Bioinorganic Chemistry and Redox Homeostasis
Our website :
Metals in Biology and Redox Homeostasis
A new name for our research group: METROX
CONGRATULATIONS to our former PhD students:
Jean Bouvet for his selection to the MBA « collège des ingénieurs » (jan. 2024)
Paul Demay-Drouhard, who was appointed as a CNRS researcher (section 12, ICOA Orléans) in 2023
Martha Zoumpoulaki for her selection to the MBA « collège des ingénieurs » (oct. 2021) and her recruitment at Air Liquide in 2023.
Koudedja Coulibaly, who was recruited by Air Liquide in 2021
Emilie Mathieu, who was appointed as a CNRS researcher (section 16, LCC Toulouse) in 2021
Sarah Hostachy, who was appointed as a CEAEA researcher (LCBM, Grenoble) in 2020
Our personal webpages and resumes:
Alice Balfourier (ORCID: 0000-0002-4801-1388)
Hélène Bertrand (ORCID: 0000-0002-3841-022X)
Nicolas Delsuc (ORCID: 0000-0001-5570-8311)
Clotilde Policar (ORCID: 0000-0003-0255-1650)
Christine Rampon (ORCID: 0000-0002-1444-3166)
Michel Volovitch (ORCID: 0000-0002-7488-764X)
Sophie Vriz
Some news about our work:
About our work and equity in science (in French): https://www.youtube.com/watch?v=ZfyFIkh_G4k
https://www.inc.cnrs.fr/fr/cnrsinfo/des-complexes-bio-inspires-dans-le-vent
https://www.ens.psl.eu/actualites/des-catalyseurs-bio-inspires-pour-lutter-contre-le-stress-oxydant
Publications of the group:
((Go back to the publication page of the ens-bic website))
2017 |
Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy Article de journal Nikolaos D Georgakopoulos; Michele Frison; Maria Soledad Alvarez; Hélène Bertrand; Geoff Wells; Michelangelo Campanella Scientific Reports, 7 (1), p. 10303, 2017, ISSN: 2045-2322. @article{Georgakopoulos2017, title = {Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy}, author = {Nikolaos D Georgakopoulos and Michele Frison and Maria Soledad Alvarez and H\'{e}l{\`{e}}ne Bertrand and Geoff Wells and Michelangelo Campanella}, url = {https://doi.org/10.1038/s41598-017-07679-7}, doi = {10.1038/s41598-017-07679-7}, issn = {2045-2322}, year = {2017}, date = {2017-01-01}, journal = {Scientific Reports}, volume = {7}, number = {1}, pages = {10303}, abstract = {Mitophagy orchestrates the autophagic degradation of dysfunctional mitochondria preventing their pathological accumulation and contributing to cellular homeostasis. We previously identified a novel chemical tool (hereafter referred to as PMI), which drives mitochondria into autophagy without collapsing their membrane potential ($Delta$$Psi$m). PMI is an inhibitor of the protein-protein interaction (PPI) between the transcription factor Nrf2 and its negative regulator, Keap1 and is able to up-regulate the expression of autophagy-associated proteins, including p62/SQSTM1. Here we show that PMI promotes mitochondrial respiration, leading to a superoxide-dependent activation of mitophagy. Structurally distinct Keap1-Nrf2 PPI inhibitors promote mitochondrial turnover, while covalent Keap1 modifiers, including sulforaphane (SFN) and dimethyl fumarate (DMF), are unable to induce a similar response. Additionally, we demonstrate that SFN reverses the effects of PMI in co-treated cells by reducing the accumulation of p62 in mitochondria and subsequently limiting their autophagic degradation. This study highlights the unique features of Keap1-Nrf2 PPI inhibitors as inducers of mitophagy and their potential as pharmacological agents for the treatment of pathological conditions characterized by impaired mitochondrial quality control.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Mitophagy orchestrates the autophagic degradation of dysfunctional mitochondria preventing their pathological accumulation and contributing to cellular homeostasis. We previously identified a novel chemical tool (hereafter referred to as PMI), which drives mitochondria into autophagy without collapsing their membrane potential ($Delta$$Psi$m). PMI is an inhibitor of the protein-protein interaction (PPI) between the transcription factor Nrf2 and its negative regulator, Keap1 and is able to up-regulate the expression of autophagy-associated proteins, including p62/SQSTM1. Here we show that PMI promotes mitochondrial respiration, leading to a superoxide-dependent activation of mitophagy. Structurally distinct Keap1-Nrf2 PPI inhibitors promote mitochondrial turnover, while covalent Keap1 modifiers, including sulforaphane (SFN) and dimethyl fumarate (DMF), are unable to induce a similar response. Additionally, we demonstrate that SFN reverses the effects of PMI in co-treated cells by reducing the accumulation of p62 in mitochondria and subsequently limiting their autophagic degradation. This study highlights the unique features of Keap1-Nrf2 PPI inhibitors as inducers of mitophagy and their potential as pharmacological agents for the treatment of pathological conditions characterized by impaired mitochondrial quality control. |
2016 |
Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads Article de journal Kamila K Kaminska; Helene C Bertrand; Hisashi Tajima; William C Stafford; Qing Cheng; Wan Chen; Geoffrey Wells; Elias S J Arner; Eng-Hui Chew Oncotarget, 7 (26), p. 40233–40251, 2016, ISSN: 1949-2553. @article{Kaminska2016, title = {Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads}, author = {Kamila K Kaminska and Helene C Bertrand and Hisashi Tajima and William C Stafford and Qing Cheng and Wan Chen and Geoffrey Wells and Elias S J Arner and Eng-Hui Chew}, url = {https://www.ncbi.nlm.nih.gov/pubmed/27244886 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130005/}, doi = {10.18632/oncotarget.9579}, issn = {1949-2553}, year = {2016}, date = {2016-05-01}, journal = {Oncotarget}, volume = {7}, number = {26}, pages = {40233--40251}, publisher = {Impact Journals LLC}, abstract = {Several compounds bearing the indolinone chemical scaffold are known to possess anticancer properties. For example, the tyrosine kinase inhibitor sunitinib is an arylideneindolin-2-one compound. The chemical versatility associated with structural modifications of indolinone compounds underlies the potential to discover additional derivatives possessing anticancer properties. Previously synthesized 3-(2-oxoethylidene)indolin-2-one compounds, also known as supercinnamaldehyde (SCA) compounds in reference to the parent compound 1 [1-methyl-3(2-oxopropylidene)indolin-2-one], bear a nitrogen-linked $alpha$,$beta$-unsaturated carbonyl (Michael acceptor) moiety. Here we found that analogs bearing N-substituents, in particular compound 4 and 5 carrying an N-butyl and N-benzyl substituent, respectively, were strongly cytotoxic towards human HCT 116 colorectal and MCF-7 breast carcinoma cells. These compounds also displayed strong thioredoxin reductase (TrxR) inhibitory activity that was likely attributed to the electrophilicity of the Michael acceptor moiety. Their selectivity towards cellular TrxR inhibition over related antioxidant enzymes glutathione reductase (GR), thioredoxin (Trx) and glutathione peroxidase (GPx) was mediated through targeting of the selenocysteine (Sec) residue in the highly accessible C-terminal active site of TrxR. TrxR inhibition mediated by indolin-2-one compounds led to cellular Trx oxidation, increased oxidative stress and activation of apoptosis signal-regulating kinase 1 (ASK1). These events also led to activation of p38 and JNK mitogen-activated protein kinase (MAPK) signaling pathways, and cell death with apoptotic features of PARP cleavage and caspase 3 activation. In conclusion, these results suggest that indolin-2-one-based compounds specifically targeting TrxR may serve as novel drug leads for anticancer therapy.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Several compounds bearing the indolinone chemical scaffold are known to possess anticancer properties. For example, the tyrosine kinase inhibitor sunitinib is an arylideneindolin-2-one compound. The chemical versatility associated with structural modifications of indolinone compounds underlies the potential to discover additional derivatives possessing anticancer properties. Previously synthesized 3-(2-oxoethylidene)indolin-2-one compounds, also known as supercinnamaldehyde (SCA) compounds in reference to the parent compound 1 [1-methyl-3(2-oxopropylidene)indolin-2-one], bear a nitrogen-linked $alpha$,$beta$-unsaturated carbonyl (Michael acceptor) moiety. Here we found that analogs bearing N-substituents, in particular compound 4 and 5 carrying an N-butyl and N-benzyl substituent, respectively, were strongly cytotoxic towards human HCT 116 colorectal and MCF-7 breast carcinoma cells. These compounds also displayed strong thioredoxin reductase (TrxR) inhibitory activity that was likely attributed to the electrophilicity of the Michael acceptor moiety. Their selectivity towards cellular TrxR inhibition over related antioxidant enzymes glutathione reductase (GR), thioredoxin (Trx) and glutathione peroxidase (GPx) was mediated through targeting of the selenocysteine (Sec) residue in the highly accessible C-terminal active site of TrxR. TrxR inhibition mediated by indolin-2-one compounds led to cellular Trx oxidation, increased oxidative stress and activation of apoptosis signal-regulating kinase 1 (ASK1). These events also led to activation of p38 and JNK mitogen-activated protein kinase (MAPK) signaling pathways, and cell death with apoptotic features of PARP cleavage and caspase 3 activation. In conclusion, these results suggest that indolin-2-one-based compounds specifically targeting TrxR may serve as novel drug leads for anticancer therapy. |
The Use of Mn(II) Bound to His-tags as Genetically Encodable Spin-Label for Nanometric Distance Determination in Proteins Article de journal H Y V Ching; F C Mascali; H C Bertrand; E M Bruch; P Demay-Drouhard; R M Rasia; C Policar; L C Tabares; S Un Journal of Physical Chemistry Letters, 7 (6), p. 1072–1076, 2016. @article{Ching:2016, title = {The Use of Mn(II) Bound to His-tags as Genetically Encodable Spin-Label for Nanometric Distance Determination in Proteins}, author = {H Y V Ching and F C Mascali and H C Bertrand and E M Bruch and P Demay-Drouhard and R M Rasia and C Policar and L C Tabares and S Un}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84962539336&doi=10.1021%2facs.jpclett.6b00362&partnerID=40&md5=16161dac85830ffcae821a41e6480d4c}, doi = {10.1021/acs.jpclett.6b00362}, year = {2016}, date = {2016-01-01}, journal = {Journal of Physical Chemistry Letters}, volume = {7}, number = {6}, pages = {1072--1076}, abstract = {A genetically encodable paramagnetic spin-label capable of self-assembly from naturally available components would offer a means for studying the in-cell structure and interactions of a protein by electron paramagnetic resonance (EPR). Here, we demonstrate pulse electron-electron double resonance (DEER) measurements on spin-labels consisting of Mn(II) ions coordinated to a sequence of histidines, so-called His-tags, that are ubiquitously added by genetic engineering to facilitate protein purification. Although the affinity of His-tags for Mn(II) was low (800 μM), Mn(II)-bound His-tags yielded readily detectable DEER time traces even at concentrations expected in cells. We were able to determine accurately the distance between two His-tag Mn(II) spin-labels at the ends of a rigid helical polyproline peptide of known structure, as well as at the ends of a completely cell-synthesized 3-helix bundle. This approach not only greatly simplifies the labeling procedure but also represents a first step towards using self-assembling metal spin-labels for in-cell distance measurements. © 2016 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A genetically encodable paramagnetic spin-label capable of self-assembly from naturally available components would offer a means for studying the in-cell structure and interactions of a protein by electron paramagnetic resonance (EPR). Here, we demonstrate pulse electron-electron double resonance (DEER) measurements on spin-labels consisting of Mn(II) ions coordinated to a sequence of histidines, so-called His-tags, that are ubiquitously added by genetic engineering to facilitate protein purification. Although the affinity of His-tags for Mn(II) was low (800 μM), Mn(II)-bound His-tags yielded readily detectable DEER time traces even at concentrations expected in cells. We were able to determine accurately the distance between two His-tag Mn(II) spin-labels at the ends of a rigid helical polyproline peptide of known structure, as well as at the ends of a completely cell-synthesized 3-helix bundle. This approach not only greatly simplifies the labeling procedure but also represents a first step towards using self-assembling metal spin-labels for in-cell distance measurements. © 2016 American Chemical Society. |
RIDME spectroscopy on high-spin Mn2+ centers Article de journal D Akhmetzyanov; H Y V Ching; V Denysenkov; P Demay-Drouhard; H C Bertrand; L C Tabares; C Policar; T F Prisner; S Un Physical Chemistry Chemical Physics, 18 (44), p. 30857–30866, 2016. @article{Akhmetzyanov:2016, title = {RIDME spectroscopy on high-spin Mn2+ centers}, author = {D Akhmetzyanov and H Y V Ching and V Denysenkov and P Demay-Drouhard and H C Bertrand and L C Tabares and C Policar and T F Prisner and S Un}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85025823502&doi=10.1039%2fc6cp05239h&partnerID=40&md5=d3a6cd609c88b382cf0297ed361d4003}, doi = {10.1039/c6cp05239h}, year = {2016}, date = {2016-01-01}, journal = {Physical Chemistry Chemical Physics}, volume = {18}, number = {44}, pages = {30857--30866}, abstract = {Pulsed EPR dipolar spectroscopy is a powerful tool for determining the structure and conformational dynamics of biological macromolecules, as it allows precise measurements of distances in the range of 1.5-10 nm. Utilization of high-spin Mn2+ species as spin probes for distance measurements is of significant interest, because they are biologically compatible and endogenous in numerous biological systems. However, to date dipolar spectroscopy experiments with this kind of species have been underexplored. Here we present pulsed electron electron double resonance (PELDOR also called DEER) and relaxation-induced dipolar modulation enhancement (RIDME) experiments, which have been performed at W-band (94 GHz) and J-band frequencies (263 GHz) on a bis-MnDOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) model system. The distances obtained from these experiments are in good agreement with predictions. RIDME experiments reveal a significantly higher modulation depth compared to PELDOR, which is an important consideration for biological samples. These experiments also feature higher harmonics of the dipolar coupling frequency due to effective multiple-quantum relaxation of high-spin Mn2+ as well as the multiple-component background function. Harmonics of the dipolar coupling frequency were taken into account by including additional terms in the kernel function of Tikhonov regularization analysis. © The Owner Societies 2016.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Pulsed EPR dipolar spectroscopy is a powerful tool for determining the structure and conformational dynamics of biological macromolecules, as it allows precise measurements of distances in the range of 1.5-10 nm. Utilization of high-spin Mn2+ species as spin probes for distance measurements is of significant interest, because they are biologically compatible and endogenous in numerous biological systems. However, to date dipolar spectroscopy experiments with this kind of species have been underexplored. Here we present pulsed electron electron double resonance (PELDOR also called DEER) and relaxation-induced dipolar modulation enhancement (RIDME) experiments, which have been performed at W-band (94 GHz) and J-band frequencies (263 GHz) on a bis-MnDOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) model system. The distances obtained from these experiments are in good agreement with predictions. RIDME experiments reveal a significantly higher modulation depth compared to PELDOR, which is an important consideration for biological samples. These experiments also feature higher harmonics of the dipolar coupling frequency due to effective multiple-quantum relaxation of high-spin Mn2+ as well as the multiple-component background function. Harmonics of the dipolar coupling frequency were taken into account by including additional terms in the kernel function of Tikhonov regularization analysis. © The Owner Societies 2016. |
Photophysical properties of single core multimodal probe for imaging (SCoMPI) in a membrane model and in cells Article de journal S Hostachy; J -M Swiecicki; C Sandt; N Delsuc; C Policar Dalton Transactions, 45 (7), p. 2791–2795, 2016. @article{Hostachy:2016, title = {Photophysical properties of single core multimodal probe for imaging (SCoMPI) in a membrane model and in cells}, author = {S Hostachy and J -M Swiecicki and C Sandt and N Delsuc and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84958064177&doi=10.1039%2fc5dt03819g&partnerID=40&md5=fb027086e6424b54b23cc2c11098e273}, doi = {10.1039/c5dt03819g}, year = {2016}, date = {2016-01-01}, journal = {Dalton Transactions}, volume = {45}, number = {7}, pages = {2791--2795}, abstract = {The spectroscopic properties of two luminescent Re(i) tricarbonyl complexes conjugated with two cell-penetrating peptides were examined. Fluorescence experiments and IR quantification in membrane models and in cells showed unexpectedly strong luminescence enhancement for one of the complexes in a lipid environment. © The Royal Society of Chemistry 2016.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The spectroscopic properties of two luminescent Re(i) tricarbonyl complexes conjugated with two cell-penetrating peptides were examined. Fluorescence experiments and IR quantification in membrane models and in cells showed unexpectedly strong luminescence enhancement for one of the complexes in a lipid environment. © The Royal Society of Chemistry 2016. |
New insight into the structural, electrochemical and biological aspects of macroacyclic Cu(II) complexes derived from S-substituted dithiocarbazate schiff bases Article de journal M L Low; L Maigre; M I M Tahir; E R T Tiekink; P Dorlet; R Guillot; T B Ravoof; R Rosli; J -M Pagès; C Policar; N Delsuc; K A Crouse European Journal of Medicinal Chemistry, 120 , p. 1–12, 2016. @article{Low:2016, title = {New insight into the structural, electrochemical and biological aspects of macroacyclic Cu(II) complexes derived from S-substituted dithiocarbazate schiff bases}, author = {M L Low and L Maigre and M I M Tahir and E R T Tiekink and P Dorlet and R Guillot and T B Ravoof and R Rosli and J -M Pag\`{e}s and C Policar and N Delsuc and K A Crouse}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84967102584&doi=10.1016%2fj.ejmech.2016.04.027&partnerID=40&md5=71cde180942655ac9c57205e82887fcf}, doi = {10.1016/j.ejmech.2016.04.027}, year = {2016}, date = {2016-01-01}, journal = {European Journal of Medicinal Chemistry}, volume = {120}, pages = {1--12}, abstract = {Copper (II) complexes synthesized from the products of condensation of S-methyl- and S-benzyldithiocarbazate with 2,5-hexanedione (SMHDH2 and SBHDH2 respectively) have been characterized using various physicochemical (elemental analysis, molar conductivity, magnetic susceptibility) and spectroscopic (infrared, electronic) methods. The structures of SMHDH2, its copper (II) complex, CuSMHD, and the related CuSBHD complex as well as a pyrrole byproduct, SBPY, have been determined by single crystal X-ray diffraction. In order to provide more insight into the behaviour of the complexes in solution, electron paramagnetic resonance (EPR) and electrochemical experiments were performed. Antibacterial activity and cytotoxicity were evaluated. The compounds, dissolved in 0.5% and 5% DMSO, showed a wide range of antibacterial activity against 10 strains of Gram-positive and Gram-negative bacteria. Investigations of the effects of efflux pumps and membrane penetration on antibacterial activity are reported herein. Antiproliferation activity was observed to be enhanced by complexation with copper. Preliminary screening showed Cu complexes are strongly active against human breast adenocarcinoma cancer cell lines MDA-MB-231 and MCF-7. © 2016 Published by Elsevier Masson SAS.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Copper (II) complexes synthesized from the products of condensation of S-methyl- and S-benzyldithiocarbazate with 2,5-hexanedione (SMHDH2 and SBHDH2 respectively) have been characterized using various physicochemical (elemental analysis, molar conductivity, magnetic susceptibility) and spectroscopic (infrared, electronic) methods. The structures of SMHDH2, its copper (II) complex, CuSMHD, and the related CuSBHD complex as well as a pyrrole byproduct, SBPY, have been determined by single crystal X-ray diffraction. In order to provide more insight into the behaviour of the complexes in solution, electron paramagnetic resonance (EPR) and electrochemical experiments were performed. Antibacterial activity and cytotoxicity were evaluated. The compounds, dissolved in 0.5% and 5% DMSO, showed a wide range of antibacterial activity against 10 strains of Gram-positive and Gram-negative bacteria. Investigations of the effects of efflux pumps and membrane penetration on antibacterial activity are reported herein. Antiproliferation activity was observed to be enhanced by complexation with copper. Preliminary screening showed Cu complexes are strongly active against human breast adenocarcinoma cancer cell lines MDA-MB-231 and MCF-7. © 2016 Published by Elsevier Masson SAS. |
Monitoring bicosomes containing antioxidants in normal and irradiated skin Article de journal E Fernández; S Hostachy; C Sandt; G Rodríguez; H C Bertrand; S Clède; M Cócera; A D L Maza; F Lambert; C Policar; O López RSC Advances, 6 (76), p. 72559–72567, 2016. @article{Fernandez:2016, title = {Monitoring bicosomes containing antioxidants in normal and irradiated skin}, author = {E Fern\'{a}ndez and S Hostachy and C Sandt and G Rodr\'{i}guez and H C Bertrand and S Cl\`{e}de and M C\'{o}cera and A D L Maza and F Lambert and C Policar and O L\'{o}pez}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84982684419&doi=10.1039%2fc6ra11170j&partnerID=40&md5=126bef944046a09450ae86ce5985c07f}, doi = {10.1039/c6ra11170j}, year = {2016}, date = {2016-01-01}, journal = {RSC Advances}, volume = {6}, number = {76}, pages = {72559--72567}, abstract = {This study evaluates the penetration of bicosome systems incorporating two different antioxidants into normal skin and skin exposed to ultraviolet-visible radiation (UV-VIS) by Fourier-transform infrared microspectroscopy (FT-IR) using synchrotron radiation. Bicosomes are phospholipid assemblies based on mixtures of discoidal lipid structures protected by spherical lipid vesicles able to incorporate different molecules. In the current work, the antioxidants incorporated in these systems were β-carotene and a Mn complex as a superoxide dismutase (SOD) mimic. Additionally, a rhenium tri-carbonyl derivative was incorporated in the bicosome systems in order to map their penetration following the tag specific carbonyl signal by FT-IR microspectroscopy. The characterization of bicosome systems using the dynamic light scattering technique (DLS) showed a modification in the size of the systems containing β-carotene (Bcβ) or MnII complex (BcMn). After skin permeation, FT-IR results indicated a higher and deeper penetration of the BcMn system than the Bcβ system into the skin. Likely, the different physicochemical properties of both antioxidants could be responsible for this effect. Moreover, the penetration of both bicosome systems in irradiated skin was lower in comparison with the normal skin. This fact could be a consequence of the alteration of water transport in the skin during the irradiation process. In conclusion, these results indicated the effectiveness of bicosome systems as skin carriers, and provide information to protect skin under radiation using antioxidants. © The Royal Society of Chemistry 2016.}, keywords = {}, pubstate = {published}, tppubtype = {article} } This study evaluates the penetration of bicosome systems incorporating two different antioxidants into normal skin and skin exposed to ultraviolet-visible radiation (UV-VIS) by Fourier-transform infrared microspectroscopy (FT-IR) using synchrotron radiation. Bicosomes are phospholipid assemblies based on mixtures of discoidal lipid structures protected by spherical lipid vesicles able to incorporate different molecules. In the current work, the antioxidants incorporated in these systems were β-carotene and a Mn complex as a superoxide dismutase (SOD) mimic. Additionally, a rhenium tri-carbonyl derivative was incorporated in the bicosome systems in order to map their penetration following the tag specific carbonyl signal by FT-IR microspectroscopy. The characterization of bicosome systems using the dynamic light scattering technique (DLS) showed a modification in the size of the systems containing β-carotene (Bcβ) or MnII complex (BcMn). After skin permeation, FT-IR results indicated a higher and deeper penetration of the BcMn system than the Bcβ system into the skin. Likely, the different physicochemical properties of both antioxidants could be responsible for this effect. Moreover, the penetration of both bicosome systems in irradiated skin was lower in comparison with the normal skin. This fact could be a consequence of the alteration of water transport in the skin during the irradiation process. In conclusion, these results indicated the effectiveness of bicosome systems as skin carriers, and provide information to protect skin under radiation using antioxidants. © The Royal Society of Chemistry 2016. |
Human TTR conformation altered by rhenium tris-carbonyl derivatives Article de journal L Ciccone; C Policar; E A Stura; W Shepard Journal of Structural Biology, 195 (3), p. 353–364, 2016. @article{Ciccone:2016, title = {Human TTR conformation altered by rhenium tris-carbonyl derivatives}, author = {L Ciccone and C Policar and E A Stura and W Shepard}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84991363542&doi=10.1016%2fj.jsb.2016.07.002&partnerID=40&md5=86e7e8d956bfdb39ae832e52b01a9dea}, doi = {10.1016/j.jsb.2016.07.002}, year = {2016}, date = {2016-01-01}, journal = {Journal of Structural Biology}, volume = {195}, number = {3}, pages = {353--364}, abstract = {Transthyretin (TTR) is a 54 kDa homotetrameric serum protein that transports thyroxine (T4) and retinol. TTR is potentially amyloidogenic due to homotetramer dissociation into monomeric intermediates that self-assemble as amyloid deposits and insoluble fibrils. Most crystallographic structures, including those of amyloidogenic variants show the same tetramer without major variations in the monomer-monomer interface nor in the volume of the interdimeric cavity. Soaking TTR crystals in a solution containing rhenium tris-carbonyl derivatives yields a TTR conformer never observed before. Only one of the two monomers of the crystallographic dimer is significantly altered, and the inner part of the T4 binding cavity is expanded at one end and shrunk at the other. The result redefines the mechanism of allosteric communication between the two sites, suggesting that negative cooperativity is a function of dimer asymmetry, which can be induced through internal or external binding. An aspect that remains unexplained is why the conformational changes are ubiquitous throughout the crystal although the heavy metal content of the derivatized crystals is relatively low. The conformational changes observed, which include Leu82, may represent a form of TTR better at scavenging β-Amyloid. At a resolution of 1.69 r{A}, with excellent refinement statistics and well defined electron density for all parts of the structure, it is possible to envisage answering important questions that range from protein cooperative behavior to heavy atom induced protein conformational modifications that can result in crystallographic non-isomorphism. © 2016 Elsevier Inc.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Transthyretin (TTR) is a 54 kDa homotetrameric serum protein that transports thyroxine (T4) and retinol. TTR is potentially amyloidogenic due to homotetramer dissociation into monomeric intermediates that self-assemble as amyloid deposits and insoluble fibrils. Most crystallographic structures, including those of amyloidogenic variants show the same tetramer without major variations in the monomer-monomer interface nor in the volume of the interdimeric cavity. Soaking TTR crystals in a solution containing rhenium tris-carbonyl derivatives yields a TTR conformer never observed before. Only one of the two monomers of the crystallographic dimer is significantly altered, and the inner part of the T4 binding cavity is expanded at one end and shrunk at the other. The result redefines the mechanism of allosteric communication between the two sites, suggesting that negative cooperativity is a function of dimer asymmetry, which can be induced through internal or external binding. An aspect that remains unexplained is why the conformational changes are ubiquitous throughout the crystal although the heavy metal content of the derivatized crystals is relatively low. The conformational changes observed, which include Leu82, may represent a form of TTR better at scavenging β-Amyloid. At a resolution of 1.69 Å, with excellent refinement statistics and well defined electron density for all parts of the structure, it is possible to envisage answering important questions that range from protein cooperative behavior to heavy atom induced protein conformational modifications that can result in crystallographic non-isomorphism. © 2016 Elsevier Inc. |
Bioinspired superoxide-dismutase mimics: The effects of functionalization with cationic polyarginine peptides Article de journal H Y V Ching; I Kenkel; N Delsuc; E Mathieu; I Ivanović-Burmazović; C Policar Journal of Inorganic Biochemistry, 160 , p. 172–179, 2016. @article{Ching:2016a, title = {Bioinspired superoxide-dismutase mimics: The effects of functionalization with cationic polyarginine peptides}, author = {H Y V Ching and I Kenkel and N Delsuc and E Mathieu and I Ivanovi\'{c}-Burmazovi\'{c} and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84964372716&doi=10.1016%2fj.jinorgbio.2016.01.025&partnerID=40&md5=035d0c2b5ffd4ee0b6fb74df285838da}, doi = {10.1016/j.jinorgbio.2016.01.025}, year = {2016}, date = {2016-01-01}, journal = {Journal of Inorganic Biochemistry}, volume = {160}, pages = {172--179}, abstract = {Continuing a bio-mimetic approach, we have prepared peptide conjugates of a superoxide dismutase (SOD) mimic [MnL]+ (where HL = N-(2-hydroxybenzyl)-N,N'-bis[2-(N-methylimidazolyl)methyl]ethane-1,2-diamine), namely [MnL'-Arg(n-1)]n+ (where n = 2, 4, 7 and 10) and [MnL'-Gly1]+. [MnL'-Arg(n-1)]n+ contained cationic residue(s) that emulate the electrostatic channel of the enzyme. Physicochemical methods showed that functionalization at the secondary amine of HL did not impair coordination to MnII with association constants (Kassoc) between 1.6 and 3.3 × 106 M- 1. The MnIII/MnII redox potential of the conjugates was between 0.27 and 0.30 V vs SCE, slightly higher than [MnL]+ under the same conditions, but remain at a value that facilitates O2•- dismutation. The catalytic rate constant (kcat) of the dismutation for the series was studied using a direct stopped-flow method, which showed that for compounds with the same overall charge, the alkylation of the secondary amine of [MnL]+ (kcat = 5.0 ± 0.1 × 106 M- 1 s- 1) led to a lower value (i.e. for [MnL'Gly]+}, keywords = {}, pubstate = {published}, tppubtype = {article} } Continuing a bio-mimetic approach, we have prepared peptide conjugates of a superoxide dismutase (SOD) mimic [MnL]+ (where HL = N-(2-hydroxybenzyl)-N,N'-bis[2-(N-methylimidazolyl)methyl]ethane-1,2-diamine), namely [MnL'-Arg(n-1)]n+ (where n = 2, 4, 7 and 10) and [MnL'-Gly1]+. [MnL'-Arg(n-1)]n+ contained cationic residue(s) that emulate the electrostatic channel of the enzyme. Physicochemical methods showed that functionalization at the secondary amine of HL did not impair coordination to MnII with association constants (Kassoc) between 1.6 and 3.3 × 106 M- 1. The MnIII/MnII redox potential of the conjugates was between 0.27 and 0.30 V vs SCE, slightly higher than [MnL]+ under the same conditions, but remain at a value that facilitates O2•- dismutation. The catalytic rate constant (kcat) of the dismutation for the series was studied using a direct stopped-flow method, which showed that for compounds with the same overall charge, the alkylation of the secondary amine of [MnL]+ (kcat = 5.0 ± 0.1 × 106 M- 1 s- 1) led to a lower value (i.e. for [MnL'Gly]+ |
Bimodal X-ray and Infrared Imaging of an Organometallic Derivative of Praziquantel in Schistosoma mansoni Article de journal S Clède; N Cowan; F Lambert; H C Bertrand; R Rubbiani; M Patra; J Hess; C Sandt; N Trcera; G Gasser; J Keiser; C Policar ChemBioChem, 17 (11), p. 1004–1007, 2016. @article{Clede:2016, title = {Bimodal X-ray and Infrared Imaging of an Organometallic Derivative of Praziquantel in Schistosoma mansoni}, author = {S Cl\`{e}de and N Cowan and F Lambert and H C Bertrand and R Rubbiani and M Patra and J Hess and C Sandt and N Trcera and G Gasser and J Keiser and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84973124415&doi=10.1002%2fcbic.201500688&partnerID=40&md5=608b1bb28a5237e0717a29ee815e73bc}, doi = {10.1002/cbic.201500688}, year = {2016}, date = {2016-01-01}, journal = {ChemBioChem}, volume = {17}, number = {11}, pages = {1004--1007}, abstract = {An organometallic derivative of praziquantel was studied directly in worms by using inductively coupled plasma-mass spectrometry (ICP-MS) for quantification and synchrotron-based imaging. X-ray fluorescence (XRF) and IR absorption spectromicroscopy were used for the first time in combination to directly locate this organometallic drug candidate in schistosomes. The detection of both CO (IR) and Cr (XRF) signatures proved that the Cr(CO)3 core remained intact in the worms. Images showed a preferential accumulation at the worm's tegument, consistent with a possible targeting of the calcium channel but not excluding other biological targets inside the worm. Imaginative imaging: Two synchrotron-based techniques - X-ray fluorescence and IR absorption spectroscopy - were used in combination for the first time to directly locate an organometallic drug candidate in schistosomes. This represents a novel approach to examine mechanisms of actions for organometallic compounds and might lead to the discovery of new drug candidates. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.}, keywords = {}, pubstate = {published}, tppubtype = {article} } An organometallic derivative of praziquantel was studied directly in worms by using inductively coupled plasma-mass spectrometry (ICP-MS) for quantification and synchrotron-based imaging. X-ray fluorescence (XRF) and IR absorption spectromicroscopy were used for the first time in combination to directly locate this organometallic drug candidate in schistosomes. The detection of both CO (IR) and Cr (XRF) signatures proved that the Cr(CO)3 core remained intact in the worms. Images showed a preferential accumulation at the worm's tegument, consistent with a possible targeting of the calcium channel but not excluding other biological targets inside the worm. Imaginative imaging: Two synchrotron-based techniques - X-ray fluorescence and IR absorption spectroscopy - were used in combination for the first time to directly locate an organometallic drug candidate in schistosomes. This represents a novel approach to examine mechanisms of actions for organometallic compounds and might lead to the discovery of new drug candidates. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
A Bis-Manganese(II)–DOTA Complex for Pulsed Dipolar Spectroscopy Article de journal P Demay-Drouhard; H Y V Ching; D Akhmetzyanov; R Guillot; L C Tabares; H C Bertrand; C Policar ChemPhysChem, p. 2066–2078, 2016. @article{Demay-Drouhard:2016, title = {A Bis-Manganese(II)\textendashDOTA Complex for Pulsed Dipolar Spectroscopy}, author = {P Demay-Drouhard and H Y V Ching and D Akhmetzyanov and R Guillot and L C Tabares and H C Bertrand and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84977597209&doi=10.1002%2fcphc.201600234&partnerID=40&md5=38a2466ad0f00d0edb158d200429986c}, doi = {10.1002/cphc.201600234}, year = {2016}, date = {2016-01-01}, journal = {ChemPhysChem}, pages = {2066--2078}, abstract = {High-spin gadolinium(III) and manganese(II) complexes have emerged as alternatives to standard nitroxide radical spin labels for measuring nanometric distances by using pulsed electron\textendashelectron double resonance (PELDOR or DEER) at high fields/frequencies. For certain complexes, particularly those with relatively small zero-field splitting (ZFS) and short distances between the two metal centers, the pseudosecular term of the dipolar coupling Hamiltonian is non-negligible. However, in general, the contribution from this term during conventional data analysis is masked by the flexibility of the molecule of interest and/or the long tethers connecting them to the spin labels. The efficient synthesis of a model system consisting of two [Mn(dota)]2− (MnDOTA; DOTA4−=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) directly connected to the ends of a central rodlike oligo(phenylene\textendashethynylene) (OPE) spacer is reported. The rigidity of the OPE is confirmed by Q-band PELDOR measurements on a bis-nitroxide analogue. The MnII−MnII distance distribution profile determined by W-band PELDOR is in reasonable agreement with one simulated by using a simple rotamer analysis. The small degree of flexibility arising from the linking MnDOTA arm appears to outweigh the contribution from the pseudosecular term at this interspin distance. This study illustrates the potential of MnDOTA-based spin labels for measuring fairly short nanometer distances, and also presents an interesting candidate for in-depth studies of pulsed dipolar spectroscopy methods on MnII−MnII systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim}, keywords = {}, pubstate = {published}, tppubtype = {article} } High-spin gadolinium(III) and manganese(II) complexes have emerged as alternatives to standard nitroxide radical spin labels for measuring nanometric distances by using pulsed electron–electron double resonance (PELDOR or DEER) at high fields/frequencies. For certain complexes, particularly those with relatively small zero-field splitting (ZFS) and short distances between the two metal centers, the pseudosecular term of the dipolar coupling Hamiltonian is non-negligible. However, in general, the contribution from this term during conventional data analysis is masked by the flexibility of the molecule of interest and/or the long tethers connecting them to the spin labels. The efficient synthesis of a model system consisting of two [Mn(dota)]2− (MnDOTA; DOTA4−=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) directly connected to the ends of a central rodlike oligo(phenylene–ethynylene) (OPE) spacer is reported. The rigidity of the OPE is confirmed by Q-band PELDOR measurements on a bis-nitroxide analogue. The MnII−MnII distance distribution profile determined by W-band PELDOR is in reasonable agreement with one simulated by using a simple rotamer analysis. The small degree of flexibility arising from the linking MnDOTA arm appears to outweigh the contribution from the pseudosecular term at this interspin distance. This study illustrates the potential of MnDOTA-based spin labels for measuring fairly short nanometer distances, and also presents an interesting candidate for in-depth studies of pulsed dipolar spectroscopy methods on MnII−MnII systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim |
Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads Article de journal K K Kaminska; H C Bertrand; H Tajima; W C Stafford; Q Cheng; W Chen; G Wells; E S J Arner; E -H Chew Oncotarget, 7 (26), p. 40233–40251, 2016. @article{Kaminska:2016, title = {Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads}, author = {K K Kaminska and H C Bertrand and H Tajima and W C Stafford and Q Cheng and W Chen and G Wells and E S J Arner and E -H Chew}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84983002228&doi=10.18632%2foncotarget.9579&partnerID=40&md5=21b5120cc53147d2dce47cf9545ab207}, doi = {10.18632/oncotarget.9579}, year = {2016}, date = {2016-01-01}, journal = {Oncotarget}, volume = {7}, number = {26}, pages = {40233--40251}, abstract = {Several compounds bearing the indolinone chemical scaffold are known to possess anticancer properties. For example, the tyrosine kinase inhibitor sunitinib is an arylideneindolin-2-one compound. The chemical versatility associated with structural modifications of indolinone compounds underlies the potential to discover additional derivatives possessing anticancer properties. Previously synthesized 3-(2-oxoethylidene)indolin-2-one compounds, also known as supercinnamaldehyde (SCA) compounds in reference to the parent compound 1 [1-methyl-3(2- oxopropylidene)indolin-2-one], bear a nitrogen-linked α,β-unsaturated carbonyl (Michael acceptor) moiety. Here we found that analogs bearing N-substituents, in particular compound 4 and 5 carrying an N-butyl and N-benzyl substituent, respectively, were strongly cytotoxic towards human HCT 116 colorectal and MCF-7 breast carcinoma cells. These compounds also displayed strong thioredoxin reductase (TrxR) inhibitory activity that was likely attributed to the electrophilicity of the Michael acceptor moiety. Their selectivity towards cellular TrxR inhibition over related antioxidant enzymes glutathione reductase (GR), thioredoxin (Trx) and glutathione peroxidase (GPx) was mediated through targeting of the selenocysteine (Sec) residue in the highly accessible C-terminal active site of TrxR. TrxR inhibition mediated by indolin-2-one compounds led to cellular Trx oxidation, increased oxidative stress and activation of apoptosis signal-regulating kinase 1 (ASK1). These events also led to activation of p38 and JNK mitogen-activated protein kinase (MAPK) signaling pathways, and cell death with apoptotic features of PARP cleavage and caspase 3 activation. In conclusion, these results suggest that indolin-2-one-based compounds specifically targeting TrxR may serve as novel drug leads for anticancer therapy.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Several compounds bearing the indolinone chemical scaffold are known to possess anticancer properties. For example, the tyrosine kinase inhibitor sunitinib is an arylideneindolin-2-one compound. The chemical versatility associated with structural modifications of indolinone compounds underlies the potential to discover additional derivatives possessing anticancer properties. Previously synthesized 3-(2-oxoethylidene)indolin-2-one compounds, also known as supercinnamaldehyde (SCA) compounds in reference to the parent compound 1 [1-methyl-3(2- oxopropylidene)indolin-2-one], bear a nitrogen-linked α,β-unsaturated carbonyl (Michael acceptor) moiety. Here we found that analogs bearing N-substituents, in particular compound 4 and 5 carrying an N-butyl and N-benzyl substituent, respectively, were strongly cytotoxic towards human HCT 116 colorectal and MCF-7 breast carcinoma cells. These compounds also displayed strong thioredoxin reductase (TrxR) inhibitory activity that was likely attributed to the electrophilicity of the Michael acceptor moiety. Their selectivity towards cellular TrxR inhibition over related antioxidant enzymes glutathione reductase (GR), thioredoxin (Trx) and glutathione peroxidase (GPx) was mediated through targeting of the selenocysteine (Sec) residue in the highly accessible C-terminal active site of TrxR. TrxR inhibition mediated by indolin-2-one compounds led to cellular Trx oxidation, increased oxidative stress and activation of apoptosis signal-regulating kinase 1 (ASK1). These events also led to activation of p38 and JNK mitogen-activated protein kinase (MAPK) signaling pathways, and cell death with apoptotic features of PARP cleavage and caspase 3 activation. In conclusion, these results suggest that indolin-2-one-based compounds specifically targeting TrxR may serve as novel drug leads for anticancer therapy. |
Small Fluorescence-Activating and Absorption-Shifting Tag for Tunable Protein Imaging in Vivo Article de journal Marie-Aude Plamont; Emmanuelle Billon-Denis; Sylvie Maurin; Carole Gauron; Frederico M Pimenta; Christian G Specht; Jian Shi; Jérôme Querard; Buyan Pan; Julien Rossignol; Karine Moncoq; Nelly Morellet; Michel Volovitch; Ewen Lescop; Yong Chen; Antoine Triller; Sophie Vriz; Thomas Le Saux; Ludovic Jullien; Arnaud Gautier Proceedings of the National Academy of Sciences, 113 (3), p. 497, 2016. @article{RN50, title = {Small Fluorescence-Activating and Absorption-Shifting Tag for Tunable Protein Imaging in Vivo}, author = {Marie-Aude Plamont and Emmanuelle {Billon-Denis} and Sylvie Maurin and Carole Gauron and Frederico M Pimenta and Christian G Specht and Jian Shi and J\'{e}r\^{o}me Querard and Buyan Pan and Julien Rossignol and Karine Moncoq and Nelly Morellet and Michel Volovitch and Ewen Lescop and Yong Chen and Antoine Triller and Sophie Vriz and Thomas Le Saux and Ludovic Jullien and Arnaud Gautier}, doi = {10.1073/pnas.1513094113}, year = {2016}, date = {2016-01-01}, journal = {Proceedings of the National Academy of Sciences}, volume = {113}, number = {3}, pages = {497}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
2015 |
Structure-based design of novel naproxen derivatives targeting monomeric nucleoprotein of Influenza A virus Article de journal Bogdan Tarus; Hélène Bertrand; Gloria Zedda; Carmelo Di Primo; Stéphane Quideau; Anny Slama-Schwok Journal of biomolecular structure & dynamics, 33 (9), p. 1899–1912, 2015, ISSN: 1538-0254. @article{Tarus2015, title = {Structure-based design of novel naproxen derivatives targeting monomeric nucleoprotein of Influenza A virus}, author = {Bogdan Tarus and H\'{e}l{\`{e}}ne Bertrand and Gloria Zedda and Carmelo {Di Primo} and St\'{e}phane Quideau and Anny Slama-Schwok}, url = {https://www.ncbi.nlm.nih.gov/pubmed/25333630 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548311/}, doi = {10.1080/07391102.2014.979230}, issn = {1538-0254}, year = {2015}, date = {2015-09-01}, journal = {Journal of biomolecular structure & dynamics}, volume = {33}, number = {9}, pages = {1899--1912}, publisher = {Taylor & Francis}, edition = {2014/11/19}, abstract = {The nucleoprotein (NP) binds the viral RNA genome as oligomers assembled with the polymerase in a ribonucleoprotein complex required for transcription and replication of influenza A virus. Novel antiviral candidates targeting the nucleoprotein either induced higher order oligomers or reduced NP oligomerization by targeting the oligomerization loop and blocking its insertion into adjacent nucleoprotein subunit. In this study, we used a different structure-based approach to stabilize monomers of the nucleoprotein by drugs binding in its RNA-binding groove. We recently identified naproxen as a drug competing with RNA binding to NP with antiinflammatory and antiviral effects against influenza A virus. Here, we designed novel derivatives of naproxen by fragment extension for improved binding to NP. Molecular dynamics simulations suggested that among these derivatives, naproxen A and C0 were most promising. Their chemical synthesis is described. Both derivatives markedly stabilized NP monomer against thermal denaturation. Naproxen C0 bound tighter to NP than naproxen at a binding site predicted by MD simulations and shown by competition experiments using wt NP or single-point mutants as determined by surface plasmon resonance. MD simulations suggested that impeded oligomerization and stabilization of monomeric NP is likely to be achieved by drugs binding in the RNA grove and inducing close to their binding site conformational changes of key residues hosting the oligomerization loop as observed for the naproxen derivatives. Naproxen C0 is a potential antiviral candidate blocking influenza nucleoprotein function.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The nucleoprotein (NP) binds the viral RNA genome as oligomers assembled with the polymerase in a ribonucleoprotein complex required for transcription and replication of influenza A virus. Novel antiviral candidates targeting the nucleoprotein either induced higher order oligomers or reduced NP oligomerization by targeting the oligomerization loop and blocking its insertion into adjacent nucleoprotein subunit. In this study, we used a different structure-based approach to stabilize monomers of the nucleoprotein by drugs binding in its RNA-binding groove. We recently identified naproxen as a drug competing with RNA binding to NP with antiinflammatory and antiviral effects against influenza A virus. Here, we designed novel derivatives of naproxen by fragment extension for improved binding to NP. Molecular dynamics simulations suggested that among these derivatives, naproxen A and C0 were most promising. Their chemical synthesis is described. Both derivatives markedly stabilized NP monomer against thermal denaturation. Naproxen C0 bound tighter to NP than naproxen at a binding site predicted by MD simulations and shown by competition experiments using wt NP or single-point mutants as determined by surface plasmon resonance. MD simulations suggested that impeded oligomerization and stabilization of monomeric NP is likely to be achieved by drugs binding in the RNA grove and inducing close to their binding site conformational changes of key residues hosting the oligomerization loop as observed for the naproxen derivatives. Naproxen C0 is a potential antiviral candidate blocking influenza nucleoprotein function. |
Design, Synthesis, and Evaluation of Triazole Derivatives That Induce Nrf2 Dependent Gene Products and Inhibit the Keap1–Nrf2 Protein–Protein Interaction Article de journal Hélène C Bertrand; Marjolein Schaap; Liam Baird; Nikolaos D Georgakopoulos; Adrian Fowkes; Clarisse Thiollier; Hiroko Kachi; Albena T Dinkova-Kostova; Geoff Wells Journal of Medicinal Chemistry, 58 (18), p. 7186–7194, 2015, ISSN: 0022-2623. @article{Bertrand2015, title = {Design, Synthesis, and Evaluation of Triazole Derivatives That Induce Nrf2 Dependent Gene Products and Inhibit the Keap1\textendashNrf2 Protein\textendashProtein Interaction}, author = {H\'{e}l{\`{e}}ne C Bertrand and Marjolein Schaap and Liam Baird and Nikolaos D Georgakopoulos and Adrian Fowkes and Clarisse Thiollier and Hiroko Kachi and Albena T Dinkova-Kostova and Geoff Wells}, url = {https://doi.org/10.1021/acs.jmedchem.5b00602}, doi = {10.1021/acs.jmedchem.5b00602}, issn = {0022-2623}, year = {2015}, date = {2015-09-01}, journal = {Journal of Medicinal Chemistry}, volume = {58}, number = {18}, pages = {7186--7194}, publisher = {American Chemical Society}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Nanometric distance measurements between Mn(II)DOTA centers Article de journal H Y Vincent Ching; P Demay-Drouhard; H C Bertrand; C Policar; L C Tabares; S Un Physical Chemistry Chemical Physics, 17 (36), p. 23368–23377, 2015. @article{VincentChing:2015, title = {Nanometric distance measurements between Mn(II)DOTA centers}, author = {H Y Vincent Ching and P Demay-Drouhard and H C Bertrand and C Policar and L C Tabares and S Un}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84941299721&doi=10.1039%2fc5cp03487f&partnerID=40&md5=bfd7a9aac0fc115147eb207f0fbeb05b}, doi = {10.1039/c5cp03487f}, year = {2015}, date = {2015-01-01}, journal = {Physical Chemistry Chemical Physics}, volume = {17}, number = {36}, pages = {23368--23377}, abstract = {Pulse electron-electron double resonance (PELDOR) is a versatile technique for probing the structures and functions of complex biological systems. Despite the recent interest in high-spin metal-ions for high field/frequency applications, PELDOR measurements of Mn(II) remain relatively underexplored. Here we present Mn(II)-Mn(II) PELDOR distance measurements at 94 GHz on polyproline II (PPII) helices doubly spin-labeled with Mn(II)DOTA, which are distinguished by their small zero-field interaction. The measured Mn-Mn distances and distribution profiles were in good agreement with the expected values from molecular models. Additional features in the frequency-domain spectra became apparent at certain combinations of detect and pump frequencies. Spin-Hamiltonian calculations showed that they likely arose from contributions from the pseudo-secular component of the dipolar interaction that were found to be non-negligible for Mn(II)DOTA. However, the influence of the pseudo-secular component on the distance distribution profiles apparently was limited. The results show the potential of Mn(II)DOTA spin labels for high-field PELDOR distance measurements in proteins and other biological systems. © the Owner Societies 2015.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Pulse electron-electron double resonance (PELDOR) is a versatile technique for probing the structures and functions of complex biological systems. Despite the recent interest in high-spin metal-ions for high field/frequency applications, PELDOR measurements of Mn(II) remain relatively underexplored. Here we present Mn(II)-Mn(II) PELDOR distance measurements at 94 GHz on polyproline II (PPII) helices doubly spin-labeled with Mn(II)DOTA, which are distinguished by their small zero-field interaction. The measured Mn-Mn distances and distribution profiles were in good agreement with the expected values from molecular models. Additional features in the frequency-domain spectra became apparent at certain combinations of detect and pump frequencies. Spin-Hamiltonian calculations showed that they likely arose from contributions from the pseudo-secular component of the dipolar interaction that were found to be non-negligible for Mn(II)DOTA. However, the influence of the pseudo-secular component on the distance distribution profiles apparently was limited. The results show the potential of Mn(II)DOTA spin labels for high-field PELDOR distance measurements in proteins and other biological systems. © the Owner Societies 2015. |
Synthesis, characterization and biological activity of Cu(II), Zn(II) and Re(I) complexes derived from S-benzyldithiocarbazate and 3-acetylcoumarin Article de journal M L Low; G Paulus; P Dorlet; R Guillot; R Rosli; N Delsuc; K A Crouse; C Policar BioMetals, 28 (3), p. 553–566, 2015. @article{Low:2015, title = {Synthesis, characterization and biological activity of Cu(II), Zn(II) and Re(I) complexes derived from S-benzyldithiocarbazate and 3-acetylcoumarin}, author = {M L Low and G Paulus and P Dorlet and R Guillot and R Rosli and N Delsuc and K A Crouse and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84939939059&doi=10.1007%2fs10534-015-9831-2&partnerID=40&md5=8d0220a2a88cc9eb122f191d65c87199}, doi = {10.1007/s10534-015-9831-2}, year = {2015}, date = {2015-01-01}, journal = {BioMetals}, volume = {28}, number = {3}, pages = {553--566}, abstract = {Cu(II), Zn(II) and Re(I) complexes have been synthesized with the Schiff base, N′-[1-(2-oxo-2H-chromen-3-yl)-ethylidene]-hydrazinecarbodithioic acid benzyl ester (SBCM-H) which was prepared by condensation of S-benzyldithiocarbazate and 3-acetylcoumarin. The metal complexes were characterized on the basis of various physico-chemical and spectroscopic techniques including elemental analysis and electrochemical studies, and FT-IR, UV-Vis, NMR, EPR and mass spectroscopy. The Schiff base was found to behave as a bidentate ligand coordinating with Cu(II) and Zn(II) in the thiolate form with 1:2 metal to ligand stoichiometry. Crystals suitable for X-ray diffractometry (XRD) were obtained from the reaction of ReCl(CO)5 with SBCM-H forming a centrosymmetric dimeric complex Re2L2(CO)6 linked by Re-S-Re bridges, where S is the thiolate sulfur of the N,S-bidentate ligand. This Re(I) complex is the first metal carbonyl complex with a bidentate dithiocarbazate ligand to have been characterized by XRD. Cytotoxicity assays revealed enhancement of the bioactivity of SBCM-H upon complexation. Both Cu(II) and Re(I) complexes are found to be active against human breast adenocarcinoma cancer cell lines MDA-MB-231 and MCF-7. Graphical Abstract: TOC diagram [Figure not available: see fulltext.] © 2015 Springer Science+Business Media New York.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Cu(II), Zn(II) and Re(I) complexes have been synthesized with the Schiff base, N′-[1-(2-oxo-2H-chromen-3-yl)-ethylidene]-hydrazinecarbodithioic acid benzyl ester (SBCM-H) which was prepared by condensation of S-benzyldithiocarbazate and 3-acetylcoumarin. The metal complexes were characterized on the basis of various physico-chemical and spectroscopic techniques including elemental analysis and electrochemical studies, and FT-IR, UV-Vis, NMR, EPR and mass spectroscopy. The Schiff base was found to behave as a bidentate ligand coordinating with Cu(II) and Zn(II) in the thiolate form with 1:2 metal to ligand stoichiometry. Crystals suitable for X-ray diffractometry (XRD) were obtained from the reaction of ReCl(CO)5 with SBCM-H forming a centrosymmetric dimeric complex Re2L2(CO)6 linked by Re-S-Re bridges, where S is the thiolate sulfur of the N,S-bidentate ligand. This Re(I) complex is the first metal carbonyl complex with a bidentate dithiocarbazate ligand to have been characterized by XRD. Cytotoxicity assays revealed enhancement of the bioactivity of SBCM-H upon complexation. Both Cu(II) and Re(I) complexes are found to be active against human breast adenocarcinoma cancer cell lines MDA-MB-231 and MCF-7. Graphical Abstract: TOC diagram [Figure not available: see fulltext.] © 2015 Springer Science+Business Media New York. |
Metal-carbonyl units for vibrational and luminescence imaging: Towards multimodality Article de journal S Clède; C Policar Chemistry - A European Journal, 21 (3), p. 942–958, 2015. @article{Clede:2015, title = {Metal-carbonyl units for vibrational and luminescence imaging: Towards multimodality}, author = {S Cl\`{e}de and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84920784874&doi=10.1002%2fchem.201404600&partnerID=40&md5=eaf7654638733b121ed1fe744e71b7b5}, doi = {10.1002/chem.201404600}, year = {2015}, date = {2015-01-01}, journal = {Chemistry - A European Journal}, volume = {21}, number = {3}, pages = {942--958}, abstract = {Metal-carbonyl complexes are attractive structures for bio-imaging. In addition to unique vibrational properties due to the CO moieties enabling IR and Raman cell imaging, the appropriate choice of ancillary ligands opens up the opportunity for luminescence detection. Through a classification by techniques, past and recent developments in the application of metal-carbonyl complexes for vibrational and luminescence bio-imaging are reviewed. Finally, their potential as bimodal IR and luminescent probes is addressed. © 2015 Wiley-VCH Verlag GmbH & Co. KGaA.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Metal-carbonyl complexes are attractive structures for bio-imaging. In addition to unique vibrational properties due to the CO moieties enabling IR and Raman cell imaging, the appropriate choice of ancillary ligands opens up the opportunity for luminescence detection. Through a classification by techniques, past and recent developments in the application of metal-carbonyl complexes for vibrational and luminescence bio-imaging are reviewed. Finally, their potential as bimodal IR and luminescent probes is addressed. © 2015 Wiley-VCH Verlag GmbH & Co. KGaA. |
An easy-to-detect nona-arginine peptide for epidermal targeting Article de journal S Clède; N Delsuc; C Laugel; F Lambert; C Sandt; A Baillet-Guffroy; C Policar Chemical Communications, 51 (13), p. 2687–2689, 2015. @article{Clede:2015a, title = {An easy-to-detect nona-arginine peptide for epidermal targeting}, author = {S Cl\`{e}de and N Delsuc and C Laugel and F Lambert and C Sandt and A Baillet-Guffroy and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84922637409&doi=10.1039%2fc4cc08737b&partnerID=40&md5=a0e333e8498570e4d4ceb500066d9c1e}, doi = {10.1039/c4cc08737b}, year = {2015}, date = {2015-01-01}, journal = {Chemical Communications}, volume = {51}, number = {13}, pages = {2687--2689}, abstract = {A correlative approach combining synchrotron radiation based IR microscopy and fluorescence microscopy enabled the successful detection and quantification of a nona-arginine peptide labelled with a Single Core Multimodal Probe for Imaging (SCoMPI) in skin biopsies. The topical penetration of the conjugate appeared to be time dependent and occurred most probably via the extracellular matrix. This journal is © The Royal Society of Chemistry 2015.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A correlative approach combining synchrotron radiation based IR microscopy and fluorescence microscopy enabled the successful detection and quantification of a nona-arginine peptide labelled with a Single Core Multimodal Probe for Imaging (SCoMPI) in skin biopsies. The topical penetration of the conjugate appeared to be time dependent and occurred most probably via the extracellular matrix. This journal is © The Royal Society of Chemistry 2015. |
Fast magnetically driven electrodeposition of amorphous metal oxide water oxidation catalysts from carbon-coated metallic nanoparticles Article de journal J Zhu; F Lambert; C Policar; F Mavré; B Limoges Journal of Materials Chemistry A, 3 (31), p. 16190–16197, 2015. @article{Zhu:2015, title = {Fast magnetically driven electrodeposition of amorphous metal oxide water oxidation catalysts from carbon-coated metallic nanoparticles}, author = {J Zhu and F Lambert and C Policar and F Mavr\'{e} and B Limoges}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84938100019&doi=10.1039%2fc5ta03430b&partnerID=40&md5=ac4e0e0dc5c94a4c574b14d5b17ac552}, doi = {10.1039/c5ta03430b}, year = {2015}, date = {2015-01-01}, journal = {Journal of Materials Chemistry A}, volume = {3}, number = {31}, pages = {16190--16197}, abstract = {We report a new approach for efficient electrodeposition of amorphous metal oxide water oxidation catalysts on an electrode surface. A catalytic metal-based film was obtained by means of anodic oxidation of metallic nanoparticles, namely carbon-coated cobalt nanoparticles or carbon-coated nickel nanoparticles. Interestingly, these particles are intrinsically conductive and possess magnetic properties which make it easy to collect them on an electrode surface using a simple magnet to form a porous conductive particulate film. Upon anodic polarization in an appropriate electrolyte, the particulate film is rapidly converted into an amorphous metal-based catalytic film that efficiently catalyzes the oxidation of water at neutral pH. Compared to Nocera's method based on anodic electrodeposition of a metal salt in solution, this new electrodeposition strategy offers the key advantage of supplying metal ions in a solid and metallic form, leading to a fast release of high local concentrations of metal ions right at the spot of the film formation (i.e., in the vicinity of the electrode surface). This plays a decisive role in the formation rate of the catalytic film, allowing the deposition of the oxygen-evolving catalyst in a remarkably short-time. Moreover, the methodology can be easily extended to a wide range of metal particles of different nature and sizes, and also to their mixtures, finally offering a new degree of flexibility and opportunities not only in the preparation of metal-based water oxidation catalysts, but also in the preparation of inorganic metal-based catalysts for hydrogen or oxygen evolution. © 2015 The Royal Society of Chemistry.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We report a new approach for efficient electrodeposition of amorphous metal oxide water oxidation catalysts on an electrode surface. A catalytic metal-based film was obtained by means of anodic oxidation of metallic nanoparticles, namely carbon-coated cobalt nanoparticles or carbon-coated nickel nanoparticles. Interestingly, these particles are intrinsically conductive and possess magnetic properties which make it easy to collect them on an electrode surface using a simple magnet to form a porous conductive particulate film. Upon anodic polarization in an appropriate electrolyte, the particulate film is rapidly converted into an amorphous metal-based catalytic film that efficiently catalyzes the oxidation of water at neutral pH. Compared to Nocera's method based on anodic electrodeposition of a metal salt in solution, this new electrodeposition strategy offers the key advantage of supplying metal ions in a solid and metallic form, leading to a fast release of high local concentrations of metal ions right at the spot of the film formation (i.e., in the vicinity of the electrode surface). This plays a decisive role in the formation rate of the catalytic film, allowing the deposition of the oxygen-evolving catalyst in a remarkably short-time. Moreover, the methodology can be easily extended to a wide range of metal particles of different nature and sizes, and also to their mixtures, finally offering a new degree of flexibility and opportunities not only in the preparation of metal-based water oxidation catalysts, but also in the preparation of inorganic metal-based catalysts for hydrogen or oxygen evolution. © 2015 The Royal Society of Chemistry. |
Entasis through Hook-and-Loop fastening in a glycoligand with cumulative weak forces stabilizing CuI Article de journal L Garcia; F Cisnetti; N Gillet; R Guillot; M Aumont-Nicaise; J -P Piquemal; M Desmadril; F Lambert; C Policar Journal of the American Chemical Society, 137 (3), p. 1141–1146, 2015. @article{Garcia:2015, title = {Entasis through Hook-and-Loop fastening in a glycoligand with cumulative weak forces stabilizing CuI}, author = {L Garcia and F Cisnetti and N Gillet and R Guillot and M Aumont-Nicaise and J -P Piquemal and M Desmadril and F Lambert and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84921832039&doi=10.1021%2fja510259p&partnerID=40&md5=eb31b469985f0f4759bf0f0869f067c9}, doi = {10.1021/ja510259p}, year = {2015}, date = {2015-01-01}, journal = {Journal of the American Chemical Society}, volume = {137}, number = {3}, pages = {1141--1146}, abstract = {The idea of a possible control of metal ion properties by constraining the coordination sphere geometry was introduced by Vallee and Williams with the concept of entasis, which is frequently postulated to be at stake in metallobiomolecules. However, the interactions controlling the geometry at metal centers remain often elusive. In this study, the coordination properties toward copper ions - CuII or CuI - of a geometrically constrained glycoligand centered on a sugar scaffold were compared with those of an analogous ligand built on an unconstrained alkyl chain. The sugar-centered ligand was shown to be more preorganized for CuII coordination than its open-chain analogue, with an unusual additional stabilization of the CuI redox state. This preference for CuI was suggested to arise from geometric constraints favoring an optimized folding of the glycoligand minimizing steric repulsions. In other words, the CuI d10 species is stabilized by valence shell electron pair repulsion (VSEPR). This idea was rationalized by a theoretical noncovalent interactions (NCI) analysis. The cumulative effects of weak forces were shown to create an efficient buckle as in a hook-and-loop fastener, and fine structural features within the glycoligand reduce repulsive interactions for the CuI state. This study emphasizes that monosaccharide platforms are appropriate ligand backbones for a delicate geometric control at the metal center, with a network of weak interactions within the ligand. This structuration availing in glycoligands makes them attractive for metallic entasis. © 2015 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The idea of a possible control of metal ion properties by constraining the coordination sphere geometry was introduced by Vallee and Williams with the concept of entasis, which is frequently postulated to be at stake in metallobiomolecules. However, the interactions controlling the geometry at metal centers remain often elusive. In this study, the coordination properties toward copper ions - CuII or CuI - of a geometrically constrained glycoligand centered on a sugar scaffold were compared with those of an analogous ligand built on an unconstrained alkyl chain. The sugar-centered ligand was shown to be more preorganized for CuII coordination than its open-chain analogue, with an unusual additional stabilization of the CuI redox state. This preference for CuI was suggested to arise from geometric constraints favoring an optimized folding of the glycoligand minimizing steric repulsions. In other words, the CuI d10 species is stabilized by valence shell electron pair repulsion (VSEPR). This idea was rationalized by a theoretical noncovalent interactions (NCI) analysis. The cumulative effects of weak forces were shown to create an efficient buckle as in a hook-and-loop fastener, and fine structural features within the glycoligand reduce repulsive interactions for the CuI state. This study emphasizes that monosaccharide platforms are appropriate ligand backbones for a delicate geometric control at the metal center, with a network of weak interactions within the ligand. This structuration availing in glycoligands makes them attractive for metallic entasis. © 2015 American Chemical Society. |
Control of brain patterning by engrailed paracrine transfer: A new function of the pbx interaction domain Article de journal C Rampon; C Gauron; T Lin; F Meda; E Dupont; A Cosson; E Ipendey; A Frerot; I Aujard; T Le Saux; D Bensimon; L Jullien; M Volovitch; S Vriz; A Joliot Development (Cambridge), 142 (10), p. 1840–1849, 2015. @article{Rampon:2015, title = {Control of brain patterning by engrailed paracrine transfer: A new function of the pbx interaction domain}, author = {C Rampon and C Gauron and T Lin and F Meda and E Dupont and A Cosson and E Ipendey and A Frerot and I Aujard and T Le Saux and D Bensimon and L Jullien and M Volovitch and S Vriz and A Joliot}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84929206944&doi=10.1242%2fdev.114181&partnerID=40&md5=016ff1da90c2292976a12fee82b3ed59}, doi = {10.1242/dev.114181}, year = {2015}, date = {2015-01-01}, journal = {Development (Cambridge)}, volume = {142}, number = {10}, pages = {1840--1849}, abstract = {Homeoproteins of the Engrailed family are involved in the patterning of mesencephalic boundaries through a mechanism classically ascribed to their transcriptional functions. In light of recent reports on the paracrine activity of homeoproteins, including Engrailed, we asked whether Engrailed intercellular transfer was also involved in brain patterning and boundary formation. Using time-controlled activation of Engrailed combined with tools that block its transfer, we show that the positioning of the diencephalic-mesencephalic boundary (DMB) requires Engrailed paracrine activity. Both zebrafish Eng2a and Eng2b are competent for intercellular transfer in vivo, but only extracellular endogenous Eng2b, and not Eng2a, participates in DMB positioning. In addition, disruption of the Pbx-interacting motif in Engrailed, known to strongly reduce the gain-of-function phenotype, also downregulates Engrailed transfer, thus revealing an unsuspected participation of the Pbx interaction domain in this pathway. © 2015. Published by The Company of Biologists Ltd.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Homeoproteins of the Engrailed family are involved in the patterning of mesencephalic boundaries through a mechanism classically ascribed to their transcriptional functions. In light of recent reports on the paracrine activity of homeoproteins, including Engrailed, we asked whether Engrailed intercellular transfer was also involved in brain patterning and boundary formation. Using time-controlled activation of Engrailed combined with tools that block its transfer, we show that the positioning of the diencephalic-mesencephalic boundary (DMB) requires Engrailed paracrine activity. Both zebrafish Eng2a and Eng2b are competent for intercellular transfer in vivo, but only extracellular endogenous Eng2b, and not Eng2a, participates in DMB positioning. In addition, disruption of the Pbx-interacting motif in Engrailed, known to strongly reduce the gain-of-function phenotype, also downregulates Engrailed transfer, thus revealing an unsuspected participation of the Pbx interaction domain in this pathway. © 2015. Published by The Company of Biologists Ltd. |
Photoswitching Kinetics and Phase-Sensitive Detection Add Discriminative Dimensions for Selective Fluorescence Imaging Article de journal Jérôme Querard; Tal-Zvi Markus; Marie-Aude Plamont; Carole Gauron; Pengcheng Wang; Agathe Espagne; Michel Volovitch; Sophie Vriz; Vincent Croquette; Arnaud Gautier; Thomas Le Saux; Ludovic Jullien Angewandte Chemie International Edition, 54 (9), p. 2633-2637, 2015, ISSN: 1433-7851. @article{RN43b, title = {Photoswitching Kinetics and Phase-Sensitive Detection Add Discriminative Dimensions for Selective Fluorescence Imaging}, author = {J\'{e}r\^{o}me Querard and Tal-Zvi Markus and Marie-Aude Plamont and Carole Gauron and Pengcheng Wang and Agathe Espagne and Michel Volovitch and Sophie Vriz and Vincent Croquette and Arnaud Gautier and Thomas Le Saux and Ludovic Jullien}, doi = {10.1002/anie.201408985}, issn = {1433-7851}, year = {2015}, date = {2015-01-01}, journal = {Angewandte Chemie International Edition}, volume = {54}, number = {9}, pages = {2633-2637}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
2014 |
PMI: a $Delta$$Psi$m independent pharmacological regulator of mitophagy Article de journal Daniel A East; Francesca Fagiani; James Crosby; Nikolaos D Georgakopoulos; Hélène Bertrand; Marjolein Schaap; Adrian Fowkes; Geoff Wells; Michelangelo Campanella Chemistry & biology, 21 (11), p. 1585–1596, 2014, ISSN: 1879-1301. @article{East2014, title = {PMI: a $Delta$$Psi$m independent pharmacological regulator of mitophagy}, author = {Daniel A East and Francesca Fagiani and James Crosby and Nikolaos D Georgakopoulos and H\'{e}l{\`{e}}ne Bertrand and Marjolein Schaap and Adrian Fowkes and Geoff Wells and Michelangelo Campanella}, url = {https://www.ncbi.nlm.nih.gov/pubmed/25455860 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245710/}, doi = {10.1016/j.chembiol.2014.09.019}, issn = {1879-1301}, year = {2014}, date = {2014-11-01}, journal = {Chemistry & biology}, volume = {21}, number = {11}, pages = {1585--1596}, publisher = {Elsevier}, abstract = {Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential ($Delta$$Psi$m) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent. We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing $Delta$$Psi$m and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of $Delta$$Psi$m by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential ($Delta$$Psi$m) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent. We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing $Delta$$Psi$m and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of $Delta$$Psi$m by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy. |
Influence of the side-chain length on the cellular uptake and the cytotoxicity of rhenium triscarbonyl derivatives: A bimodal infrared and luminescence quantitative study Article de journal S Clède; F Lambert; R Saint-Fort; M -A Plamont; H Bertrand; A Vessières; C Policar Chemistry - A European Journal, 20 (28), p. 8714–8722, 2014. @article{Clede:2014, title = {Influence of the side-chain length on the cellular uptake and the cytotoxicity of rhenium triscarbonyl derivatives: A bimodal infrared and luminescence quantitative study}, author = {S Cl\`{e}de and F Lambert and R Saint-Fort and M -A Plamont and H Bertrand and A Vessi\`{e}res and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84903724808&doi=10.1002%2fchem.201402471&partnerID=40&md5=7334edd420d748a4418df936173a79b9}, doi = {10.1002/chem.201402471}, year = {2014}, date = {2014-01-01}, journal = {Chemistry - A European Journal}, volume = {20}, number = {28}, pages = {8714--8722}, abstract = {Rhenium triscarbonyl complexes fac-[Re(CO)3(NtextasciicircumN)] with appropriate ancillary NtextasciicircumN ligands are relevant for fluorescent bio-imaging. Recently, we have shown that [Re(CO)3] cores can also be efficiently mapped inside cells using their IR signature and that they can thus be used in a bimodal approach. To describe them we have coined the term SCoMPIs for single-core multimodal probes for imaging. In the context of the use of these SCoMPIs in bio-imaging, the questions of their cellular uptake and cytotoxicity are critical. We report here a series of compounds derived from the [Re(CO) 3Cl(pyta)] core (pyta=4-(2-pyridyl)-1,2,3-triazole). The pyta ligand is of interest because it can be easily functionalized. Aliphatic side chains (C4, C8, and C12) were appended to this core. A correlative study involving IR and luminescence was performed to monitor and quantify their cellular internalization. We studied the relationship between lipophilicity (log P(o/w)), cytotoxicity (IC50), and cellular uptake, and we showed that both uptake and cytotoxicity increase with the length of the side chain, with a higher uptake for the C12 derivative. This study stresses the distinction that has to be made between apparent toxicity, determined as an incubation concentration IC50, and intrinsic toxicity. Indeed, the intrinsic toxicity of a compound can remain hidden if it is not cell permeable. Therefore it must be kept in mind that IC50 values are composite values, reflecting both cellular uptake and intrinsic toxicity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Rhenium triscarbonyl complexes fac-[Re(CO)3(NtextasciicircumN)] with appropriate ancillary NtextasciicircumN ligands are relevant for fluorescent bio-imaging. Recently, we have shown that [Re(CO)3] cores can also be efficiently mapped inside cells using their IR signature and that they can thus be used in a bimodal approach. To describe them we have coined the term SCoMPIs for single-core multimodal probes for imaging. In the context of the use of these SCoMPIs in bio-imaging, the questions of their cellular uptake and cytotoxicity are critical. We report here a series of compounds derived from the [Re(CO) 3Cl(pyta)] core (pyta=4-(2-pyridyl)-1,2,3-triazole). The pyta ligand is of interest because it can be easily functionalized. Aliphatic side chains (C4, C8, and C12) were appended to this core. A correlative study involving IR and luminescence was performed to monitor and quantify their cellular internalization. We studied the relationship between lipophilicity (log P(o/w)), cytotoxicity (IC50), and cellular uptake, and we showed that both uptake and cytotoxicity increase with the length of the side chain, with a higher uptake for the C12 derivative. This study stresses the distinction that has to be made between apparent toxicity, determined as an incubation concentration IC50, and intrinsic toxicity. Indeed, the intrinsic toxicity of a compound can remain hidden if it is not cell permeable. Therefore it must be kept in mind that IC50 values are composite values, reflecting both cellular uptake and intrinsic toxicity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Electrochemical formation and reactivity of a manganese peroxo complex: Acid driven Ħ2O2 generation vs. O-O bond cleavage Article de journal H Y V Ching; E Anxolabéhère-Mallart; H E Colmer; C Costentin; P Dorlet; T A Jackson; C Policar; M Robert Chemical Science, 5 (6), p. 2304–2310, 2014. @article{Ching:2014, title = {Electrochemical formation and reactivity of a manganese peroxo complex: Acid driven {H}2O2 generation vs. O-O bond cleavage}, author = {H Y V Ching and E Anxolab\'{e}h\`{e}re-Mallart and H E Colmer and C Costentin and P Dorlet and T A Jackson and C Policar and M Robert}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84900329910&doi=10.1039%2fc3sc53469c&partnerID=40&md5=8b4ecc598d6455d82b1681e608484bc1}, doi = {10.1039/c3sc53469c}, year = {2014}, date = {2014-01-01}, journal = {Chemical Science}, volume = {5}, number = {6}, pages = {2304--2310}, abstract = {The formation of a side-on peroxo [MnIIIL(O2)] complex (L = phenolato-containing pentadentate ligand), resulting from the reaction of electrochemically reduced O2 and [MnIIL] +, is monitored in DMF using cyclic voltammetry, low temperature electronic absorption spectroscopy and electron paramagnetic resonance spectroscopy. Mechanistic studies based on cyclic voltammetry reveal that upon addition of a strong acid the Mn-O bond is broken, resulting in the release of H2O2, whereas in the presence of a weak acid the O-O bond is cleaved via a concerted dissociative electron transfer. This dichotomy of M-O versus O-O bond cleavage is unprecedented for peroxomanganese(iii) complexes and the latter offers a route for electrochemical O2 activation by a manganese(ii) complex. This journal is © the Partner Organisations 2014.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The formation of a side-on peroxo [MnIIIL(O2)] complex (L = phenolato-containing pentadentate ligand), resulting from the reaction of electrochemically reduced O2 and [MnIIL] +, is monitored in DMF using cyclic voltammetry, low temperature electronic absorption spectroscopy and electron paramagnetic resonance spectroscopy. Mechanistic studies based on cyclic voltammetry reveal that upon addition of a strong acid the Mn-O bond is broken, resulting in the release of H2O2, whereas in the presence of a weak acid the O-O bond is cleaved via a concerted dissociative electron transfer. This dichotomy of M-O versus O-O bond cleavage is unprecedented for peroxomanganese(iii) complexes and the latter offers a route for electrochemical O2 activation by a manganese(ii) complex. This journal is © the Partner Organisations 2014. |
Conjugation of a new series of dithiocarbazate schiff base copper(II) complexes with vectors selected to enhance antibacterial activity Article de journal M L Low; L Maigre; P Dorlet; R Guillot; J -M Pagès; K A Crouse; C Policar; N Delsuc Bioconjugate Chemistry, 25 (12), p. 2269–2284, 2014. @article{Low:2014, title = {Conjugation of a new series of dithiocarbazate schiff base copper(II) complexes with vectors selected to enhance antibacterial activity}, author = {M L Low and L Maigre and P Dorlet and R Guillot and J -M Pag\`{e}s and K A Crouse and C Policar and N Delsuc}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84918505283&doi=10.1021%2fbc5004907&partnerID=40&md5=d51ad81235fa7fd9aec14b7acd2c908a}, doi = {10.1021/bc5004907}, year = {2014}, date = {2014-01-01}, journal = {Bioconjugate Chemistry}, volume = {25}, number = {12}, pages = {2269--2284}, abstract = {A new series of six Schiff bases derived from S-methyldithiocarbazate (SMDTC) and S-benzyldithiocarbazate (SBDTC) with methyl levulinate (SMML, SBML), levulinic acid (SMLA, SBLA), and 4-carboxybenzaldehyde (SM4CB, SB4CB) were reacted with copper(II), producing complexes of general formula MLtextlessinftextgreater2textless/inftextgreater (M = Cu(II)}, keywords = {}, pubstate = {published}, tppubtype = {article} } A new series of six Schiff bases derived from S-methyldithiocarbazate (SMDTC) and S-benzyldithiocarbazate (SBDTC) with methyl levulinate (SMML, SBML), levulinic acid (SMLA, SBLA), and 4-carboxybenzaldehyde (SM4CB, SB4CB) were reacted with copper(II), producing complexes of general formula MLtextlessinftextgreater2textless/inftextgreater (M = Cu(II) |
Apo-neocarzinostatin: A protein carrier for Cu(II) glycocomplexes and Cu(II) into U937 and HT29 cell lines Article de journal L Garcia; S Franzoni; F Mussi; M Aumont-Niçaise; H Bertrand; M Desmadril; G Pelosi; A Buschini; C Policar Journal of Inorganic Biochemistry, 135 , p. 40–44, 2014. @article{Garcia:2014, title = {Apo-neocarzinostatin: A protein carrier for Cu(II) glycocomplexes and Cu(II) into U937 and HT29 cell lines}, author = {L Garcia and S Franzoni and F Mussi and M Aumont-Ni\c{c}aise and H Bertrand and M Desmadril and G Pelosi and A Buschini and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84896943429&doi=10.1016%2fj.jinorgbio.2014.02.006&partnerID=40&md5=81ab9f0bb44feb00966cfb5735d8901a}, doi = {10.1016/j.jinorgbio.2014.02.006}, year = {2014}, date = {2014-01-01}, journal = {Journal of Inorganic Biochemistry}, volume = {135}, pages = {40--44}, abstract = {In the field of pharmaceuticals there is an increasing need for new delivery systems to overcome the issues of solubility, penetration, toxicity and drug resistance. One of the possible strategies is to use biocarriers such as proteins to encourage the cell-penetration of drugs. In this paper, the use of the apo-protein neocarzinostatin (apo-NCS) as a carrier-protein for two Cu(II) glycocomplexes, previously characterized, and Cu(II) ions was investigated. Its interaction with the metallic compounds was analyzed using microcalorimetry. The dissociation constants were shown to be in the micromolar range. The Cu(II) glycocomplexes, in absence of apo-NCS, were found to be cytotoxic in the U937 and HT29 cell lines whereas the corresponding glycoligands showed no toxicity. The leukemic cell line (U937) seems to be more sensitive to glycocomplexes than the colon cancer cell line (HT29). Interestingly, apo-NCS was shown to increase systematically the antiproliferative activity by a factor of 2 and 3 for Cu(II) glycocomplexes and Cu(II) respectively. The antiproliferative activity detected was not related to proteasome inhibition. This result stresses the importance of new molecular tools for the delivery of Cu(II) to tumor cells using non-covalent association with carriers proteins. © 2014 Elsevier Inc. All rights reserved.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In the field of pharmaceuticals there is an increasing need for new delivery systems to overcome the issues of solubility, penetration, toxicity and drug resistance. One of the possible strategies is to use biocarriers such as proteins to encourage the cell-penetration of drugs. In this paper, the use of the apo-protein neocarzinostatin (apo-NCS) as a carrier-protein for two Cu(II) glycocomplexes, previously characterized, and Cu(II) ions was investigated. Its interaction with the metallic compounds was analyzed using microcalorimetry. The dissociation constants were shown to be in the micromolar range. The Cu(II) glycocomplexes, in absence of apo-NCS, were found to be cytotoxic in the U937 and HT29 cell lines whereas the corresponding glycoligands showed no toxicity. The leukemic cell line (U937) seems to be more sensitive to glycocomplexes than the colon cancer cell line (HT29). Interestingly, apo-NCS was shown to increase systematically the antiproliferative activity by a factor of 2 and 3 for Cu(II) glycocomplexes and Cu(II) respectively. The antiproliferative activity detected was not related to proteasome inhibition. This result stresses the importance of new molecular tools for the delivery of Cu(II) to tumor cells using non-covalent association with carriers proteins. © 2014 Elsevier Inc. All rights reserved. |
Luminescence modulations of rhenium tricarbonyl complexes induced by structural variations Article de journal H C Bertrand; S Clède; R Guillot; F Lambert; C Policar Inorganic Chemistry, 53 (12), p. 6204–6223, 2014. @article{Bertrand:2014, title = {Luminescence modulations of rhenium tricarbonyl complexes induced by structural variations}, author = {H C Bertrand and S Cl\`{e}de and R Guillot and F Lambert and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84902530649&doi=10.1021%2fic5007007&partnerID=40&md5=f3030a715ad7c095b013503a9d5b44a8}, doi = {10.1021/ic5007007}, year = {2014}, date = {2014-01-01}, journal = {Inorganic Chemistry}, volume = {53}, number = {12}, pages = {6204--6223}, abstract = {Octahedral d6 low-spin Re(I) tricarbonyl complexes are of considerable interest as noninvasive imaging probes and have been deeply studied owing to their biological stability, low toxicity, large Stokes shifts, and long luminescence lifetimes. We reported recently the bimodal IR and luminescence imaging of a Re(I) tricarbonyl complex with a Pyta ligand (4-(2-pyridyl)-1,2,3-triazole) in cells and labeled such metal-carbonyl complexes SCoMPIs for single-core multimodal probes for imaging. Re(I) tricarbonyl complexes have unique photophysical properties allowing for their unequivocal detection in cells but also present some weaknesses such as a very low luminescence quantum yield in aqueous medium. Further optimizations would thus be desirable. We therefore developed new Re(I) tricarbonyl complexes prepared from different ancillary ligands. Complexes with benzothiadiazole- triazole ligands show interesting luminescent quantum yields in acetonitrile and may constitute valuable luminescent metal complexes in organic media. A series of complexes with bidentate 1-(2-quinolinyl)-1,2,3-triazole (Taquin) and 1-(2-pyridyl)-1,2,3-triazole (Tapy) ligands bearing various 4-substituted alkyl side chains has been designed and synthesized with efficient procedures. Their photophysical properties have been characterized in acetonitrile and in a H 2O/DMSO (98/2) mixture and compared with those of the parent Quinta- and Pyta-based complexes. Tapy complexes bearing long alkyl chains show impressive enhancement of their luminescent properties relative to the parent Pyta complex. Theoretical calculations have been performed to further characterize this new class of rhenium tricarbonyl complexes. Preliminary cellular imaging studies in MDA-MB231 breast cancer cells reveal a strong increase in the luminescence signal in cells incubated with the Tapy complex substituted with a C12 alkyl chain. This study points out the interesting potential of the Tapy ligand in coordination chemistry, which has been so far underexploited. © 2014 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Octahedral d6 low-spin Re(I) tricarbonyl complexes are of considerable interest as noninvasive imaging probes and have been deeply studied owing to their biological stability, low toxicity, large Stokes shifts, and long luminescence lifetimes. We reported recently the bimodal IR and luminescence imaging of a Re(I) tricarbonyl complex with a Pyta ligand (4-(2-pyridyl)-1,2,3-triazole) in cells and labeled such metal-carbonyl complexes SCoMPIs for single-core multimodal probes for imaging. Re(I) tricarbonyl complexes have unique photophysical properties allowing for their unequivocal detection in cells but also present some weaknesses such as a very low luminescence quantum yield in aqueous medium. Further optimizations would thus be desirable. We therefore developed new Re(I) tricarbonyl complexes prepared from different ancillary ligands. Complexes with benzothiadiazole- triazole ligands show interesting luminescent quantum yields in acetonitrile and may constitute valuable luminescent metal complexes in organic media. A series of complexes with bidentate 1-(2-quinolinyl)-1,2,3-triazole (Taquin) and 1-(2-pyridyl)-1,2,3-triazole (Tapy) ligands bearing various 4-substituted alkyl side chains has been designed and synthesized with efficient procedures. Their photophysical properties have been characterized in acetonitrile and in a H 2O/DMSO (98/2) mixture and compared with those of the parent Quinta- and Pyta-based complexes. Tapy complexes bearing long alkyl chains show impressive enhancement of their luminescent properties relative to the parent Pyta complex. Theoretical calculations have been performed to further characterize this new class of rhenium tricarbonyl complexes. Preliminary cellular imaging studies in MDA-MB231 breast cancer cells reveal a strong increase in the luminescence signal in cells incubated with the Tapy complex substituted with a C12 alkyl chain. This study points out the interesting potential of the Tapy ligand in coordination chemistry, which has been so far underexploited. © 2014 American Chemical Society. |
Fourier transform infrared (FT-IR) spectromicroscopy to identify cell organelles: Correlation with fluorescence staining in MCF-7 breast cancer cells Article de journal S Clède; C Policar; C Sandt Applied Spectroscopy, 68 (1), p. 113–117, 2014. @article{Clede:2014a, title = {Fourier transform infrared (FT-IR) spectromicroscopy to identify cell organelles: Correlation with fluorescence staining in MCF-7 breast cancer cells}, author = {S Cl\`{e}de and C Policar and C Sandt}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84893060662&doi=10.1366%2f13-07139&partnerID=40&md5=f492b0918395dff47f71071460ac1f20}, doi = {10.1366/13-07139}, year = {2014}, date = {2014-01-01}, journal = {Applied Spectroscopy}, volume = {68}, number = {1}, pages = {113--117}, abstract = {Biomolecules display specific vibrational signatures in the infrared (IR) range, and organelles that concentrate these biomolecules can be identified by these IR signatures. Subcellular identification and location of cell organelles using IR signatures is attractive as it does not require the use of any specific trackers and is thus noninvasive and non-destructive. We show here that endogenous IR absorptions are relevant to detecting and imaging the nucleus, the cytoplasm, and the Golgi apparatus/endoplasmic reticulum in MCF- 7 breast cancer cells, and we compare these results with our previous work on the HeLa cell line. We correlate maps of fixed and dried cells obtained by synchrotron radiation Fourier transform infrared (SR FT-IR) spectromicroscopy with epifluorescence images using fluorescent trackers for Golgi apparatus and nucleus, namely BODIPY TR C5-ceramide complexed to BSA and DAPI, respectively. Interestingly, the ratios of the IR bands CH2:CH 3 (both asymmetric and symmetric) and CO(ester):amide I were shown to be reliable gauges of the lipidic character of a cellular compartment, the -CH2 and the CO(ester) absorptions increasing with the presence of inner membranes like in the Golgi apparatus. © 2014 Society for Applied Spectroscopy.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Biomolecules display specific vibrational signatures in the infrared (IR) range, and organelles that concentrate these biomolecules can be identified by these IR signatures. Subcellular identification and location of cell organelles using IR signatures is attractive as it does not require the use of any specific trackers and is thus noninvasive and non-destructive. We show here that endogenous IR absorptions are relevant to detecting and imaging the nucleus, the cytoplasm, and the Golgi apparatus/endoplasmic reticulum in MCF- 7 breast cancer cells, and we compare these results with our previous work on the HeLa cell line. We correlate maps of fixed and dried cells obtained by synchrotron radiation Fourier transform infrared (SR FT-IR) spectromicroscopy with epifluorescence images using fluorescent trackers for Golgi apparatus and nucleus, namely BODIPY TR C5-ceramide complexed to BSA and DAPI, respectively. Interestingly, the ratios of the IR bands CH2:CH 3 (both asymmetric and symmetric) and CO(ester):amide I were shown to be reliable gauges of the lipidic character of a cellular compartment, the -CH2 and the CO(ester) absorptions increasing with the presence of inner membranes like in the Golgi apparatus. © 2014 Society for Applied Spectroscopy. |