Isabelle Artaud

Université René Descartes - Paris 5, Lutetia Parisorum, Île-de-France, France

Are you Isabelle Artaud?

Claim your profile

Publications (67)279.7 Total impact

  • Isabelle Artaud, Erwan Galardon
    [Show abstract] [Hide abstract]
    ABSTRACT: The proposal of the post-translational modification “S-sulfhydration” as a major pathway for H2S-induced signaling has recently shed light on persulfides. However, the study of these species is hampered by their instability under biologically relevant conditions; this requires generating them in situ immediately prior to use. The current methods to prepare persulfides in aqueous solution suffer from several drawbacks. In particular, their formation requires (or generates) hydrogen sulfide, thus resulting in difficulties in distinguishing polysulfide reactivity from that of H2S. Here we report the H2S-free formation, characterization, and some biologically relevant reactions of a water-soluble persulfide analogue of the nitrosothiol SNAP, a widely used nitric oxide donor.
    ChemBioChem 09/2014; 15(16). DOI:10.1002/cbic.201402312 · 3.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Many new designed molecules that target efficiently in vitro bacterial metalloproteases were completely inactive in cellulo against Gram negative bacteria. Their activities were limited by the severe restriction of the penetration/diffusion rate through the outer membrane barrier. To bypass this limitation, we have assayed the strategy of metallodrugs, to improve the delivery of hydroxamic acid inhibitors to peptide deformylase. In this metal-chaperone, to facilitate bacterial uptake, the ancillary ligand tris(2-pyridylmethyl)amine (TPA) or di-(picolyl)amine (DPA) was functionalized by a tetrapeptide analogue of antimicrobial peptide, RWRW(OBn) (AA08 with TPA) and/or an efflux pump modulator PAβN (AA09 with TPA and AA27 with DPA). We prepared Co(III), Zn(II) and Cu(II) metallodrugs. Using a fluorescent hydroxamic acid, we showed that, in contrast to Cu(II) metallodrugs, Co(III) metallodrugs were stable in the Mueller Hinton (MH) broth during the time required for bacterial assays. The antibacterial activities were determined against E. coli strain wild type (AG100) and E. coli strain deleted from acrAB efflux pump (AG100A). While none of the PDFinhs used in this study (SMP289 with an indole scaffold, AT015 and AT019 built on a 1,2,4-oxadiazole scaffold) displayed activities higher than 128 μM, all the metallodrugs were active with MICs around 8 μM both against AG100 and AG100A. However, compared to the activities of equimolar combinations of PDFinhs and the free chelating peptides (AA08, AA09 or AA27), they showed similar activities. A synergistic association between AT019 and AA08 or AA09 was determined using the fractional inhibitory concentration with AG100 and AG100A. Combinations of peptides lack-ing the chelating group with PDFinhs were inefficient. LC-MS analyses showed that the chelating peptides bind Zn(II) cation when incubated in MH broth. These results support the in situ formation of a zinc metallodrug, but we failed to detect it by LC-MS in MH. Nevertheless, this chelating peptides metallated with zinc act as permeabilizers which are more efficient than PAβN to facilitate the uptake of PDFinhs by Gram(-) bacteria.
    Bioconjugate Chemistry 09/2014; 25(10). DOI:10.1021/bc500317u · 4.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The formation of 8-SH-cGMP from the reaction between hydrogen sulfide and 8-nitro-guanosine-3',5'-cyclic monophosphate in the presence of thiols does not take place by nucleophilic attack of the hydrosulfide anion, as previously proposed, but first involves the formation of reactive species containing sulfane sulfur, like persulfides.
    Organic & Biomolecular Chemistry 06/2014; 12(29). DOI:10.1039/c4ob00868e · 3.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Generous donors: The dithioperoxyanhydrides (CH3 COS)2 , (PhCOS)2 , CH3 COSSCO2 Me and PhCOSSCO2 Me act as thiol-activated hydrogen sulfide donors in aqueous buffer solution. The most efficient donor (CH3 COS)2 can induce a biological response in cells, and advantageously replace hydrogen sulfide in ex vivo vascular studies.
    ChemBioChem 11/2013; 14(17). DOI:10.1002/cbic.201300552 · 3.06 Impact Factor
  • Dominique Padovani, Isabelle Artaud
    [Show abstract] [Hide abstract]
    ABSTRACT: Sulfur metabolism furnishes cells with important metabolic compounds, among which glutathione (GSH), cysteine (Cys) and hydrogen sulfide (H2S) [1,2]. GSH is important in protecting cells against oxidative injuries and its intracellular redox couple varies within cells depending on their biological status. Cys is a precursor of several important macromolecules and participates in redox-based signaling via post-translational modifications (PTMs). H2S is a small "gaseous" molecule, which exerts important signaling functions in the vascular and neuronal systems and might signal through S-sulfhydration and HSNO formation [3]. As a result of their crucial role in cellular physiology and the reactivity of their SH group, sulfur metabolism is tightly controlled in response to environmental changes and defects affecting sulfur metabolic compounds and redox-based signaling are often associated with severe pathologies [e.g. [4-7]]. In here we pursue the efforts in understanding the biology of sulfur compounds at the interface of chemistry and biology. We thus seek to explore in vitro the various effects elicited by RSH/H2S under normal versus pathological conditions. To "mimic" pathological conditions, we employed trace elements whose acute toxicity is well-known and are often used as tumor biomarkers, e.g. iron or copper. As model we chose a heme-containing constituent of the innate immune system, catalase (Cat) that has been reported to be inactivated due to sulfur compounds homeostasis deregulation, e.g. in animals bearing tumors due to aberrancy in cystine metabolism or in animal models of chronic hyperhomocysteinemia [8-11]. Our results indicate for the first time the peculiar formation of sulfcatalase in the presence of RSH alone. Furthermore, the observed IC50 greatly decreased in the presence of trace elements and felt within the physiological thiol concentrations, elucidating the aforementioned inactivation of Cat due to sulfur compounds homeostasis deregulation. In contrast, in the presence of H2S, we observed a new PTM of Cat. This latter is responsible for Cat activation in the presence of trace elements and physiological H2S concentrations.
    Nitric Oxide 09/2013; 31 Suppl 2:S52. DOI:10.1016/j.niox.2013.06.101 · 3.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The crucial role played by hydrogen sulfide in biology [1] has called for the development of new molecular tools to assist the biologists in their studies, like the numerous probes to detect hydrogen sulfide in cells synthesized in the last two years [2] During this time, hydrogen sulfide donors have emerged to replace the widely used salts NaHS or Na2S, which are instantaneous H2S donors, that consequently do not reproduce the steady biosynthesis [3]. Here, we will present our "chemist's" approach towards such donors, with two strategies based either on inorganic or on organic molecules. The iron complex 2 from scheme A [4], the first Fe (II)-SH complex in which the hydrogen (sulfido) ligand is stabilized by H-bond, slowly liberates H2S in organic solutions through an original equilibrium involving a protonation/deprotonation process on the ligand. On another hand, the organic donors from Scheme B [5] are activated by thiols and able to release H2S in simple buffer as well as in more complex systems like cells or tissues. In particular, the stability of the donor MeCOSSCOMe towards oxidation makes it a useful alternative to the use of sulfide salts in ex-vivo assays of the vascular function, with the lowest EC50 reported to date for the relaxation of pre-contracted rat aorta rings under the standard 95% O2/5% CO2 conditions.
    Nitric Oxide 09/2013; 31 Suppl 2:S40-1. DOI:10.1016/j.niox.2013.06.077 · 3.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: New peptide molecules with metal binding abilities proved to be active against multidrug resistant clinical isolates. One of them labeled with a dansylated lysine has been imaged inside single-multidrug resistant bacteria cells by deep ultraviolet fluorescence, showing a heterogeneous subcellular localization. The fluorescence intensity is clearly related to the accumulation of the drug inside the bacteria, being dependent both on its concentration and on the incubation time with cells.
    ACS Medicinal Chemistry Letters 06/2013; 4(6):556-9. DOI:10.1021/ml400073g · 3.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have recently reported that cationic thiosulfonato ruthenium complexes [(p-cymene)Ru(bipy)(SSO(2)Ar)](+) (bipy: 2-2'-bipyridine, Ar: phenyl or p-tolyl) react with thiolates (RS(-), R = alkyl or aryl) by cleavage of the S-SO(2) bond and formation of a new S-S bond. In this work, we report that the outcome of the reaction is different if the hydrosulfide anion (R = H) is used, the product obtained being the hydrogen(sulfido) derivative [(p-cymene)Ru(bipy)(SH)](+). The bipy ligand is crucial in this result, and its replacement by ethylenediamine leads to a different product, the trisulfido-bridged dinuclear complex [[(p-cymene)Ru(en)(S)](2)S](2+). These two new species have been fully characterized, including by X-ray diffraction studies, and the two different mechanisms leading to their formation are discussed.
    Dalton Transactions 12/2012; 42(8). DOI:10.1039/c2dt31758c · 4.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Through use of the reversible protonation of an iron(II) complex containing a deprotonated carboxamido moiety, we prepared and fully characterized the first hydrogen(sulfido)iron(II) complex stabilized by an intramolecular hydrogen bond, which acts as a H(2)S donor in solution.
    Inorganic Chemistry 09/2012; 51(19):10068-70. DOI:10.1021/ic300952d · 4.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Six Co(III) complexes based on unsubstituted or substituted TPA ligands (where TPA is tris(2-pyridylmethyl)amine) and acetohydroxamic acid (A), N-methyl-acetohydroxamic acid (B), or N-hydroxy-pyridinone (C) were prepared and characterized by mass spectrometry, elemental analysis, and electrochemistry: [Co(III)(TPA)(A-2H)](Cl) (1a), [Co(III)((4-Cl(2))TPA)(A-2H)](Cl) (2a), [Co(III)((6-Piva)TPA)(A-2H)](Cl) (3a), [Co(III)((4-Piva)TPA)(A-2H)](Cl) (4a) and [Co(III)(TPA)(B-H)](Cl)(2) (1b), and [Co(III)(TPA)(C-H)](Cl)(2) (1c). Complexes 1a-c and 3a were analyzed by (1)H NMR, using 2D ((1)H, (1)H) COSY and 2D ((1)H, (13)C) HMBC and HSQC, and shown to exist as a mixture of two geometric isomers based on whether the hydroxamic oxygen was trans to a pyridine nitrogen or to the tertiary amine nitrogen. Complex 3a exists as a single isomer that was crystallized. Its crystal structure revealed the presence of an H-bond between the pivaloylamide and the hydroximate oxygen. Complexes 1a, 2a, and 4a are irreversibly reduced beyond -900 mV versus SCE, while complexes 1b and 1c are reduced at less negative values of -330 and -190 mV, respectively. The H-bond in 3a increased the redox potential up to -720 mV. Reaction of complex 1a with L-cysteine methyl ester CysOMe was monitored by (1)H NMR and UV-vis at 2 mM and 0.2 mM in an aqueous buffered solution at pH 7.5. Complex 1a was successively converted into an intermediate [Co(III)(TPA)(CysOMe-H)](2+), 1d, by exchange of the hydroximate with the cysteinate ligand, and further into Co(III)(CysOMe-H)(3), 5. An authentic sample of 1d was prepared and thoroughly characterized. A detailed (1)H NMR analysis showed there was only one isomer, in which the thiolate was trans to the tertiary amine nitrogen.
    Inorganic Chemistry 08/2012; 51(17):9350-6. DOI:10.1021/ic301090t · 4.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: New series of acids and hydroxamic acids linked to five-membered heterocycles including furan, oxazole, 1,2,4- or 1,3,4-oxadiazole, and imidazole were synthesized and tested as inhibitors against the Fe(II) , Co(II) , and Mn(II) forms of E. coli methionine aminopeptidase (MetAP) and as antibacterial agents against wild-type and acrAB E. coli strains. 2-Aryloxazol-4-ylcarboxylic acids appeared as potent and selective inhibitors of the Co(II) MetAP form, with IC(50) values in the micromolar range, whereas 5-aryloxazol-2-ylcarboxylic acid regioisomers and 5-aryl-1,2,4-oxadiazol-3-ylcarboxylic acids were shown to be inefficient against all forms of EcMetAP. Regardless of the heterocycle, all the hydroxamic acids are highly potent inhibitors and are selective for the Mn(II) and Fe(II) forms, with IC(50) values between 1 and 2 μM. One indole hydroxamic acid that we previously reported as a potent inhibitor of E. coli peptide deformylase also demonstrated efficiency against EcMetAP. To gain insight into the positioning of the oxazole heterocycle with reversed substitutions at positions 2 and 5, X-ray crystal structures of EcMetAP-Mn complexed with two such oxazole hydroxamic acids were solved. Irrespective of the [metal]/[apo-MetAP] ratio, the active site consistently contains a dinuclear manganese center, with the hydroxamate as bridging ligand. Asp 97, which adopts a bidentate binding mode to the Mn2 site in the holoenzyme, is twisted in both structures toward the hydroxamate bridging ligand to favor the formation of a strong hydrogen bond. Most of the compounds show weak antibacterial activity against a wild-type E. coli strain. However, increased antibacterial activity was observed mainly for compounds with a 2-substituted phenyl group in the presence of the nonapeptide polymyxin B and phenylalanine-arginine-β-naphthylamide as permeabilizer and efflux pump blocker, respectively, which boost the intracellular uptake of the inhibitors.
    ChemMedChem 04/2012; 7(6):1020-30. DOI:10.1002/cmdc.201200076 · 3.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bacterial drug resistance is a worrying public health problem and there is an urgent need for research and development to provide new antibacterial molecules. Peptide deformylase (PDF) is now a well-described intracellular target selected for the design of a new antibiotic group, PDF inhibitors (PDFIs). The initial bacterial susceptibility to an inhibitor of a cytoplasmic target is directly associated with the diffusion of the compound through the membrane barrier of Gram-negative bacteria and with its cytosolic accumulation at the required concentration. We have recently demonstrated that the activity of different PDFIs is strongly dependent on the accumulation of the active molecules by using permeabilizing agents, efflux inhibitors or efflux-mutated strains. In this work we assessed various combination protocols using different putative inhibitors (PDFIs, methionine aminopeptidase inhibitors etc.) to improve antibacterial activity against various resistant Gram-negative bacteria. The maximum effect was observed when combining actinonin with a dual inhibitor of methionine aminopeptidase and PDF, this molecule being also able to interact with the target while actinonin is bound to the PDF active site. Such a combination of inhibitors acting on two tightly associated metabolic steps results in a cooperative effect on bacterial cells and opens an original way to combat multidrug-resistant bacteria.
    Journal of Antimicrobial Chemotherapy 02/2012; 67(6):1392-400. DOI:10.1093/jac/dks058 · 5.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The cover picture shows an oxazole derivative in complex with Escherichia coli methionine aminopeptidase (MetAP) in its MnII form. The enzyme is consistently dinuclear even when crystallized with a substoichiometric ratio of MnII/apo‐protein. The derivative shown is part of a new series of hydroxamic acids linked to five‐membered heterocycles, such as oxazole and oxadiazole or imidazole, that are potent and specific inhibitors of both the MnII and FeII forms of E. coli MetAP. For more details, see the Full Paper by Isabelle Artaud et al. on p. 1020 ff.
    ChemMedChem 01/2012; 7(6). DOI:10.1002/cmdc.201290024 · 3.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepcidin, a 25 amino acid peptide hormone containing a complex network of four disulfide bonds is the hormone regulator of iron homeostasis. Three bridges synthetic peptide analogs have been prepared following two synthetic strategies and two oxidation procedures: i) a microwave-assisted solid phase synthesis followed by air oxidation of the six free cysteines ii) a manual solid phase synthesis followed by stepwise deprotection and oxidation of cysteine pairs. All the peptides with different connectivities have been characterized by MALDI ToF spectrometry, and tested for their ability to degrade the cellular iron exporter, ferroportin. While linear peptides are inactive, the one-bridge and two-bridge peptides retaining protected cysteines by bulky substituents are active. Similarly, the three-bridge peptides are active irrespective of their disulfide connectivities.
    Protein and Peptide Letters 08/2011; 19(2):219-27. DOI:10.2174/092986612799080167 · 1.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Reaction of the complex [(TPA)Zn(H2O)]2+ [TPA = tris(2-pyridylmethyl)amine] with hydrogen sulfide in aqueous buffered solution gives the corresponding monomeric hydrogensulfido complex [(TPA)Zn(SH)]+, which was fully characterized, including by XRD. This complex is stable at neutral pH, but decomposes under basic conditions to yield the free ligand and zinc sulfide, and under acidic conditions to give hydrogen sulfide and the starting aqua complex. In organic solvents, the coordinated sulfur atom reacts with electrophiles such as methylmethanethiosulfonate to yield methyltrisulfide. Reaction with the hydroxo complex [(TpPh,Me)Zn(OH)] [TpPh,Me = hydridotris{(5-methyl-3-phenyl)pyrazolyl}borate] promotes the formation of the unsymmetrical dinuclear μ-sulfido species [(TPA)Zn–S–Zn(TpPh,Me)]+, which, upon treatment with one molar equivalent of trifluoroacetic acid, dissociates into [(TpPh,Me)Zn(SH)] and [(TPA)Zn(CF3CO2)]+, resulting in the transfer of the hydrogensulfido ligand from one zinc center to another.
    Berichte der deutschen chemischen Gesellschaft 08/2011; 2011(25). DOI:10.1002/ejic.201100527 · 2.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: For several decades, molecular recognition has been considered one of the most fundamental processes in biochemistry. For enzymes, substrate binding is often coupled to conformational changes that alter the local environment of the active site to align the reactive groups for efficient catalysis and to reach the transition state. Adaptive substrate recognition is a well-known concept; however, it has been poorly characterized at a structural level because of its dynamic nature. Here, we provide a detailed mechanism for an induced-fit process at atomic resolution. We take advantage of a slow, tight binding inhibitor-enzyme system, actinonin-peptide deformylase. Crystal structures of the initial open state and final closed state were solved, as well as those of several intermediate mimics captured during the process. Ligand-induced reshaping of a hydrophobic pocket drives closure of the active site, which is finally "zipped up" by additional binding interactions. Together with biochemical analyses, these data allow a coherent reconstruction of the sequence of events leading from the encounter complex to the key-lock binding state of the enzyme. A "movie" that reconstructs this entire process can be further extrapolated to catalysis.
    PLoS Biology 05/2011; 9(5):e1001066. DOI:10.1371/journal.pbio.1001066 · 11.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepcidin, a 25-amino-acid peptide secreted by the liver, distributed in the plasma and excreted in urine, is a key central regulator of body iron homeostasis. This hormone decreases export of cellular iron by binding to ferroportin, an iron exporter present at the basolateral surface of enterocytes and macrophages (the sites of dietary iron absorption and iron recycling, respectively), inducing its internalization and degradation. Hepcidin contains eight cysteine residues that form four disulfide bridges, which stabilize a hairpin-shaped structure with two beta sheets. We noticed in the sequence of hepcidin a Cys*-X-Cys* motif which can act as a metal binding site able to trap iron and/or copper. We have tested this hypothesis using a pseudopeptidic synthetic bis-disulfide analogue and we have shown that direct metalation of such ligand leads to the formation of a copper(III) complex with the typical N(2)S(2) donor set. This compound crystallizes in the orthorhombic system, space group Imma. The Cu(III) configuration is square planar, built up from two carboximado-N and two thiolato-S donors. This complex is converted back to the bis-disulfide, with release of the copper salt, upon oxidation with iodine.
    Annales Pharmaceutiques Françaises 11/2010; 68(6):388-96. DOI:10.1016/j.pharma.2010.08.002
  • [Show abstract] [Hide abstract]
    ABSTRACT: The reaction of the thiosulfonato complexes [(p-cym)Ru(bipy)(S-SO(2)R)](+) (R = Ph, p-Tol) with the thiolates R'S(-) (R' = alkyl or aryl) leads to S-S bond cleavage and to the quantitative formation of the corresponding disulfanido derivatives [(p-cym)Ru(bipy)(S-SR')](+). The aryldisulfanido complexes also react with benzyl thiolate by S-S bond cleavage to give [(p-cym)Ru(bipy)(SSCH(2)Ph)](+).
    Inorganic Chemistry 10/2010; 49(20):9119-21. DOI:10.1021/ic101795s · 4.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cyclic and acyclic pseudopeptidic bis-disulfides built on an o-phenylene diamine scaffold were prepared: (N(2)H(2)S(2))(2), 1a, N(2)H(2)(S-SCH(3))(2), 1b, and N(2)H(2)(S-StBu)(2), 1c. Reductive metalation of these disulfides with (PF(6))[Cu(CH(3)CN)(4)] in the presence of Et(4)NOH as a base, or with (Et(4)N)[Fe(SEt)(4)] and Et(4)NCl, yields the corresponding diamidato/dithiolato copper(III) or iron(III) complex, (Et(4)N)[Cu(N(2)S(2))], 2, or (Et(4)N)(2)[Fe(N(2)S(2))Cl], 5. These complexes display characteristics similar to those previously described in the literature. The mechanism of the metalation with copper has been investigated by X-band electron paramagnetic resonance (EPR) spectroscopy at 10 K. After metalation of the bis-disulfide 1c and deprotonation of the amide nitrogens, the reductive cleavage of the S-S bonds occurs by two one-electron transfers leading to the intermediate formation of a copper(II) complex and a thyil radical. Complexes 2 and 5 can be converted back to the cyclic bis-disulfide 1a with iodine in an 80% yield. Reaction of 5 with iodine in the presence of CH(3)S-SCH(3) affords a 1/1 mixture of the acyclic N(2)H(2)(S-SCH(3))(2) disulfide 1b and cyclic bis-disulfide 1a. From 2, the reaction was monitored by (1)H NMR and gives 1b as major product. While there is no reaction of 2 or 5 with tBuS-StBu and iodine, reaction with an excess of tBuSI affords quantitatively the di-tert-butyl disulfide 1c. To assess the role of the Cu(III) oxidation state, control experiments were carried out under strictly anaerobic conditions with the copper(II) complex, (Et(4)N)(2)[Cu(N(2)S(2))], 6. Complex 6 is oxidized to 2 by iodine, and it reacts with an excess of tBuSI, yielding 1c as final product, through the intermediate formation of complex 2.
    Inorganic Chemistry 09/2010; 49(18):8637-44. DOI:10.1021/ic101148c · 4.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Electron-rich methoxyarenes were oxidized with high yields (55–100%) and under mild conditions to the corresponding paraquinones by magnesium monoperoxyphthalate in the presence of catalytic amounts of a water-soluble iron porphyrin; the reaction was used to prepare methoxatin.
    ChemInform 05/2010; 22(21):103-103. DOI:10.1002/chin.199121103

Publication Stats

626 Citations
279.70 Total Impact Points


  • 1991–2014
    • Université René Descartes - Paris 5
      • • Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (Lcbpt) (UMR 8601)
      • • UMR 8601 Chimie et Biochimie Pharmacologiques et Toxicologiques
      Lutetia Parisorum, Île-de-France, France
  • 2001–2011
    • French National Centre for Scientific Research
      • • Institute of Plant Science
      • • Laboratoire de Cristallographie et de RMN Biologiques
      Lutetia Parisorum, Île-de-France, France
  • 2004
    • Brookhaven National Laboratory
      New York, New York, United States