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The very wide applications of LTA zeolites, e.g., tritiated water storage, imply that a precise atomic-scale description of the adsorption processes taking place in their structure is crucial.

Up to now the lipid bilayers were rarely considered as targets in cancer therapy despite pronounced differences in lipid composition between plasma membranes of benign and malignant cells. In this study we demonstrate that the lipid bilayer of the plasma membrane is druggable and suitable for facilitating selective delivery of amphiphilic gemcitabine-squalene nanomedicines to cancer cells. Data from radioactive assays, fluorescent membrane probes and molecular dynamics simulations provide evidence of selective accumulation of gemcitabine-squalene in the plasma membranes with disrupted lipid asymmetry and its subsequent preferential uptake by malignant cells. This causes pronounced cytotoxicity on cancer cells in comparison to their benign counterparts originating from the same tissue.

Pristine graphene, a range of graphene oxides, and silica substrates were used to investigate the effect of surface hydrophilicity on supported lipid bilayers by means of all-atom molecular dynamics simulations. Supported 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayers were found in close-contact conformations with hydrophilic substrates with as low as 5% oxidation level, while self-assembled monolayers occur on pure hydrophobic graphene only. Lipids and water at the surface undergo large redistribution to maintain the stability of the supported bilayers. Deposition of bicelles on increasingly hydrophilic substrates shows the continuous process of reshaping of the supported system and makes intermediate stages between self-assembled monolayers and supported bilayers. The bilayer thickness changes with hydrophilicity in a complex manner, while the number of water molecules per lipid in the hydration layer increases together with hydrophilicity.

The very wide range of applications of LTA zeolites, including the storage of tritiated water, implies that a detailed and accurate atomic-scale description of the adsorption processes taking place in their structure is crucial. To unravel with an unprecedented accuracy the mechanisms behind the water filling in NaA, we have conducted a systematic ab initio molecular dynamics investigation. Two LTA structural models, the conventional Z4A and the reduced one ZK4, have been used for static and dynamic ab initio calculations, respectively. After assessing this reduced model with comparative static DFT calculations, we start the filling of the α and β cages by water, molecule by molecule. This allowed us to thoroughly study the interaction of water molecules with the zeolite structure and between water molecules, progressively forming H-bond chains and ring patterns as the cage is being filled. The adsorption energies could then be calculated with an unprecedented accuracy, which showed that the interaction of the molecules with the zeolite weakens as their number increases. By these methods, we have been able to highlight the primary role of Na+ cations in the interaction of water with zeolite, and inversely, the role of water in the displacement of cations when it is sufficiently solvated, allowing the passage between the α and β cages. This phenomenon is possible thanks to the inhomogeneous distribution of water molecules on the cationic sites, as shown by our AIMD simulations, which allows the formation of water clusters. These results are important because they help in understanding how the coverage of cationic sites by water will affect the adsorption of other molecules inside the Na-LTA zeolite.

The composition of the plasma membrane of malignant cells is thought to influence the cellular uptake of cisplatin and to take part in developing resistance to this widespread anti-cancer drug. In this work we study the permeation of cisplatin through the model membranes of normal and cancer cells using molecular dynamics simulations. A special attention is paid to lipid asymmetry and cholesterol content of the membranes. The loss of lipid asymmetry, which is common for cancer cells, leads to a decrease in their permeability to cisplatin by one order of magnitude in comparison to the membranes of normal cells. The change in the cholesterol molar ratio from 0% to 33% also decreases the permeability of the membrane by approximately one order of magnitude. The permeability of pure DOPC membrane is 5–6 orders of magnitude higher than one of the membranes with realistic lipid composition, which makes it as an inadequate model for the studies of drug permeability.

Molecular modeling in pharmacology is a promising emerging tool for exploring drug interactions with cellular components. Recent advances in molecular simulations, big data analysis, and artificial intelligence (AI) have opened new opportunities for rationalizing drug interactions with their pharmacological targets. Despite the obvious utility and increasing impact of computational approaches, their development is not progressing at the same speed in different fields of pharmacology. Here, we review current in silico techniques used in cardiovascular diseases (CVDs), cardiological drug discovery, and assessment of cardiotoxicity. In silico techniques are paving the way to a new era in cardiovascular medicine, but their use somewhat lags behind that in other fields.

This work is motivated by the results obtained during a study on the tritiated water adsorbed in zeolite [L. Frances et al., J. Phys. Chem. C, 119, 28462 (2015)]. The decomposition of water by radiolysis leads to the production of dioxygen and dihydrogen as main stable products. By studying the evolution of their quantities of matter, one can note an increase in a first stage, followed by a decrease after a few hundred days of storage until complete disappearance. This interesting process depends on the water loading ratios, expressed in mass percentage, lying between 4%, and 19%; such a phenomenon is not observed in saturated zeolite. Our goal is to determine, through numerical simulations, how this disappearance, which is associated with the recombination of the radiolysis products, occurs by making a microscopic study on the adsorption of H2O, H2, and O2 molecules on 4A zeolite (Z4A). Computational physics is useful to understand the effects of molecule adsorption on its structure and also to closely examine the molecule-zeolite and molecule-molecule interactions. Indeed, different simulation methods are used from static to dynamic studies employing both quantum and classical tools with the periodical structure of Z4A. To summarize, the adsorption of molecules from the radiolysis of water are studied according to different points of view (quantum and classical) using various numerical simulation tools, such as density functional theory for ab initio structural optimization and energy calculation, Monte Carlo to study the distribution of the adsorbed molecules in the zeolite, and molecular dynamics to follow the evolution of the system (molecule + zeolite) over time depending on the temperature, in order to extract as much information as possible (structurally, statistically, energy, electronically) to understand the main problematic of this work: How do stable molecules issued from radiolysis recombine in Z4A?

free open access article 31 p.; International audience; In this work, we have explored natural unmodified low- and high-density lipoproteins (LDL and HDL) as selective delivery vectors in colorectal cancer therapy. We show in vitro in cultured cells and in vivo (NanoSPECT/CT) in the CT-26 mice colorectal cancer model that LDLs are mainly taken up by cancer cells, while HDLs are preferentially taken up by macrophages. We loaded LDLs with cisplatin and HDLs with the heat shock protein-70 inhibitor AC1LINNC, turning them into a pair of “Trojan horses” delivering drugs selectively to their target cells as demonstrated in vitro in human colorectal cancer cells and macrophages, and in vivo. Coupling of the drugs to lipoproteins and stability was assessed by mass and raman spectrometry analysis. Cisplatin vectorized in LDLs led to better tumor growth suppression with strongly reduced adverse effects such as a renal or liver toxicity. AC1LINNC vectorized into HDLs induced a strong oxidative burst in macrophages and innate anti-cancer immune response. Cumulative anti-tumor effect was observed for both drug-loaded lipoproteins. Altogether, our data show that lipoproteins from patient’s blood can be used as natural nanocarriers allowing cell specific targeting, paving the way toward more efficient, safer and personalized use of chemo-and immunotherapeutic drugs in cancer

International audience; Arginase is involved in a wide range of pathologies including cardiovascular diseases and infectious diseases whilst it is also a promising target to improve cancer immunotherapy. To date, only a limited number of inhibitors of arginase have been reported. Natural polyphenols, among them piceatannol, are moderate inhibitors of arginase. Herein, we report our efforts to investigate catechol binding by quantum chemistry and generate analogues of piceatannol. In this work, we synthesized a novel series of amino-polyphenols which were then evaluated as arginase inhibitors. Their structure–activity relationships were elucidated by deep quantum chemistry modelling. 4-((3,4-Dihydroxybenzyl)amino)benzene-1,2-diol 3t displays a mixed inhibition activity on bovine and human arginase I with IC50 (Ki) values of 76 (82) μM and 89 μM, respectively.

The development of elongated nanoparticles for drug delivery is of growing interest in recent years, due to longer blood circulation and improved efficacy compared to spherical counterparts. Squalenoyl-doxorubicin (SQ-Dox) conjugate was previously shown to form elongated nanoparticles with improved therapeutic efficacy and decreased toxicity compared to free doxorubicin. By using experimental and computational techniques, we demonstrate here that the specific physical properties of SQ-Dox, which include stacking and electrostatic interactions of doxorubicin as well as hydrophobic interactions of squalene, are involved in the formation of nanoassemblies with diverse elongated structures. We show that SQ-Dox bioconjugate concentration, ionic strength, and anion nature can be used to modulate the shape and stiffness of SQ-Dox nanoparticles. As those parameters are involved in nanoparticle behavior in biological media, these findings could bring interesting opportunities for drug delivery and serve as an example for the design of original nanodrugs with stacking properties tuned for particular clinical purposes.

International audience; In the field of nanomedicine, nanostructured nanoparticles (NPs) made of self-assembling prodrugs emerged in the recent years with promising properties. In particular, squalene-based drug nanoparticles have already shown their efficiency through in vivo experiments. However, a complete pattern of their stability and interactions in the blood stream is still lacking. In this work we assess the behavior of squalene-adenosine (SQAd) nanoparticles-whose neuroprotective effect has already been demonstrated in murine models-in the presence of fetal bovine serum (FBS) and of bovine serum albumin (BSA), the main protein of blood plasma. Extensive physicochemical characterizations were performed using Small Angle Neutron Scattering (SANS), cryogenic transmission electron microscopy (Cryo-TEM), circular dichroism (CD), steady-state fluorescence spectroscopy (SSFS) and isothermal titration calorimetry (ITC) and in silico by means of ensemble docking simulations with human serum albumin (HSA). Significant changes in the colloidal stability of the nanoparticles in the presence of serum albumin were observed. SANS, CD and SSFS analyses demonstrated an interaction 2 between SQAd and BSA, with a partial disassembly of the nanoparticles in the presence of BSA and the formation of a complex between SQAd and BSA. The interaction free energy of SQAd nanoparticles with BSA derived from ITC experiments, is about-8 kcal/mol which is further supported in silico by ensemble docking simulations. Overall, our results show that serum albumin partially disassembles SQAd nanoparticles by extracting individual SQAd monomers from them. As a consequence, the SQAd nanoparticles would act as a circulating reservoir in the blood stream. The approach developed in this study could be extended to other soft organic nanoparticles.

Interaction of platinum-based drugs with proteins containing sulphur amino acids is usually argued as one of the major reasons for the observed resistance to these drugs, mainly due to the deactivation of the native compounds by very efficient thiolation processes in the organism. In this work, we have investigated the detailed thermodynamics and kinetics of reaction between cisplatin cis-[PtCl2(NH3)2] and its major hydrolysed forms (monohydroxocisplatin cis-[PtCl(OH)(NH3)2] and monoaquacisplatin cis-[PtCl(H2O)(NH3)2]+) with various thiolates (methanethiolate, cysteine and glutathione) and methionine. We have used a demanding quantum chemistry approach at the MP2 and DFT levels of theory to determine the Gibbs free energies and the barrier of reactions of the most possible reaction paths. The substitution of the four ligands of the complexes studied here (Cl−, OH−, H2O and NH3) can either proceed by direct thiolations or bidentations. Our Raman spectroscopy measurements show that only two thiolations actually occur, although four are possible in principle. The reason could lie in the bidentation reactions eventually taking place after each thiolation, which is backed up by our computational results. The observed lability scale of the ligands under thiolate exposure was found to be in the following order H2O > Cl− ≈ NH3(trans) > NH3(cis) > OH−, the difference between ammine ligands being induced by a significant trans-labilization by thiolates. Finally, the S,N bidentation is shown to be preferred with respect to the S,O one.

In this work the permeability of a model asymmetric plasma membrane, for ions, water and the anti-cancer drugs cisplatin and gemcitabine is studied by means of all-atom molecular dynamics simulations. It is shown that permeability of the membranes increases from one to three orders of magnitude upon membrane bending depending on the compound and the sign of curvature. Our results show that the membrane curvature is an important factor which should be considered during evaluation of drug translocation.TOC GRAPHICS

Comptes Rendus Chimie - In Press.Proof corrected by the author Available online since jeudi 22 mars 2018

In this work, realistic models of membranes of normal and cancer cells are developed. A special focus is given to their cholesterol content. It is shown that the loss of lipid asymmetry in the membranes of cancer cells leads to a decrease of their permeability to cisplatin by one order of magnitude in comparison to the membranes of normal cells. The change of cholesterol molar ratio from 0% to 33% also decreases the permeability of the membrane by approximately one order of magnitude. The permeability of pure DOPC membrane is 5-6 orders of magnitude higher than one of the membrane with realistic lipid composition, which makes it as an inadequate model for the studies of drug permeability.

We have studied the interaction of three clinically promising squalenoylated drugs (gemcitabine-squalene, adenine-squalene, and doxorubicin-squalene) with low-density lipoproteins (LDL) by means of atomistic molecular dynamics simulations. It is shown that all studied squalenoylated drugs accumulate inside the LDL particles. This effect is promoted by the squalene moiety, which acts as an anchor and drives the hydrophilic drugs into the hydrophobic core of the LDL lipid droplet. Our data suggest that LDL particles could be a universal carriers of squalenoylated drugs in the bloodstream. Interaction of gemcitabine-squalene with human serum albumin (HSA) was also studied by ensemble of docking simulations. It is shown that HSA could also act as a passive carrier of this bioconjugate. It should be noted that the binding of squalene moiety to HSA was unspecific and did not occur in the binding pockets devoted to fatty acids.

STAT3 protein, which is known to be involved in cancer development, is a promising target for anticancer therapy. Successful inhibitors of STAT3 should not affect an activity of closely related protein STAT1, which makes their development challenging. The mechanisms of selectivity of several existing STAT3 inhibitors are not clear. In this work, we studied molecular mechanisms of selectivity of 13 experimentally tested STAT3 inhibitors by means of extensive molecular dynamics and ensemble docking simulations. It is shown that all studied inhibitors bind to the large part of the protein surface in an unspecific statistical manner. The binding to the dimerization interface of the SH2 domain, which is usually considered as the main target region, is not energetically preferable. Binding in this region is remarkably similar for STAT1 and STAT3 proteins and cannot explain experimentally observed selectivity toward STAT3. We propose a new mechanism of selectivity called "selectivity by distraction" for existing STAT3 inhibitors. This mechanism is based on equilibrium statistical partitioning of inhibitor molecules between protein domains. The unspecific binding of inhibitors to the DNA-binding and the coil-coil domains is stronger in STAT1 in comparison to STAT3 while the energies of their binding to SH2 domains are comparable. This "distracts" inhibitor molecules from the SH2 domain of STAT1 and leads to higher effective concentration of inhibitors in the vicinity of the SH2 domain of STAT3.

Interaction of fullerenes with asymmetric and curved DOPC/DOPS bicelles is studied by means of coarse-grained molecular dynamics simulations. The effects caused by asymmetric lipid composition of the membrane leaflets and the curvature of the membrane are analyzed. It is shown that the aggregates of fullerenes prefer to penetrate into the membrane in the regions of the moderately positive mean curvature. Upon penetration into the hydrophobic core of the membrane fullerenes avoid the regions of the extreme positive or the negative curvature. Fullerenes increase the ordering of lipid tails, which are in direct contact with them, but do not influence other lipids significantly. Our data suggest that the effects of the membrane curvature should be taken into account in the studies concerning permeability of the membranes to fullerenes and fullerene-based drug delivery systems.

International audience; Parameterization of molecular complexes containing a metallic compound, such as cisplatin, is challenging due to the unconventional coordination nature of the bonds which involve platinum atoms. In this work, we develop a new methodology of parameterization for such compounds based onquantum dynamics (QD) calculations. We show that the coordination bonds and angles are more flexible than in normal covalent compounds. The influence of explicit solvent is also shown to be crucial to determine the flexibility of cisplatin in quantum dynamics simulations. Two empirical topologies of cisplatin were produced by fitting its atomic fluctuations against QD in vacuum and QD with explicit first solvation shell of water molecules respectively. A third topology built in a standard way from the static optimized structure was used for comparison. The later one leads to an excessively rigid molecule and exhibits much smaller fluctuations of the bonds and angles than QD reveals. It is shown that accounting for thehigh flexibility of cisplatin molecule is needed for adequate description of its first hydration shell. MD simulations with flexible QD-based topology also reveal a significant decrease of the barrier of passive diffusion of cisplatin accross the model lipid bilayer. These results confirm that flexibility of organ-ometallic compounds is an important feature to be considered in classical molecular dynamics topologies. Proposed methodology based on QD simulations provides a systematic way of building such topologies.

The development of inhibitors blocking STAT3 transcriptional activity is a promising therapeutic approach against cancer and inflammatory diseases. In this context, the selectivity of inhibitors against the STAT1 transcription factor is crucial as STAT3 and STAT1 play opposite roles in the apoptosis of tumor cells and polarization of the immune response. A structure-based virtual screening followed by a luciferase-containing promoter assay on STAT3 and STAT1 signaling were used to identify a selective STAT3 inhibitor. An important role of the aminotetrazole group in modulating STAT3 and STAT1 inhibitory activities has been established. Optimization of the hit compound leads to 23. This compound inhibits growth and survival of cells with STAT3 signaling pathway while displaying a minimal effect on STAT1 signaling. Moreover, it prevents lymphocyte T polarization into Th17 and Treg without affecting their differentiation into Th1 lymphocyte.

International audience; The unfolding of the reduced human serum albumin (HSA) was simulated by generating four molecular dynamics (MD) trajectories of 160 ns each at 350, 375, 400, and 425 K, respectively. A principal components analysis (PCA) was performed on the four trajectories. Based on this analysis, 17 representative protein conformers were identified and subsequently used to construct a sequence of partially unfolded structures. They were ordered according to their decreasing α-helix fractions. The structural evolution in this unfolding sequence was found to be continuous at global but also at local level supporting the hypothesis that the protein unfolding pathway is not significantly dependent on the simulation temperature. As a result, the α-helix fraction of the protein appears to be a good reaction coordinate for the unfolding process, as it was previously suggested by experiments. Based on this observation, two conformers in the unfolding sequence were predicted to be close to the equilibrium structure of reduced HSA thus providing a first theoretical model for this protein form.

Membranes in cells are usually considered to act as physical barriers that allow compartmentalization and specialization of the intracellular medium. They are also highly dynamic assemblies, changing their shape, composition and properties on a variety of spatial and temporal scales. This dynamical reshaping of membranes occurs during different cell processes such as motion, division, differentiation and vesicle trafficking. Membranes must thus be sufficiently rigid and robust to maintain the integrity of the cell compartments and flexible enough to allow continuous changes of their shapes. Many of their properties like thermodynamic and mechanical properties have been elucidated on the basis of lipid self-organization arguments. However, many open questions remain concerning the links between membranes composition and their permeability to drugs. Determination of permeability of such membranes to drugs is indeed of great importance for toxicology reason, for addressing cell resistance issues to chemodrugs, but also for finding new strategies for targeting cells, especially cancer ones. In this thesis, we searched for chemical and physical features connected to membrane lipids that could help to differentiate cancer and normal cells and though be potential markers for selective targeting. We investigated three “main ingredients” that may play an important role on the membrane permeation to drugs, namely composition (lipids and cholesterol contents), curvature and asymmetry between leaflets of the lipid membranes. Two realistic models of “cancer” and “normal” lipid matrix of the plasma membranes were built to study the permeation of small molecules – especially cancer drugs. The modes of action and transport of cisplatin – one of the main anticancer drugs – were reviewed. Cisplatin permeation was addressed to understand thoroughly the interplay in between the membrane properties and the passive diffusion process.; Les membranes cellulaires sont généralement considérées comme des barrières physiques permettant la compartimentation et la spécialisation du milieu intracellulaire. Ce sont des systèmes dynamiques, dont la forme, la composition et les propriétés changent sur une large gamme des échelles de temps et d’espace. Ce remodelage des membranes a lieu au sein de différents processus cellulaires comme leur déplacement, leur différenciation ou encore le transport de vésicules. Les membranes doivent être suffisamment robustes et rigides pour maintenir l’intégrité de la cellule et dans le même temps, suffisamment flexibles pour permettre un continuel changement de forme. Plusieurs de leurs propriétés, telles que leurs propriétés thermodynamiques ou mécaniques ont été étudiées et associées à l’auto-organisation des lipides. Cependant, plusieurs questions restent ouvertes, en particulier en ce qui concerne le lien entre la composition des membranes et leur perméabilité face à des médicaments. La détermination de leur perméabilité est d’une grande importance pour des raisons toxicologiques, pour remédier à la problématique de résistance aux médicaments de chimiothérapie exprimée par certaines lignées cancéreuses, mais aussi dans le but de développer de nouvelles stratégies pour le ciblage cellulaire. Au cours de ce travail de thèse, nous avons recherché les propriétés chimiques et physiques connectées à la matrice lipidique des membranes plasmiques qui pourraient permettre de différencier les cellules cancéreuses des cellules saines et qui pourraient ainsi devenir de potentiels marqueurs pour un ciblage sélectif. Nous avons sélectionné trois principaux « ingrédients » qui sont susceptibles de jouer un rôle important sur la perméation : la composition de la membrane (en lipides et en cholestérol), la courbure de la membrane et l’asymétrie entre les monocouches de la membrane. Deux modèles réalistes de la matrice lipidique de la membrane plasmique de cellules cancéreuses et saines ont été construits pour étudier la perméation de petites molécules et particulièrement d’anticancéreux. Les modes d’action et de transport du cisplatine – l’un des médicaments anticancéreux les plus utilisés à ce jour – ont été étudié. Une analyse de la perméation du cisplatine a été menée pour comprendre la relation entre les différentes propriétés de la matrice lipidique de la membrane plasmique et sa diffusion passive.

Membranes in cells are usually considered to act as physical barriers that allow compartmentalization and specialization of the intracellular medium. They are also highly dynamic assemblies, changing their shape, composition and properties on a variety of spatial and temporal scales. This dynamical reshaping of membranes occurs during different cell processes such as motion, division, differentiation and vesicle trafficking. Membranes must thus be sufficiently rigid and robust to maintain the integrity of the cell compartments and flexible enough to allow continuous changes of their shapes. Many of their properties like thermodynamic and mechanical properties have been elucidated on the basis of lipid self-organization arguments. However, many open questions remain concerning the links between membranes composition and their permeability to drugs. Determination of permeability of such membranes to drugs is indeed of great importance for toxicology reason, for addressing cell resistance issues to chemodrugs, but also for finding new strategies for targeting cells, especially cancer ones. In this thesis, we searched for chemical and physical features connected to membrane lipids that could help to differentiate cancer and normal cells and though be potential markers for selective targeting. We investigated three “main ingredients” that may play an important role on the membrane permeation to drugs, namely composition (lipids and cholesterol contents), curvature and asymmetry between leaflets of the lipid membranes. Two realistic models of “cancer” and “normal” lipid matrix of the plasma membranes were built to study the permeation of small molecules – especially cancer drugs. The modes of action and transport of cisplatin – one of the main anticancer drugs – were reviewed. Cisplatin permeation was addressed to understand thoroughly the interplay in between the membrane properties and the passive diffusion process., Les membranes cellulaires sont généralement considérées comme des barrières physiques permettant la compartimentation et la spécialisation du milieu intracellulaire. Ce sont des systèmes dynamiques, dont la forme, la composition et les propriétés changent sur une large gamme des échelles de temps et d’espace. Ce remodelage des membranes a lieu au sein de différents processus cellulaires comme leur déplacement, leur différenciation ou encore le transport de vésicules. Les membranes doivent être suffisamment robustes et rigides pour maintenir l’intégrité de la cellule et dans le même temps, suffisamment flexibles pour permettre un continuel changement de forme. Plusieurs de leurs propriétés, telles que leurs propriétés thermodynamiques ou mécaniques ont été étudiées et associées à l’auto-organisation des lipides. Cependant, plusieurs questions restent ouvertes, en particulier en ce qui concerne le lien entre la composition des membranes et leur perméabilité face à des médicaments. La détermination de leur perméabilité est d’une grande importance pour des raisons toxicologiques, pour remédier à la problématique de résistance aux médicaments de chimiothérapie exprimée par certaines lignées cancéreuses, mais aussi dans le but de développer de nouvelles stratégies pour le ciblage cellulaire. Au cours de ce travail de thèse, nous avons recherché les propriétés chimiques et physiques connectées à la matrice lipidique des membranes plasmiques qui pourraient permettre de différencier les cellules cancéreuses des cellules saines et qui pourraient ainsi devenir de potentiels marqueurs pour un ciblage sélectif. Nous avons sélectionné trois principaux « ingrédients » qui sont susceptibles de jouer un rôle important sur la perméation : la composition de la membrane (en lipides et en cholestérol), la courbure de la membrane et l’asymétrie entre les monocouches de la membrane. Deux modèles réalistes de la matrice lipidique de la membrane plasmique de cellules cancéreuses et saines ont été construits pour étudier la perméation de petites molécules et particulièrement d’anticancéreux. Les modes d’action et de transport du cisplatine – l’un des médicaments anticancéreux les plus utilisés à ce jour – ont été étudié. Une analyse de la perméation du cisplatine a été menée pour comprendre la relation entre les différentes propriétés de la matrice lipidique de la membrane plasmique et sa diffusion passive.

The study of the reactions between thiolates and derivatives of cisplatin are key to improving the understanding of the behaviour of this anticancer drug. These reactions, namely thiolations (replacement of a ligand by a thiolate) or bidentations (replacement of another ligand by a second group of the considered thiolate), are involved in the mechanisms which give rise to the destruction of cancer cells. They are also involved in the development of resistance mechanisms towards the treatment. We have used quantum chemistry methods (Møller-Plesset perturbation theory at degree 2 (MP2) completed by large basis functions set) to build a robust theoretical study of the reactions between cisplatin (and its main hydrolyzed products) and some thiolates of biological interest, such as cysteine and glutathione. Kinetic and thermodynamic data obtained for both thiolations and bidentations shed light on the nature of the preferred chemical pathways. Our Raman spectroscopy measurements show that only two thiolations actually occur, possibly due to bidentation reactions eventually taking place after each thiolation. In addition, the S,N bidentation is shown to be preferred with respect to the S,O bidentation. Also, the lability scale of the ligands was found to be almost systematically H2O > Cl– ≈ NH3(trans) > NH3(cis) > OH–, the difference between ammine ligands being induced by a significant trans-labilization by thiolates, due to the trans effect inherent in the planar square structure of platinum (II) complexes., L’étude des réactions entre thiolates et dérivés du cisplatine est une étape essentielle pour améliorer la compréhension du comportement de ce médicament anti-cancéreux en milieu biologique. Ces réactions, qu’il s'agisse de thiolations (remplacement d'un ligand par un thiolate) ou de bidentations (remplacement d'un autre ligand par un second groupement du thiolate considéré), sont en effet impliquées à la fois dans les mécanismes de destruction des cellules cancéreuses et dans le développement de mécanismes de résistance vis-à-vis du traitement.À l’aide de simulations de chimie quantique à un niveau de théorie élevé (méthode de perturbationMøller-Plesset au degré 2 (MP2) et des jeux de fonctions de base très complets), nous avons mené une étude robuste et complète des réactions entre le cisplatine (et ses dérivés d’hydrolyse principaux) et des thiolates d’intérêt biologique comme la cystéine et le glutathion.Les caractéristiques cinétiques et thermodynamiques obtenues pour les thiolations et les bidentations permettent de mettre en lumière les chemins de réactions les plus probables. Nos résultats de spectroscopie Raman montrent également que deux thiolations au maximum peuvent avoir lieu, probablement en raison de bidentations après chaque thiolation. En outre, les bidentations S,N semblent favorisées par rapport aux bidentations S,O. Nous avons également observé de manière presque systématique l'échelle de labilité des ligands suivante : H2O > Cl– ≈ NH3(trans) > NH3(cis) > OH–. La différence entre les ammines vient d'une forte translabilisation par les thiolates, due à l’effet trans inhérent aux structures carrée plane des sels de platine (II).

The study of the reactions between thiolates and derivatives of cisplatin are key to improving the understanding of the behaviour of this anticancer drug. These reactions, namely thiolations (replacement of a ligand by a thiolate) or bidentations (replacement of another ligand by a second group of the considered thiolate), are involved in the mechanisms which give rise to the destruction of cancer cells. They are also involved in the development of resistance mechanisms towards the treatment. We have used quantum chemistry methods (Møller-Plesset perturbation theory at degree 2 (MP2) completed by large basis functions set) to build a robust theoretical study of the reactions between cisplatin (and its main hydrolyzed products) and some thiolates of biological interest, such as cysteine and glutathione. Kinetic and thermodynamic data obtained for both thiolations and bidentations shed light on the nature of the preferred chemical pathways. Our Raman spectroscopy measurements show that only two thiolations actually occur, possibly due to bidentation reactions eventually taking place after each thiolation. In addition, the S,N bidentation is shown to be preferred with respect to the S,O bidentation. Also, the lability scale of the ligands was found to be almost systematically H2O > Cl– ≈ NH3(trans) > NH3(cis) > OH–, the difference between ammine ligands being induced by a significant trans-labilization by thiolates, due to the trans effect inherent in the planar square structure of platinum (II) complexes.; L’étude des réactions entre thiolates et dérivés du cisplatine est une étape essentielle pour améliorer la compréhension du comportement de ce médicament anti-cancéreux en milieu biologique. Ces réactions, qu’il s'agisse de thiolations (remplacement d'un ligand par un thiolate) ou de bidentations (remplacement d'un autre ligand par un second groupement du thiolate considéré), sont en effet impliquées à la fois dans les mécanismes de destruction des cellules cancéreuses et dans le développement de mécanismes de résistance vis-à-vis du traitement.À l’aide de simulations de chimie quantique à un niveau de théorie élevé (méthode de perturbationMøller-Plesset au degré 2 (MP2) et des jeux de fonctions de base très complets), nous avons mené une étude robuste et complète des réactions entre le cisplatine (et ses dérivés d’hydrolyse principaux) et des thiolates d’intérêt biologique comme la cystéine et le glutathion.Les caractéristiques cinétiques et thermodynamiques obtenues pour les thiolations et les bidentations permettent de mettre en lumière les chemins de réactions les plus probables. Nos résultats de spectroscopie Raman montrent également que deux thiolations au maximum peuvent avoir lieu, probablement en raison de bidentations après chaque thiolation. En outre, les bidentations S,N semblent favorisées par rapport aux bidentations S,O. Nous avons également observé de manière presque systématique l'échelle de labilité des ligands suivante : H2O > Cl– ≈ NH3(trans) > NH3(cis) > OH–. La différence entre les ammines vient d'une forte translabilisation par les thiolates, due à l’effet trans inhérent aux structures carrée plane des sels de platine (II).