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A toolbox for enzymatic modification of nucleic acids with photosensitizers for photodynamic therapy
No full textInternational audiencePhotodynamic therapy (PDT) is an approved cancer treatment modality. Despite its high efficiency, PDT is limited in terms of specificity and by the poor solubility of the rather lipophilic photosensitizers (PSs). In order to alleviate these limitations, PSs can be conjugated to oligonucleotides. However, most conjugation methods often involve complex organic synthesis and result in the appendage of single modifications at the 3′/5′ termini of oligonucleotides. Here, we have investigated the possibility of bioconjugating a range of known PSs by polymerase-mediated synthesis. We have prepared a range of modified nucleoside triphosphates by different conjugation methods and investigated the substrate tolerance of these nucleotides for template-dependent and -independent DNA polymerases. This method represents a mild and versatile approach for the conjugation of single or multiple PSs onto oligonucleotides and can be useful to further improve the efficiency of the PDT treatment
One touch is all it takes: the supramolecular interaction between ubiquitin and lanthanide complexes revisited by paramagnetic NMR and molecular dynamics
No full textInternational audienceThe supramolecular interaction between lanthanide complexes and proteins is at the heart of numerous chemical and biological studies. Some of these complexes have demonstrated remarkable interaction properties with proteins or peptides in solution and in the crystalline state. Here we have used the paramagnetism of lanthanide ions to characterize the affinity of two lanthanide complexes for ubiquitin. As the interaction process is dynamic, the acquired NMR data only reflect the time average of the different steps. We have used molecular dynamics (MD) simulations to get a deeper insight into the detailed interaction scenario at the microsecond scale. This NMR/MD approach enabled us to establish that the tris-dipicolinate complex interacts specifically with arginines and lysines, while the crystallophore explores the protein surface through weak interactions with carboxylates. These observations shed new light on the dynamic interaction properties of these complexes, which will ultimately enable us to propose a crystallization mechanism
A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction through dual-targeting mitochondrial and nuclear G4 enriched genome
No full textInternational audienceAbstract Background G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored. Methods The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays. Results Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes’ transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy’s efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin. Conclusion This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy. Graphical Abstrac
Palladium‐Catalyzed/Mn(OAc) 3 ‐Mediated 1,2‐Diazidation and 1,2‐Acetoxy/Hydroxylation of N ‐Allyl Sulfonamides
No full textInternational audiencePalladium‐catalyzed conditions for diazidation or acetoxy/hydroxylation of N ‐allyl sulfonamides by using Pd(OAc) 2 as the catalyst combined with Mn(OAc) 3 ⋅ 2H 2 O have been developed. The 1,2‐diazidation reaction of the carbon‐carbon double bond occurs in mild conditions ( i. e . NaN 3 as azide source in THF at room temperature), whereas the 1,2‐acetoxy/hydroxylation requires an excess of Mn(OAc) 3 ⋅ 2H 2 O. The well‐known ability of this reagent to act through single‐electron transfer (SET) makes plausible a radical mechanism involving high valent palladium complexes
DFT study on Mo-stabilized passive films: Hydroxylation effects on chromium and iron oxide surfaces
No full textInternational audienceHydrous Cr2O3 and Fe2O3 surfaces without and with substitutional molybdenum were simulated by DFT modelling to investigate at the atomic scale the role of Mo in improving the corrosion resistance of passive films on stainless steels. The surface structures most energetically favoured were determined in the conditions of interest. For surfaces with a high degree of hydroxylation, the preferential location of substitutional Mo is just under the hydroxyl groups, in agreement with the experimental observations. The substitution by Mo is exothermic and Mo preferentially substitutes in Fe- than in Cr-rich zone of the inner barrier layer of passive films
Identification of Cellular Protein Targets of a Half-Sandwich Iridium(III) Complex Reveals Its Dual Mechanism of Action via Both Electrophilic and Oxidative Stresses
No full textInternational audienceIdentification of intracellular targets of anticancer drug candidates provides key information on their mechanism of action. Exploiting the ability of the anticancer (C∧N)-chelated half-sandwich iridium(III) complexes to covalently bind proteins, click chemistry with a bioorthogonal azido probe was used to localize a phenyloxazoline-chelated iridium complex within cells and profile its interactome at the proteome-wide scale. Proteins involved in protein folding and actin cytoskeleton regulation were identified as high-affinity targets. Upon iridium complex treatment, the folding activity of Heat Shock Protein HSP90 was inhibited in vitro and major cytoskeleton disorganization was observed. A wide array of imaging and biochemical methods validated selected targets and provided a multiscale overview of the effects of this complex on live human cells. We demonstrate that it behaves as a dual agent, inducing both electrophilic and oxidative stresses in cells that account for its cytotoxicity. The proposed methodological workflow can open innovative avenues in metallodrug discovery
Light-Induced, Structural Matrix Guided Stepwise Spin-State Switching in 3d-5d Molecular Assembly
No full textInternational audienceA new iron(II) molecular complex {[W(CN)8][Fe(bik*)3]2}BF4·7H2O·1.5CH3OH (1) was synthesized using versatile octacyanotungstate(V) building block and N-donor bidentate ligand (bik* = bis(1-ethyl-1H-imidazol-2-yl)ketone) and detailed characterization was carried out. The crystal structure of 1 is composed of the ionic salts of one anionic [W(CN)8]3- unit, two isolated cationic [Fe(bik*)3]2+ units and one BF4- counter ion in the asymmetric unit. Magnetic studies of 1 display interesting two-step reversible thermo-induced spin-state switching and photo-magnetic effect at low temperatures. Additionally, the physical properties of 1 were compared with the monomeric unit of {[Fe(bik*)3]2}4ReO4·H2O (2) and detailed photophysical studies were also carried out to investigate the effect of structural matrix {[W(CN)8]3- and ReO4- unit} on the spin-state switching properties of the [Fe(bik*)3]2+ unit on both systems (1 and 2)
Optimization of the Microstructure of Carbon Felt Electrodes by Applying the Lattice Boltzmann Method and Bayesian Optimizer
No full textIn this study, we propose a computational methodology to optimize the microstructure of the carbon felt electrode employed in redox flow batteries. Our optimization objective is to maximize the electrolyte utilization rate, which is affected by the fibrous electrode’s microstructure, in addition to the properties of the active species. The active surface area for the electron transfer process depends on the electrode microstructure, which is also critical for the convection of the electrolyte flow. By combining the stochastic generation of the electrode microstructure, the digital compression of the electrode, the Lattice Boltzmann Method, and the Bayesian optimization approach, we established our computational workflow that predicts an optimized set of parameters for electrode design. The optimization results demonstrate that a high compression ratio with thick aligned fibers favors better electrode performance. For a highly compressed felt electrode, the pore size generally decreases while a small amount of large-sized pores remain in the structure, facilitating the convection in the electrolyte flow. Due to the heterogeneous distribution of pores in the compressed felt electrode, the specific surface area and the hydraulic permeability are balanced to an optimized point
Increasing tap density of carbon-coated Na3V2(PO4)2F3 via mechanical grinding: good or bad idea?
No full textInternational audiencePolyanionic positive electrode materials such as Na3V2(PO4)2F3 are renowned for their exceptional rate performance and long-term stability during cycling. However, they present low tap densities that penalize the volumetric energy density when it comes to practical applications. In this study, we successfully increased the tap density of carbon-coated Na3V2(PO4)2F3 by 40% through mechanical grinding of dense particles previously obtained via the solid-state reaction, resulting in an impressively high tap density of 1.4 g/cm3. Comprehensive structural and microstructural investigations revealed that this mechanical process reduces both particle and crystallite sizes without affecting the structure or the composition of the active material. Besides extensive electrochemical experiments, including evaluation of capacity retention upon long-term cycling and at high rates, electrochemical impedance spectroscopy as well as self-discharge tests were conducted to assess the impact of the change in microstructure on the energy storage performance. Furthermore, thermal stability assessments of electrodes in contact with electrolytes and at different states of charge were also performed to complete the study and provide a complete overview of the influence of such mechanical grinding processes commonly employed in the field of energy storage
Mechanistic Insights to CO2 Adsorption and Activation on Hydroxylated Chromia (0001) surface
No full textInternational audienceIn the context of stainless-steel corrosion encountered during the transportation of CO2 in carbon capture, utilization and sequestration (CCUS), an attempt is made to apprehend the role of the hydroxylation of the surface of the chromia passive layer concerning the anhydrous Cr2O3 surface. A computational investigation is carried out for the CO2 interaction with chromia (0001) surface in the presence of water using periodic DFT+U methods. Different hydroxylation models (dissociated and molecularly adsorbed) of the chromia (0001) surface, and the mechanistic pathway for CO2 adsorption on hydroxylated chromia (0001), and further its protonation to form bicarbonate have been explored. Because of its high activation energy and endothermicity, the protonation of carbonate to bicarbonate species appears kinetically unfavorable at room temperature. However, the overall reaction profile for bicarbonate formation on hydroxylated chromia is exothermic. The charge density difference analysis of the charge transfer from the surface Cr atom to the O atoms of the CO2 molecule is followed by vibrational analysis to characterize the formation of adsorbed species. Moreover, preadsorbed water on the chromia surface enhances the surface activity for the adsorption of CO2. This study will serve as a basis to further investigate CO2 corrosion via point defect mechanism