journal of inorganic biochemistry 04/2013; 126C:7-16. · 3.25 Impact Factor
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    ABSTRACT: A series of bis-indolone-N-oxides, 1a-f, was prepared from bis(ethynyl)benzenes and o-halonitroaryls and studied for their in vitro antiplasmodial activities against Plasmodium falciparum and representative strains of bacteria and candida as well as for their cytotoxicity against a human tumor cell line (MCF7). They did not cause any haemolysis (300μgmL(-1)). Of the synthesized bis-indolones, compound 1a had the most potent antiplasmodial activity (IC50=0.763μmolL(-1) on the FcB1 strain) with a selectivity index (CC50 MCF7/IC50 FcB1) of 35.6. No potency against the tested microbial strains was observed.
    Bioorganic Chemistry 04/2013; 48C:16-21. · 1.73 Impact Factor
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    ABSTRACT: Indolone-N-oxide derivatives possess interesting biological properties. The analysis of these compounds using mass spectrometry (MS) may lead to interference or under-estimation due to the tendency of the N-oxides to lose oxygen. All the previous works focused only on the temperature of the heated parts (vaporizer and ion-transfer tube) of the mass spectrometer without investigating other parameters. This work is extended to the investigation of other parameters. The behavior of N-oxides during atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI) has been investigated using MS(n) ion trap mass spectrometry. Different parameters were investigated to clarify the factors implicated in the deoxygenation process. The investigated parameters were vaporizer temperature (APCI), ion-transfer tube temperature, solvent type, and the flow rates of the sheath gas, auxiliary gas, sweep gas and mobile phase. The deoxygenation increased when the vaporizer temperature increased. The extent of the 'thermally' induced deoxygenation was inversely proportional to the ion-transfer tube temperature and auxiliary gas flow rate and in direct proportion to the mobile phase flow rate. Deoxygenation was not detected under MS/MS fragmentation and hence it is a non-collision-induced dissociation. N-Oxides have the tendency to form abundant 'non-classical' dimers under ESI, which fragment via dehydration rather than giving their corresponding monomer. Deoxygenation is not solely a 'classical' thermal process but it is a thermal process that is solvent-mediated in the source. Deoxygenation was maximal with an APCI source while dimerization was predominant with an ESI source. Therefore, attention should be paid to these molecular changes in the mass spectrometer as well as to the choice of the ionization mode for N-oxides. Copyright © 2013 John Wiley & Sons, Ltd.
    Rapid Communications in Mass Spectrometry 03/2013; 27(5):621-8. · 2.51 Impact Factor
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    ABSTRACT: New series of 10-anilino-9-alkyl-12-aryl-10,12-dihydro-11H-benzo[5,6] chromeno [2,3-d]pyrimidin-11-ones 5(a-e) and 9-anilino-10-alkyl-7-aryl-7,9-dihydro-8H-benzo[7,8]chromeno[2,3-d]pyrimidin-8-ones 6(a-f) were prepared in three steps with microwave irradiation. The procedure is easy, avoiding time-consuming syntheses are note costly.
    Arabian Journal of Chemistry 01/2013; · 2.27 Impact Factor
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    ABSTRACT: Bei der Alzheimer‐Krankheit kann das am Amyloid‐beta‐Peptid gebundene, redoxaktive Kupfer reaktive Sauerstoffspezies über einen wenig bevölkerten redoxkompetenten Zustand produzieren. In ihrer Zuschrift auf S. 11316 ff. geben P. Faller, F. Collin et al. einen Einblick in die Koordinationssphäre dieses Zustands. Kupfer ist durch das N‐terminale Aspartat und die Histidindyade gebunden, während das dritte Histidin als “Gatekeeper” fungiert.
    Angewandte Chemie 01/2013; 125(42).
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    ABSTRACT: In Alzheimer's disease, the redox‐active copper center bound to the amyloid‐beta peptide is able to produce reactive oxygen species by way of a low‐populated redox‐competent state. Insights into the coordination sphere of this state are reported by P. Faller, F. Collin, and co‐workers in their Communication on page 11110 ff. The copper atom is bound by the N‐terminal aspartate and the histidine dyad, while the third histidine acts as a gate keeper.
    Angewandte Chemie International Edition 01/2013; 52(42). · 11.34 Impact Factor
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    ABSTRACT: An alarming increase in microbial resistance to traditional drugs and classical pharmacophores has spurred the search for new antimicrobial compounds. Indolone-N-oxides (INODs) possess a redox pharmacophore with promising, recently established, antimalarial activities. In this study, the anti-infectious properties of a series of INODs were investigated. The antibacterial activity was evaluated against five bacterial strains Gram-positive (Staphylococcus aureus, Enterococcus hirae), Gram-negative (Pseudomonas aeruginosa, Escherichia coli) and acid-fast (Mycobacterium tuberculosis). The antifungal activity was assessed using two fungal strains (Aspergillus niger, Candida albicans). The antileishmanial activity was tested against two leishmanial strains, axenically-cultured amastigote (Leishmania infantum, Leishmania amazonensis). The pharmacological activities are discussed as a function of structural and lipophilic characteristics. The Gram-positive bacterial strain E. hirae was found to be the most sensitive strain, whereas the Gram-negative E. coli was resistant to this family of compounds. One compound (64) was more potent than nalidixic acid against E. hirae, whereas another one (52) was equipotent as clotrimazole against C. albicans. INODs were microbe -cidal rather than -static. INODs showed good antitubercular activity in the low micromolar range (similar to ciprofloxacin). In addition, INOD-antiprotozoal potencies were confirmed against the leishmania parasite. INODs showed a broad spectrum of antimicrobial activity and offer a promising anti-infectious prototype worthy of being developed.The Journal of Antibiotics advance online publication, 25 July 2012; doi:10.1038/ja.2012.60.
    The Journal of Antibiotics 07/2012; · 2.19 Impact Factor
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    ABSTRACT: Indolone-N-oxides exert high parasiticidal activity at the nanomolar level in vitro against Plasmodium falciparum, the parasite responsible for malaria. The bioreductive character of these molecules was investigated using cyclic voltammetry and EPR spectroelectrochemistry to examine the relationship between electrochemical behavior and antimalarial activity and to understand their mechanisms of action. For all the compounds (37 compounds) studied, the voltammograms recorded in acetonitrile showed a well-defined and reversible redox couple followed by a second complicated electron transfer. The first reduction (-0.88V<E(1/2)<-0.50V vs. SCE) was attributed to the reduction of the N-oxide function to form a radical nitroxide anion. The second reduction (-1.65V<E(1/2)<-1.14V vs. SCE) was assigned to the reduction of the ketone function. By coupling electrochemistry with EPR spectroscopy, the EPR spectra confirmed the formation of the nitroxide anion radical. Moreover, the experiments demonstrated that a slow protonation occurs at the carbon of the nitrone function and not at the NO function. A relationship between electrochemical behavior and indolone-N-oxide structure can be established for compounds with R(1)=-OCH(3), R(2)=H, and electron-withdrawing substituents on the phenyl group at R(3). The results help in the design of new molecules with more potent in vivo antimalarial activity.
    Bioelectrochemistry (Amsterdam, Netherlands) 04/2012; 88:57-64. · 2.65 Impact Factor
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    ABSTRACT: Although indolone-N-oxide (INODs) genereting long-lived radicals possess antiplasmodial activity in the low-nanomolar range, little is known about their mechanism of action. To explore the molecular basis of INOD activity, we screened for changes in INOD-treated malaria-infected erythrocytes (Pf-RBCs) using a proteomics approach. At early parasite maturation stages, treatment with INODs at their IC(50) concentrations induced a marked tyrosine phosphorylation of the erythrocyte membrane protein band 3, whereas no effect was observed in control RBCs. After INOD treatment of Pf-RBCs we also observed: (i) accelerated formation of membrane aggregates containing hyperphosphorylated band 3, Syk kinase, and denatured hemoglobin; (ii) dose-dependent release of microvesicles containing the membrane aggregates; (iii) reduction in band 3 phosphorylation, Pf-RBC vesiculation, and antimalarial effect of INODs upon addition of Syk kinase inhibitors; and (iv) correlation between the IC(50) and the INOD concentrations required to induce band 3 phosphorylation and vesiculation. Together with previous data demonstrating that tyrosine phosphorylation of oxidized band 3 promotes its dissociation from the cytoskeleton, these results suggest that INODs cause a profound destabilization of the Pf-RBC membrane through a mechanism apparently triggered by the activation of a redox signaling pathway rather than direct oxidative damage.
    Free Radical Biology & Medicine 11/2011; 52(2):527-36. · 5.27 Impact Factor
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    ABSTRACT: Indolone-N-oxides, long known for their biological activities, possess remarkable anti-infectious properties. With the aim of improving the pharmacological and antimalarial properties of indolone-N-oxide derivatives (INODs), 6-(4-chlorophenyl)-7H-[1,3]dioxolo[4,5-f]indol-7-one-5-oxide, compound 1, was selected to study its penetration and biotransformation in red blood cells (RBC) in vitro. Compound 1 accumulated inside RBCs and was rapidly bio-transformed giving a major fluorescent metabolite, the dihydroanalogue, 1-HH, identified after extraction, through LC-MS and NMR analyses. This bioreductive transformation was (i) observed with other INOD derivatives (i: 1–7); (ii) observed in normal, β-thalassemic and Plasmodium falciparum infected RBCs; (iii) temperature and thiol-dependent; (iv) not observed with heat-denatured RBCs, suggesting an enzyme-dependent biotransformation. The dihydro form, 1-HH, has antiplasmodial activity but lower than the parent compound. Since the RBCs represent 99% of the total cellular space of blood in humans, this leads to extensive metabolism of indolone-N-oxide type compounds. Given the redox events occurring in Plasmodium infected RBCs, this bioreductive transformation may be pivotal for parasite redox balance and antiplasmodial activity. However, it may be a drawback when other pharmacological properties of INODs are investigated. These results show the importance of RBCs as an in vitro model to study the biotransformation of drugs, especially antimalarialdrugs in the early discovery stages.
    Medicinal Chemistry Communication 08/2011; 2(9):860-869. · 2.72 Impact Factor

Publication Stats

533 Citations
232.83 Total Impact Points


  • 2010–2014
    • University of Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1992–2014
    • Paul Sabatier University - Toulouse III
      • Faculté des sciences pharmaceutiques
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2013
    • Ho Chi Minh City Medicine and Pharmacy University
      Thành phố Hồ Chí Minh, Ho Chi Minh City, Vietnam
    • Aix-Marseille Université
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 2009
    • INSA
      Альтамира, Tamaulipas, Mexico
  • 2006
    • University of Strasbourg
      Strasburg, Alsace, France
  • 2003
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1994
    • Max Planck Institute for Solid State Research
      Stuttgart, Baden-Württemberg, Germany