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Co-targeting CDK 4/6 and C-MYC/STAT3/CCND1 axis and inhibition of tumorigenesis and epithelial-mesenchymal-transition in triple negative breast cancer by Pt(II) complexes bearing NH3 as trans-co-ligand
No full textInternational audienceIn search of potential anticancer agents, we synthesized SNO-donor salicylaldimine main ligand-based Pt(II) complexes bearing NH as co-ligand at trans-position (C1-C6). These complexes showed similarity in structure with transplatin as the two N donor atoms of the main ligand and NH co-ligand were coordinated to Pt in trans position to each other. Each complex with different substituents on the main ligand was characterized thoroughly by detailed spectroscopic and spectrophotometric methods. Four of these complexes were studied in solid state by single crystal X-ray analysis. The stability of reference complex C1 was measured in solution state in DMSO‑d6 or its mixture with DO using H NMR methods. These complexes were further investigated for their anticancer activity in triple-negative-breast (TNBC) cells including MDA-MB-231, MDA-MB-468 and MDA-MB-436 cells. All these complexes showed satisfactory cytotoxic effect as revealed by the MTT results. Importantly, the highly active complex C4 anticancer effect was compared to the standard chemotherapeutic agents including cisplatin, oxaliplatin and 5-fluorouracil (5-FU). Functionally, C4 suppressed invasion, spheroids formation ability and clonogenic potential of cancer cells. C4 showed synergistic anticancer effect when used in combination with palbociclib, JQ1 and paclitaxel in TNBC cells. Mechanistically, C4 inhibited cyclin-dependent kinase (CDK)4/6 pathway and targeted the expressions of MYC/STAT3/CCND1/CNNE1 axis. Furthermore, C4 suppressed the EMT signaling pathway that suggested a role of C4 in the inhibition of TNBC metastasis. Our findings may pave further in detailed mechanistic study on these complexes as potential chemotherapeutic agents in different types of human cancers
Dynamics and Energetics of Ion Adsorption at the Interface between a Pure Ionic Liquid and Carbon Electrodes
No full textThis document is the Accepted Manuscript version of a Published Work that appeared in final form in The Journal of Physical Chemistry B, copyright © 2024 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jpcb.4c01192.International audienceMolecular dynamics simulations have been used extensively to determine equilibrium properties of the electrode–electrolyte interface in supercapacitors held at various potentials. While such studies are essential to understand and optimize the performance of such energy storage systems, investigation of the dynamics of adsorption during the charge of the supercapacitors is also necessary. Dynamical properties are especially important to get an insight into the power density of supercapacitors, one of their main assets. In this work, we propose a new method to coarse-grain simulations of all-atom systems and compute effective Lennard-Jones and Coulomb parameters, allowing subsequently to analyze the trajectories of adsorbing ions. We focus on pure 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide in contact with planar carbon electrodes. We characterize the evolution of the ion orientation and ion–electrode distance during adsorption and show that ions reorientate as they adsorb. We then determine the forces experienced by the adsorbing ions and demonstrate that Coulomb forces are dominant at a long range while van der Waals forces are dominant at a short range. We also show that there is an almost equal contribution from the two forces at an intermediate distance, explaining the peak of ion density close to the electrode surface
From Molecules to Devices: Effect of Pd-Catalyzed C–H Bond Arylation to Improve Metrics
No full textInternational audienceIn this study, we detail advancements in the design and application of neutral, arylated, cyclometalated iridium(III) complexes in the use of OLEDs. We utilized the “catalysis-on-the-complex” approach to directly arylate (C^N)2Ir(acac) [where C^N represents either 2-(2,4-difluorophenyl)pyridine or 2-(2,4-difluorophenyl)-5-methoxypyridine] through Pd-catalyzed C–H bond arylation with 4-bromobenzotrifluoride. The reaction regioselectivity occurred on both cyclometalated ligands at the C–H bonds flanked by two fluorine atoms. Photophysical measurements in solution indicated that while the emission energy remained unchanged (blue colors, λmax EL = 482–490 nm), a significant enhanced quantum yield was observed for arylated complex. Impressively, devices incorporating these complexes as green-blue emitters revealed that arylation also boosts device performance metrics in terms of luminance efficiency, external quantum efficiency (EQE), and brightness. In contrast, the introduction of methoxy substituent at the meta-position of the nitrogen–iridium bond yielded modest metrics. This study illustrates the crucial role of ligand design in the rational development of blue emitters
Understanding Na + Diffusion, Physicochemical Behavior, and Electrochemical Performance of a Gel Polymer Electrolyte
No full textInternational audienceGel polymer electrolytes (GPEs) represent a credible alternative to organic liquid electrolytes (LEs) for safer sodium metal batteries. As a compromise between solid polymer electrolytes and LEs, GPEs ensure a good ionic conductivity, improve the electrolyte/electrode interface, and prevent solvent leaks. Herein, a GPE based on acrylate-bifunctionalized polyethylene glycol chains mixed with an ether solvent (TEGDME) and a polyethylene glycol diacrylate (PEG600DA) in a 50/50 wt % ratio was prepared by ultraviolet photopolymerization. Sodium bis(fluorosulfonyl)imide salt (NaFSI) was added at different concentrations to study its interactions with the solvent and/or the cross-linked polymer. Infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and swelling ratio characterizations were combined to determine the physicochemical properties of the GPE. Complementary characterizations including electrochemical impedance spectroscopy, chronopotentiometry, and cyclic voltammetry allowed correlating the physicochemical properties of the GPE to its electrochemical performance. Then, improvements were obtained by careful combination of its components. The cross-linking agent allowed us to obtain a polymer matrix that traps the organic solvent and prevents leakage. Such a solvent inclusion reduces the rigidity of the membrane and lowers its viscosity, offering a room temperature ionic conductivity of 4.8 × 10–4 Ω–1 cm–1. The control of polymer’s tortuosity leads to a stable cycling vs sodium metal over several hundred hours without increase of the polarization. Finally, optimization of the salt loading plays a major role in electrostatic cross-linking, leading to an improvement of the mechanical properties of the GPE without reducing its conductivity
Garnet solid-state electrolyte: A new single-step elaboration by electric arc-melting
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Non-stoichiometry and electrochemical properties of lithiated iron hydroxysulfides
No full textInternational audienceLiFeOHS is a material with Li2(OH)2 layers intercalated between Fe2S2 planes. Its hydrothermal synthesis in various concentrations of LiOH yields materials with a high non-stoichiometry of the Li/Fe ratio which can be explained by partial substitution of Li+ for Fe2+ in the Li2(OH)2 layers. Thermogravimetry, X-ray diffraction and Mössbauer studies indicate that the charge balance is obtained by substitution of hydroxyl ions OH- by oxide ions O2-. This material has been tested as an electrode for lithium-ion batteries against lithium metal. Specific capacities above 200 mA h g-1 at C/10 are achieved, involving 1 lithium per chemical formula when cycled between 1 V and 3 V vs. lithium. The first irreversible discharge leads to the insertion of one lithium atom and the evolution of hydrogen gas while iron remains in its +2-oxidation state. An original Li2OFeS oxysulfide is formed. The following reversible oxidation/reduction cycles involve the Fe3+/Fe2+ redox couple between the two limiting compositions: Li2OFeIIS and LiOFeIIIS
Interplatform comparison between three ion mobility techniques for human plasma lipid collision cross sections
No full textInternational audienceThe implementation of ion mobility spectrometry (IMS) in liquid chromatography-high-resolution mass spectrometry (LC-HRMS) workflows has become a valuable tool for improving compound annotation in metabolomics analyses by increasing peak capacity and by adding a new molecular descriptor, the collision cross section (CCS). Although some studies reported high repeatability and reproducibility of CCS determination and only few studies reported good interplatform agreement for small molecules, standardized protocols are still missing due to the lack of reference CCS values and reference materials. We present a comparison of CCS values of approximatively one hundred lipid species either commercially available or extracted from human plasma. We used three different commercial ion mobility technologies from different laboratories, drift tube IMS (DTIMS), travelling wave IMS (TWIMS) and trapped IMS (TIMS), to evaluate both instrument repeatability and interlaboratory reproducibility. We showed that CCS discrepancies of 0.3% (average) could occur depending on the data processing software tools. Moreover, eleven CCS calibrants were evaluated yielding mean RSD below 2% for eight calibrants, ESI Low concentration tuning mix (Tune Mix) showing the lowest RSD ( < 0.5%) in both ion modes. Tune Mix calibrated CCS from the three different IMS instruments proved to be well correlated and highly reproducible (R 2 > 0.995 and mean RSD <= 1%). More than 90% of the lipid CCS had deviations of less than 1%, demonstrating high comparability between techniques, and the possibility to use the CCS as molecular descriptor. We highlighted the need of standardized procedures for calibration, data acquisition, and data processing. This work demonstrates that using harmonized analytical conditions are required for interplatform reproducibility for CCS determination of human plasma lipids
How Does Ferrocene Correlate with Ferroptosis? Multiple Approaches to Explore Ferrocene-Appended GPX4 Inhibitors as Anticancer Agents
No full textInternational audienceFerroptosis has emerged as a form of programmed cell death and exhibits remarkable promise for anticancer therapy. However, it is challenging to discover ferroptosis inducers with new chemotypes and high ferroptosis-inducing potency. Herein, we report a new series of ferrocenyl-appended GPX4 inhibitors rationally designed in a ‶one stone kills two birds″ strategy. Ferroptosis selectivity assays, GPX4 inhibitory activity and CETSA experiments validated the inhibition of novel compounds on GPX4. In particular, the ROS-related bioactivity assays highlighted the ROS-inducing ability of 17 at the molecular level and their ferroptosis enhancement at the cellular level. These data confirmed the dual role of ferrocene as both the bioisostere motif maintaining the inhibition capacity of certain molecules with GPX4 and also as the ROS producer to enhance the vulnerability to ferroptosis of cancer cells, thereby attenuating tumor growth in vivo. This proof-of-concept study of ferrocenyl-appended ferroptosis inducers via rational design may not only advance the development of ferroptosis-based anticancer treatment, but also illuminate the multiple roles of the ferrocenyl component, thus opening the way to novel bioorganometallics for potential disease therapies
Mechanically Ultra-Robust Fluorescent Elastomer for Elaborating Auxetic Composite
No full textInternational audienceFluorescent elastomers are predominantly fabricated through doping fluorescent components or conjugating chromophores into polymer networks, which often involves detrimental effects on mechanical performance and also makes large‐scale production difficult. Inspired by the heteroatom‐rich microphase separation structures assisted by intensive hydrogen bonds in natural organisms, an ultra‐robust fluorescent polyurethane elastomer is reported, which features a remarkable fracture strength of 87.2 MPa with an elongation of 1797%, exceptional toughness of 678.4 MJ m −3 and intrinsic cyan fluorescence at 445 nm. Moreover, the reversible fluorescence variation with temperature could in situ reveal the microphase separation of the elastomer in real time. By taking advantage of mechanical properties, intrinsic fluorescence and hydrogen bonds‐promoted interfacial bonding ability, this fluorescent elastomer can be utilized as an auxetic skeleton for the elaboration of an integrated auxetic composite. Compared with the auxetic skeleton alone, the integrated composite shows an improved mechanical performance while maintaining auxetic deformation in a large strain below 185%, and its auxetic process can be visually detected under ultraviolet light by the fluorescence of the auxetic skeleton. The concept of introducing hydrogen‐bonded heteroatom‐rich microphase separation structures into polymer networks in this work provides a promising approach to developing fluorescent elastomers with exceptional mechanical properties
Enhanced structure/function of mTSPO translocator in lipid:surfactant mixed micelles
No full textInternational audienceTSPO is a ubiquitous transmembrane protein used as a pharmacological marker in neuroimaging. The only known atomic structure of mammalian TSPOs comes from the solution NMR of mouse TSPO (mTSPO) bound to the PK11195 ligand and in a DPC surfactant environment. No structure is available in a biomimetic environment and without PK11195 which strongly stiffens the protein.We measured the effect of different amphiphilic environments on ligand-free mTSPO to study its structure/function and find optimal solubilization conditions. By replacing the SDS surfactant, where the recombinant protein is purified, with mixed lipid:surfactant (DMPC:DPC) micelles at different ratios (0:1, 1:2, and 2:1, w:w), the α-helix content and interactions and the intrinsic tryptophan (Trp) fluorescence of mTSPO are gradually increased.Small-angle X-ray scattering (SAXS) shows a more extended mTSPO/belt complex with the addition of lipids: Dmax ∼95 Å in DPC alone versus ∼142 Å in DMPC:DPC (1:2). SEC-MALLS shows that the molecular composition of the mTSPO belt is ∼98 molecules for DPC alone and ∼58 DMPC and ∼175 DPC for DMPC:DPC (1:2). Additionally, DMPC:DPC micelles stabilize mTSPO compared to DPC alone, where the protein has a greater propensity to aggregate. These structural changes are consistent with the increased affinity of mTSPO for the PK11195 ligand in presence of lipids (Kd ∼70 μM in DPC alone versus ∼0.91 μM in DMPC:DPC, 1:2), as measured by microscale thermophoresis (MST).In conclusion, mixed lipid:surfactant micelles open new possibilities for the stabilization of membrane proteins and for their study in solution in a more biomimetic amphiphilic environment