Christian Périgaud

Université Montpellier 2 Sciences et Techniques, Montpelhièr, Languedoc-Roussillon, France

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Publications (165)320.58 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Choline analogues such as bis-thiazolium salts are thought to inhibit choline transport into Plasmodium-infected erythrocytes, thus preventing parasite PC biosynthesis, and also to interact with plasmodial haemoglobin degradation in the food vacuole. This new and multiple mode of action is a major asset of these new class of antimalarials, as they could help delay resistance development. We synthesized and designed various sets of analogues, notably prodrugs, since the oral bioavailability of bis-thiazolium salts is relatively low. The chemistry underlying this synthesis relies on inexpensive and readily available starting materials and is straightforward. This is essential since the ultimate objective is to obtain affordable and orally available drugs for uncomplicated malaria treatment.
    Current topics in medicinal chemistry. 08/2014;
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    ABSTRACT: Herein we report a one-pot multi-step synthesis of the cofactors CDP-Ethanolamine and CDP-Choline starting from cytidine 5′-monophosphate and using commercially available and/or easily prepared reagents. While studying the 31P NMR spectrum of CDP-Ethanolamine, an unexpected characteristic for a pyrophosphate diester was observed as it showed a singlet or two doublets depending upon the pH. Therefore, further NMR studies were undertaken to investigate the pH dependence of the peak splitting pattern and measure the acid dissociation constants of the compounds.
    Tetrahedron Letters 07/2014; 55:5306-5310. · 2.40 Impact Factor
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    ABSTRACT: A synthetic pathway to new acyclonucleoside phosphonates, designed as analogues of cidofovir, is described. The reduction of a β-ketophosphonate intermediate, readily available from the nucleobase and benzylacrylate, afforded an enantiomeric mixture of (R)- and (S)-β-hydroxyphosphonate derivatives which was resolved. The assignment of the absolute configuration was proposed on the basis of NMR studies. The influence of this modification, the presence of the hydroxyl group and chirality on the β-position related to the phosphorus atom, on antiviral activity against a broad variety of DNA and RNA viruses and also on the capacity to be recognized as substrates by human NMP kinases was investigated.
    New Journal of Chemistry 07/2014; · 2.97 Impact Factor
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    ABSTRACT: The cytosolic 5'-nucleotidase II (cN-II) has been proposed as an attractive molecular target for the development of novel drugs circumventing resistance to cytotoxic nucleoside analogues currently used for treating leukemia and other malignant hemopathies. In the present work, synthesis of β-hydroxyphosphonate nucleoside analogues incorporating modifications either on the sugar residue or the nucleobase, and their in vitro evaluation towards the purified enzyme were carried out in order to determine their potency towards the inhibition of cN-II. In addition to the biochemical investigations, molecular modeling studies revealed important structural features for binding affinities towards the target enzyme.
    European journal of medicinal chemistry 02/2014; 77C:18-37. · 3.27 Impact Factor
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    ABSTRACT: AMP mimics constitute an important class of therapeutic derivatives to treat diseases where the pool of ATP is involved. A new phosphonate derivative of 9-(5-hydroxymethylfuran-2-yl)adenine was synthesized in a multi-step sequence from commercially available adenosine. Its ability to behave as a substrate of human adenylate kinases 1 and 2 was assessed. The phosphonate was shown to be a moderate but selective substrate of the mitochondrial human AK2, better than well-known antiviral acyclic phosphonates 9-(2-phosphonomethoxyethyl)adenine (PMEA, Adefovir) and (R)-9-(2-phosphonomethoxypropyl)adenine (PMPA, Tenofovir). Putative binding mode within adenylate kinase NMP site revealed by molecular docking in comparison to AMP native substrate allowed to illustrate this selective behavior.
    Bioorganic & Medicinal Chemistry Letters 01/2014; · 2.34 Impact Factor
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    ABSTRACT: Nucleoside β-(S)-hydroxyphosphonate analogues have recently proven to be interesting bioactive compounds as 5'-nucleotidase inhibitors. These derivatives were obtained in a pyrimidine series through an ex-chiral pool pathway or the stereoselective reduction of a β-ketophosphonate intermediate. Herein, an original synthesis of these compounds using nucleoside epoxide intermediates, containing either a pyrimidine or a purine as nucleobase, was explored and allowed the direct synthesis of the corresponding bis S-acyl-2-thioethyl (SATE) prodrugs.
    Organic Letters 09/2013; · 6.14 Impact Factor
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    ABSTRACT: Racemic synthesis of novel 3′-methyl-5′-norcarbocyclic nucleoside phosphonates 1a–c and 2 was performed using 4-hydroxy-2-methylcyclo-pent-2-enone as starting material. Direct coupling of the heterocyclic base involved a Mitsunobu reaction as key step. The compounds were evaluated for their antiviral properties, but none of them showed significant activity.
    ChemInform 03/2013; 69(9):2131–2136.
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    ABSTRACT: Bis-thiazolium salts are able to inhibit phosphatidylcholine biosynthesis in Plasmodium and to block parasite proliferation in the low nanomolar range. However, due to their physicochemical properties (i.e., permanent cationic charges, the flexibility, and lipophilic character of the alkyl chain), the oral bioavailability of these compounds is low. New series of bis-thiazolium-based drugs have been designed to overcome this drawback. They feature linker rigidification via the introduction of aromatic rings and/or a decrease in the overall lipophilicity through the introduction of heteroatoms. On the basis of the structure-activity relationships, a few of the promising compounds (9, 10, and 11) were found to exhibit potent antimalarial in vitro and in vivo activities (EC(50) < 10 nM and ED(50) ip < 0.7 mg/kg).
    Journal of Medicinal Chemistry 01/2013; · 5.61 Impact Factor
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    ABSTRACT: Plasmodium falciparum is the causative agent of malaria, a deadly infectious disease for which treatments are scarce and drug-resistant parasites are now increasingly found. A comprehensive method of identifying and quantifying metabolites of this intracellular parasite could expand the arsenal of tools to understand its biology, and be used to develop new treatments against the disease. Here, we present two methods based on liquid chromatography tandem mass spectrometry for reliable measurement of water-soluble metabolites involved in phospholipid biosynthesis, as well as several other metabolites that reflect the metabolic status of the parasite including amino acids, carboxylic acids, energy-related carbohydrates, and nucleotides. A total of 35 compounds was quantified. In the first method, polar compounds were retained by hydrophilic interaction chromatography (amino column) and detected in negative mode using succinic acid-(13)C(4) and fluorovaline as internal standards. In the second method, separations were carried out using reverse phase (C18) ion-pair liquid chromatography, with heptafluorobutyric acid as a volatile ion pairing reagent in positive detection mode, using d(9)-choline and 4-aminobutanol as internal standards. Standard curves were performed in P. falciparum-infected and uninfected red blood cells using standard addition method (r(2)>0.99). The intra- and inter-day accuracy and precision as well as the extraction recovery of each compound were determined. The lower limit of quantitation varied from 50pmol to 100fmol/3×10(7)cells. These methods were validated and successfully applied to determine intracellular concentrations of metabolites from uninfected host RBCs and isolated Plasmodium parasites.
    Analytica chimica acta 08/2012; 739:47-55. · 4.31 Impact Factor
  • Ahmed Khalil, Christophe Mathé, Christian Périgaud
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    ABSTRACT: New series of 2′,3′-dideoxy-2′-fluoro-3′-(hydroxyimino)-, -3′-(methoxyimino)- and -3′-(hydroxyamino)pyrimidine nucleosides were synthesized. Structural assignments of the former two derivatives, which were obtained as inseparable mixtures of (E) and (Z) isomers, were based upon 1H and 19F NMR spectroscopic analysis. In particular, we observed striking differences in 19F NMR spectra resulting from through-space N–F coupling for compounds having proximate nitrogen (oxime) and fluorine atoms with lone-pairs correctly oriented for overlapping. Antiviral and cytotoxic activities of the target nucleosides were evaluated; however, none of them showed any antiviral activity. Only 2′,3′-dideoxy-2′-fluoro-3′-(hydroxyamino)cytidine (19) showed moderate activity against the proliferation of murine leukemia cells (L1210).
    Annalen der Chemie und Pharmacie 06/2012; 2012(16). · 3.10 Impact Factor
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    ABSTRACT: We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain. Most of the novel derivatives exhibited potent in vitro antimalarial activity against P. falciparum. After oral administration, the cyclic disulfide prodrug 8 showed the best improvement of oral efficacy in comparison to the parent drug.
    Journal of Medicinal Chemistry 05/2012; 55(10):4619-28. · 5.61 Impact Factor
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    ABSTRACT: Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches.
    Current pharmaceutical design 05/2012; 18(24):3454-66. · 4.41 Impact Factor
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    ABSTRACT: A molecularly imprinted polymer (MIP) was synthesized by non-covalent imprinting polymerization using irinotecan as template. Methacrylic acid and 4-vinylpyridine were selected as functional monomers. An optimized procedure coupled to LC-PDA analysis was developed for the selective solid-phase extraction of irinotecan from various organic media. A specific capacity of 0.65 µmol•g-1 for the MIP was determined. The high specificity of this MIP was demonstrated by studying the retention behaviour of two related compounds, camptothecin and SN-38. This support was applied for the extraction of irinotecan from human serum samples.
    Journal of functional biomaterials. 01/2012; 3(1):131-142.
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    ABSTRACT: Cytosolic 5'-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5'-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of chemical compounds, namely ribonucleoside phosphonates to predict them as potential cN-II inhibitors. These compounds incorporate a chemically and enzymatically stable phosphorus-carbon linkage instead of a regular phosphoester bond. Amongst them, six compounds were predicted as better ligands than the natural substrate of cN-II, inosine 5'-monophosphate (IMP). The study of purine and pyrimidine containing analogues and the introduction of chemical modifications within the phosphonate chain has allowed us to define general rules governing the theoretical affinity of such ligands. The binding strength of these compounds was scrutinized in silico and explained by an impressive number of van der Waals contacts, highlighting the decisive role of three cN-II residues that are Phe 157, His 209 and Tyr 210. Docking predictions were confirmed by experimental measurements of the nucleotidase activity in the presence of the three best available phosphonate analogues. These compounds were shown to induce a total inhibition of the cN-II activity at 2 mM. Altogether, this study emphasizes the importance of the non-hydrolysable phosphonate bond in the design of new competitive cN-II inhibitors and the crucial hydrophobic stacking promoted by three protein residues.
    PLoS Computational Biology 12/2011; 7(12):e1002295. · 4.87 Impact Factor
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    ABSTRACT: Nucleoside phosphonates have been designed as stable 5'-mononucleotide mimics and are nowadays considered a potent class of antiviral agents. Within cells, they must be metabolised to the corresponding diphosphate to exert their biological activity. In this process, the first phosphorylation step, catalysed by nucleoside monophosphate kinases (NMP kinases), has been proposed as a bottleneck. Herein, we report the synthesis of a series of ribonucleoside phosphonate derivatives isosteric to 5'-mononucleotides, with different degrees of flexibility within the 5',6'-C-C bond, as well as different polarities, through the introduction of hydroxy groups. The influence of these modifications on the capacity of the compounds to act as substrates for appropriate human NMP kinases, involved in nucleic acids metabolism, has been investigated. Low flexibility, as well as an absence of hydroxy groups within the ribose-phosphorus architecture, is critical for efficient phosphotransfer. Among the series of pyrimidine analogues, one derivative was shown to be phosphorylated by human UMP-CMP kinase, with rates similar to those of dUMP and even better than dCMP.
    ChemMedChem 06/2011; 6(6):1094-106. · 2.84 Impact Factor
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    ABSTRACT: A concise route to nucleoside β-hydroxyphosphonate analogues is described. The use of a nucleoside β-ketophosphonate as the key intermediate allowed both the (R) and (S) isomers of β-hydroxyphosphonate analogues in the pyrimidine series to be accessed. Such derivatives may be considered as stable mimics of 5′-monophosphate nucleosides and, therefore, could be the starting point for the development of potential therapeutic agents.
    Annalen der Chemie und Pharmacie 06/2011; 2011(20‐21):3794 - 3802. · 3.10 Impact Factor
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    ABSTRACT: We report on the first solution synthesis of lamivudine 5'-diphosphate in both high yield and purity. Efficient synthesis of lamivudine 5'-monophosphate was obtained through lamivudine H-phosphonate oxydation by (-)-(8,8-dichlorocamphorylsulfonyl)oxaridine. Diphosphorylation was performed by nucleophilic substitution of the phosphorimidazolate derivative of lamivudine HPLC coupled with UV or MS detection was found to be an invaluable tool for the follow-up of phosphorylation reactions.
    Tetrahedron Letters 03/2011; · 2.40 Impact Factor
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    Céline Crauste, Christian Périgaud, Suzanne Peyrottes
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    ABSTRACT: Phosphorylation of ddC and 3TC was efficiently performed on soluble poly(ethylene glycol) support. The corresponding 5'-monophosphate derivatives were obtained by oxidation of the support bound 5'-H-phosphonate intermediates. Then, di- and triphosphorylations were carried out using a carbonyldiimidazole activation step followed by nucleophilic substitution with suitable phosphate salts. Trivalent phosphorus chemistry appeared as a good alternative for monophosphate synthesis of acid-sensitive 2',3'-dideoxynucleosides.
    The Journal of Organic Chemistry 02/2011; 76(3):997-1000. · 4.56 Impact Factor
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    ABSTRACT: A synthetic pathway to new acyclonucleoside phosphonates, as analogues of Adefovir, is described. The reduction of an acyclonucleoside β-ketophosphonate, readily available from the nucleobase and benzylacrylate, afforded a mixture of (R)- and (S)-β-hydroxyphosphonate derivatives which was resolved. The assignment of the absolute configuration was proposed on the basis of NMR studies and was supported by molecular modelling studies.
    Tetrahedron Asymmetry 01/2011; 22(14):1505-1511. · 2.12 Impact Factor
  • European Biophysics Journal 01/2011; 40:S53. · 2.27 Impact Factor

Publication Stats

652 Citations
320.58 Total Impact Points

Institutions

  • 1992–2014
    • Université Montpellier 2 Sciences et Techniques
      • Institut des Biomolécules Max Mousseron (IBMM)
      Montpelhièr, Languedoc-Roussillon, France
  • 1994–2013
    • French National Centre for Scientific Research
      • Centre d’études d’agents Pathogènes et Biotechnologies pour la Santé
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • Stockholm University
      • Department of Organic Chemistry
      Tukholma, Stockholm, Sweden
  • 2009–2010
    • Paul Sabatier University - Toulouse III
      Tolosa de Llenguadoc, Midi-Pyrénées, France
    • University Joseph Fourier - Grenoble 1
      • Institut de Chimie Moléculaire de Grenoble
      Grenoble, Rhone-Alpes, France
  • 1999–2010
    • French Institute of Health and Medical Research
      • Centre de Physiopathologie de Toulouse Purpan (CPTP) U1043
      Paris, Ile-de-France, France
    • National Research Council
      Roma, Latium, Italy
  • 1991–2009
    • Université de Montpellier 1
      Montpelhièr, Languedoc-Roussillon, France
  • 2004
    • Université de Picardie Jules Verne
      • LG - Laboratoire des glucides
      Amiens, Picardie, France
  • 1996–2001
    • University of Alabama at Birmingham
      • Department of Pharmacology and Toxicology
      Birmingham, Alabama, United States
  • 2000
    • University of Georgia
      • Department of Pharmaceutical and Biomedical Sciences
      Athens, GA, United States
  • 1998
    • University of Wuerzburg
      • Institute of Organic Chemistry
      Würzburg, Bavaria, Germany