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International audience; We report a rh(I)-catalyzed C-H bond alkylation of PhenCarPhos [= N-(2-(diphenylphosphaneyl)phenyl)carbazole] and some congener phosphine ligands with alkenes. The C-H bond functionalization occurred exclusively at the C1 position of the carbazolyl unit because the trivalent phosphine acts as a directed group. This protocol provides straightforward access to a large library of C1-alkyl substituted PhenCarPhos, which outperformed common commercial or unfunctionalized phosphines and their precursors in the Pd-catalyzed carbon dioxide-fixation reactions with propargylic amines. Designing more active ligands is one of the most important fields of catalysis and organometallic chemistry. Despite numerous advances in transition metal-catalyzed reactions, developing efficient catalytic systems is still highly desirable for industrial application, significantly decreasing their environmental impact. Among the different classes of ligands, phosphines remain the most popular with several well-established industrial processes. 1 It is admitted that the associated phosphines can modulate the activity of metal centers of catalysts through fine-tuning of their steric and electronic properties or by weak interactions in the second coordination sphere. However, the synthesis of such multifunctional phosphines with different substituents often requires multistep synthesis and the use of organometallic reagents may limit the diversity of the functional group that can be introduced in the phosphine scaffold. Since the pioneer observation by Hartwig and co-workers on Pd-catalyzed direct polyarylation of 1-(di-tert-butylphosphino)ferrocene, 2 P(III)-chelation-assisted C-H bond functionalization has become a straightforward strategy to

Ammonia oxidation catalyzed by molecular compounds is of current interest as a carbon-free source of dihydrogen. Activation of N-H bonds through coordination to transition metal centers is a key reaction in this process. We report the substantial activation of ammonia via reaction with low-valent molybdenum complexes of a diborate pentadentate ligand system. Spontaneous loss of dihydrogen from (B

This PhD work relates to the study of cooperative effects in catalysis with group 10 metals pincer complexes, with a particular focus on palladium. In the first chapter of this manuscript, an extensive bibliographic survey on group 10 metals pincer complexes bearing a chemically non-innocent ligand is presented. Common ground and differences between the presented systems are highlighted and discussed. They have been divided in 3 big families, depending on the reactivity exhibited by the ligand backbone (electron-rich, Lewis-acid, functional group reservoir). The second chapter presents the development and application in catalysis of a new system based not only on MLC but its use in synergy with an external Lewis acid. Thanks to this new multi-cooperative system, the formation of carbocycles (and heterocycles) was efficiently promoted through a cycloisomerization reaction involving a C-C bond formation. A wide scope of substrates could be cyclized and a complementary stereoselectivity compared to that reported in the literature was displayed by our system. The third chapter is focused on the design and the synthesis of a new non-innocent pincer ligand along with its coordination to palladium. A new dearomatized species could be generated and characterized. The non-innocent behavior of the dearomatized ligand was demonstrated through stoichiometric reactions. During this work, a rare example of a palladium-hydride complex bearing an acidic hydrogen center at a non-innocent ligand was isolated and characterized. Thanks to our ligand design, a second cooperativity mode based on a palladium-sulfide interaction could be explored and is presented in the fourth chapter of this manuscript. The stoichiometric E-H bond activation (E = Si, Ge) with this complex results in the formation of a E-sulfide bond and a palladium hydride. This cooperativity was then applied to catalysis with the hydroelementation of alkynes. In this reactivity, our ligand design brings mechanistic diversity and a complementary reaction profile compared to known systems.; Ce travail de thèse porte sur l'étude des effets coopératifs en catalyse avec des complexes pince des métaux du groupe 10, et en particulier le palladium. Dans le premier chapitre de ce manuscrit, une étude bibliographique approfondie sur les complexes pince des métaux du groupe 10 comportant un ligand chimiquement non-innocent est présentée. Les points communs et les différences entre les différents systèmes sont discutés. Ils ont été divisés en 3 grandes familles, en fonction de la réactivité du site non-innocent sur le ligand (riche en électrons, acide de Lewis, réservoir de groupes fonctionnels). Le second chapitre présente le développement et l'application en catalyse d'un nouveau système multi-catalytique basé non-seulement sur la coopérativité métal-ligand mais sur sa synergie avec un acide de Lewis externe. Grâce à ce nouveau système multi-coopératif, la formation de cycles carbonés (et d'hétérocycles) a été réalisée efficacement à travers une réaction de cycloisomérization impliquant la création d'une liaison C-C. Une large librairie de substrats a pu être cyclisée et une stéréochimie complémentaire par rapport à la littérature a été montrée par notre système multi-coopératif. Ensuite, le troisième chapitre porte sur le design et la synthèse d'un nouveau ligand pince non-innocent ainsi que sa coordination sur le palladium. Une nouvelle espèce désaromatisée a pu être générée et caractérisée. Le caractère non-innocent du ligand désaromatisée a été mis en évidence au travers de réactions stoechiométriques. Au cours de ces travaux, un rare exemple de complexes palladium-hydrure portant un atome d'hydrogène acide au sein d'un ligand non-innocent a été isolé et caractérisé. Grâce à notre design de ligand, un second mode de coopérativité basé sur une liaison palladium-soufre a pu aussi être exploré, et il est présenté dans le quatrième chapitre de ce manuscrit. L'activation stoechiométrique de liaisons E-H (E = Si, Ge) par ce complexe se traduit par la formation d'une liaison E-soufre et palladium-hydrure. Cette coopérativité a pu être ensuite appliquée en catalyse à travers l'hydroélémentation d'alcynes. Dans cette réactivité, notre design de ligand apporte une diversité mécanistique et offre un profil réactionnel complémentaire par rapport aux systèmes déjà connus.

International audience; The present review describes the homogenous catalytic methodologies for the synthesis of 2,2'-bipyridines involving C-C bond formation from C-H bond. There are three main approaches to build well-decorated 2,2'-bipyridines from C-H bond cleavage: i) the formation of C2-C2 ' bond by the dimerization of (activated) pyridines, ii) the C-H bond heteroarylation of activated pyridine, or iii) the late-stage functionalization of (activated) 2,2'-bipyridines including photoredox processes. Besides the scope and limitation of each methodologies, the relevant mechanisms of reaction are also discussed.

The chemistry of the heavy alkaline-earth elements calcium, strontium and barium is open for new discoveries, especially in their stabilisation processes and ligand designs. This PhD presents new alkaline-earth complexes, based on the charge-neutral homoleptic and heteroleptic species, in addition to cationic compounds, where diverse coordination spheres were examined. First, low coordinated homoleptic compounds of the form of [Ae(OR)₂]ₙ (OR = fluorinated alkoxides) were generated devoid of coordinated Lewis bases. Furthermore, these latter were employed as starting materials for the synthesis of the fluorinated monocationic parents [{L}[Ae(OR)]⁺.[WCA]⁻ (WCA = weakly coordinating anion) with increased electrophilicity. Furthermore, the relative Lewis acidity of both families of compounds, in addition to their application as Lewis acid catalysts in the aza-Piancatelli reaction are described. The aza-Piancatelli reaction is an important catalytic procedure that produces heterocyclic products with cosmetic and therapeutic values. Next, molecular alkalineearth species [Ae(LX₂)] based on dianionic ligands were prepared. Tuning the ligands between fluorinated alkoxides and phenolates along with the metal centre, manage to display a variety of compounds with different electrophilicity and coordination spheres. Finally, the heteroleptic forms of low coordinated alkaline-earth complexes were generated based on the electron-poor boryloxides and borylamide ligands. These lasts proved their ability to stabilise the alkaline-earth metals by their steric hindrance., La chimie des larges métaux alcalinoterreux, calcium, strontium et baryum, reste ouverte à de nouvelles découvertes, notamment dans leurs processus de stabilisation et la conception de ligands. Cette thèse de doctorat présente des nouveaux complexes alcalinoterreux, basant sur les espèces homoleptiques et hétéroleptiques de charge neutre, en plus des complexes cationiques, où différents sphères de coordination ont été examinés. Premièrement, les complexes homoleptiques de basse coordinance de forme [Ae(OR)₂]ₙ (OR =alcoolate fluorés) ont été générés sans coordinence de bases de Lewis. De plus, ces derniers ont été utilisés étant des produits de départ pour la synthèse de leurs parents monocationic fluorés [{L}[Ae(OR)]⁺.[WCA]⁻(WCA = anion faiblement coordonné) avec une électrophile augmenté. L’acidité de Lewis de ces deux familles de composés, en plus de leurs applications étant des catalyseurs d’acide de Lewis dans la réaction d’aza-Piancatelli sont décrits. La reaction d’aza-Piancatelli est une procédure catalytique importante produisant des hétérocycles avec des valeurs cosmétiques et thérapeutiques. Ensuite, des espèces moléculaires d’alcalino-terreux [Ae(LX₂)] basant sur des ligands dianioniques ont été préparés. En variant les ligands entre alcoolates fluorés et phénolates de même que le centre métallique, ont abouti à avoir une variété de composés avec différents éléctrophilie et sphères de coordination. Finalement, des formes hétéroleptiques de basse coordinence des complexes alcalinoterreux ont été générés basant sur des ligands borylates et borylamides relativement pauvres en électrons. Ces derniers ont montré leur capacité à stabiliser les métaux alcalino-terreux par leur encombrement stérique.

International audience; Pseudo-benzylic substitution is an important reaction in the ferrocene series, especially to obtain ligands for catalysis. Herein, we described new reactions conditions, using fluorinated alcohols as both solvent and promoter, able to deliver iodoferrocene derivatives faster than using classical solvents. Various N, O, P and C-nucleophiles were found compatible with this transformation which occurs with full retention of stereochemistry. Original P,N-ligands were prepared by using iodine/lithium exchange-chlorophoshine trapping sequences, and their properties were evaluated in Suzuki-Miyaura and Buchwald-Hartwig coupling as well as in ketone alpha-arylation reaction.

International audience; A dimeric Cu(II) complex [Cu(II)2L2(μ2-Cl)Cl] (1) built from an asymmetric tridentate ligand (2-(((2-aminocyclohexyl)imino)methyl)-4,6-di-tert-butylphenol) and weakly coordinating anions has been synthesized and structurally characterized. In dichloromethane solution, 1 exists in a monomeric [Cu(II)LCl] (1′) (85%)–dimeric (1) (15%) equilibrium, and cyclic voltammetry (CV) and electron paramagnetic resonance (EPR) studies indicate structural stability and redox retention. Addition of phenylacetylene to the CH2Cl2 solution populates 1′ and leads to the formation of a transient radical species. Theoretical studies support this notion and show that the radical initiates an alkyne C–H bond activation process via a four-membered ring (Cu(II)–O···H–Calkyne) intermediate. This unusual C–H activation method is applicable for the efficient synthesis of propargylamines, without additives, within 16 h, at low loadings and in noncoordinating solvents including late-stage functionalization of important bioactive molecules. Single-crystal X-ray diffraction studies, postcatalysis, confirmed the framework’s stability and showed that the metal center preserves its oxidation state. The scope and limitations of this unconventional protocol are discussed.

Herein, the synthesis and characterization of the first family of multipodal ligands with a Tröger's base framework designed for the preparation of luminescent lanthanide(III) complexes are reported. Eight ligands were designed and synthesized using different strategies, including alkylation reactions, amide couplings, and Ugi multicomponent reactions. All the ligands bear carboxylate groups for the coordination of the lanthanide(III) ions, with the lanthanide(III)-sensitizing units consisting of the Tröger's base framework itself or attached benzamides. Upon irradiation of the chromophoric ligands, green terbium(III) emission was efficiently generated, whereas europium(III) emission was negligible. The geometry and substitution pattern of the ligands allow control of the stoichiometry of the species formed and the TbIII luminescence sensitization efficiency, showing that para-substitution patterns are more efficient than meta substitution for the formation of coordination compounds with lower TbIII/ligand ratio. We propose that the species formed are self-assembled 2:2 or 2:4 metallosupramolecular structures. Fil: Trupp, Leandro Julián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Centre National de la Recherche Scientifique; Francia Fil: Bruttomesso, Andrea. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Varde, Mariana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Eliseeva, Svetlana. Centre National de la Recherche Scientifique; Francia Fil: Ramirez, Javier Alberto. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Petoud, Stephane. Centre National de la Recherche Scientifique; Francia Fil: Barja, Beatriz Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina

Light-induced electron and energy transfer in molecular arrays is being extensively studied in view of artificial photosynthesis. In this context, [Ru(bpy)3]2+ derivatives have been widely used, due to their favorable photophysical properties, i.e. lifetimes in the µs range at room temperature, high emission quantum yields, and strong oxidizing and reducing capability. The electronic structural design of most ruthenium(II) complexes is of great importance by specifying the complexes’ photophysical, photochemical, and electrochemical properties. As a consequence, the main theme of this thesis is to explore the coordination properties of new tridentate ligands on the ruthenium cation. This work describes the synthesis of these new tridentate ligands based on the acridine heterocycle with different moieties at positions 4 and 5. Octahedral ruthenium(II) complexes were then constructed around these acridine-based ligands, with tuned energy levels of the functionally active 3MC and 3MLCT excited states. Very few acridine derivatives are substituted at positions 4 and 5. The synthetic strategy for the target ligands starts from acridone. The 4,5-dibromoacridine was obtained in four synthetic steps and this common precursor was subsequently used for the construction of tridentate (NNN) ligands with pyridine and pyrazole. In addition, a thioether acridine-based tridentate ligand (SNS) analogue was synthesized, and another tridentate thioether (SNS) ligand, without an acridine heterocycle, was prepared to gain some flexibility within the ligand scaffold. The corresponding homoleptic complexes with 6-membered metallacycles only adopted a facial octahedral geometry. Thus, the heteroleptic complexes were prepared in combination with a planar terpyridine ligand in order to force the constrained and rigid ligands to coordinate in a meridional fashion on the metal. The electrochemical, photophysical, and photochemical properties of all complexes were studied and the structure for most of these Ru(II) complexes was deduced by X-ray diffraction crystallography experiments. The bis-tridentate Ru(II) complexes based on the flexible (SNS) thioether ligand were photoactive: they were able to undergo a photosubstitution reaction, by replacing the tridentate thioether ligand with monodentate ligands, upon white light exposure., Le transfert d'électron et d'énergie induit par la lumière dans des dispositifs moléculaires est largement étudié dans le domaine de la photosynthèse artificielle. Dans ce contexte, les dérivés du [Ru(bpy)3]2+ ont été très utilisés, en raison de leurs propriétés photophysiques favorables, à savoir des durées de vie de l’ordre des µs à température ambiante, des rendements quantiques d’émission élevés et un fort pouvoir d’oxydation et de réduction. La conception de la structure électronique des complexes de ruthénium(II) revêt une très grande importance, car celle-ci dictera les propriétés photophysiques, photochimiques et électrochimiques de ces complexes. En conséquence, le sujet principal de cette thèse est d'explorer les propriétés de coordination de nouveaux ligands tridentes sur le cation ruthénium. Ce travail décrit la synthèse de ces nouveaux ligands basés sur l'hétérocycle acridine avec différents fragments en positions 4 et 5. Les complexes de ruthénium(II) octaédriques correspondants ont ensuite été construits autour de ces ligands à base d'acridine, avec des niveaux d'énergie ajustés des états excités 3MC et 3MLCT fonctionnellement actifs. Très peu de dérivés d’acridine sont substitués aux positions 4 et 5. La stratégie de synthèse pour les ligands cibles commence sur l’acridone. La 4,5-dibromoacridine a été obtenue en quatre étapes synthétiques et ce précurseur commun a ensuite été utilisé pour la construction de ligands tridentés (NNN) avec de la pyridine et du pyrazole. De plus, un analogue de ligand tridentate (SNS) à base de thioéther acridine a été synthétisé, et un autre ligand tridentate de thioéther (SNS), sans hétérocycle acridine, a été préparé dans le but d’acquérir une certaine flexibilité dans la structure. Les complexes homoleptiques correspondants avec des métallacycles à 6 chaînons ont tous adopté une géométrie octaédrique faciale. Ainsi, les complexes hétéroleptiques ont été préparés en combinaison avec un ligand terpyridine plan afin de forcer les ligands contraints et rigides à se coordiner de manière méridienne sur le métal. Les propriétés électrochimiques, photophysiques et photochimiques de tous les complexes ont été étudiées et la structure de la plupart de ces complexes de Ru(II) a été déduite par des expériences de cristallographie par diffraction des rayons X. Les complexes bis-tridentés de Ru(II) basés sur le ligand thioéther flexible (SNS), se sont montrés photoactifs: lors d'une exposition à la lumière blanche ils subissent une réaction de photosubstitution, remplaçant le ligand thioéther tridentate par des ligands monodentates.

Chemical modification of pseudo‐dimannoside ligands guided by fragment‐based design allowed for the exploitation of an ammonium‐binding region in the vicinity of the mannose‐binding site of DC‐SIGN, leading to the synthesis of a glycomimetic antagonist (compound 16) of unprecedented affinity and selectivity against the related lectin langerin. Here, the computational design of pseudo‐dimannoside derivatives as DC‐SIGN ligands, their synthesis, their evaluation as DC‐SIGN selective antagonists, the biophysical characterization of the DC‐SIGN/16 complex, and the structural basis for the ligand activity are presented. On the way to the characterization of this ligand, an unusual bridging interaction within the crystals shed light on the plasticity and potential secondary binding sites within the DC‐SIGN carbohydrate recognition domain., Fragment‐based design: A high affinity monovalent DC‐SIGN ligand was obtained by targeting an ammonium‐binding pocket identified by virtual screening. The structural basis of its activity was elucidated by X‐ray crystallography, also unveiling an unusual bridging interaction within the crystals.

International audience; Tris-copper centers are present at the active site of multicopper oxidases (MCO) which couple the four electron reduction of molecular oxygen to water with the oxidation of substrates. Modelling these sites with small molecular complexes has thus attracted the interest of many groups in the (bio)inorganic community over the past three decades and still appears a challenge. These enzymes and their model complexes presently enjoy a renewed interest as potential non-precious metal catalyst for the Oxygen Reduction Reaction. Moreover recent work has revealed that tris-copper centers can catalyze methane oxidation. Therefore the elaboration of tris-copper system constitutes an important and timely issue. The aim of the present review is to analyze the various attempts at preparing tris-copper complexes in terms of strategy of ligand design. Of course the challenge to be met is to force three independent binding sites to converge and react in concert. Three main approaches have been developed to anchor these binding sites based on the use of (i) a node either (a) a single atom node (tren-based systems and related), or (b) an hexa-atom node (mesityl-based systems and derivatives), (ii) macrocyclic systems, and (iii) combination of mono- and dinuclear sites. The structures of the different systems will be described and analyzed accordingly. Then the various reactivities exhibited by these systems will be presented so as to evaluate how the ligand design influences the reactivity and to discern promising future directions.

International audience; An atropisomer is a member of a subclass of restricted rotational conformers-this restricted rotation giving rise to stereogenic sigma bonds-that can be isolated as separate chemical species. Most atropisomer are six-membered-ring biaryl or heterobiaryl derivatives. The aim of this microreview is to shed light on a less common class of atropisomers, those containing at least one five-membered hetero-or carbocycle and displaying variously a stereogenic C-N, CC , or even N-N

International audience; A triflamide-tethered N-heterocyclic carbene (NHC)-bound Rh-I dicarbonyl catalyst was highly effective for both intermolecular hydroalkoxylation and intramolecular heteroannulation reactions. The involvement of both the amido nitrogen and triflato oxygen atoms of the triflamide functionality for alcohol activation and 1,2-hydrogen shift, respectively, was proposed.

International audience; Soluble platinum nanoparticles (Pt NPs) ligated by two different long-chain N-heterocyclic carbenes (LC-IPr and LC-IMe) were synthesized and fully characterized by TEM, high-resolution TEM, wide-angle X-ray scattering (WAXS), X-ray photoelectron spectroscopy (XPS), and solution NMR. The surface chemistry of these NPs (Pt@LC-IPr and Pt@LC-IMe) was investigated by FT-IR and solid state NMR using CO as a probe molecule. A clear influence of the bulkiness of the N-substituents on the size, surface state, and catalytic activity of these Pt NPs was observed. While Pt@LC-IMe showed no activity in the hydroboration of phenylacetylene, Pt@LC-IPr revealed good selectivity for the trans-isomer, which may be supported by a homogeneous species. This is the first example of hydroboration of acetylenes catalyzed by non-supported Pt NPs.

International audience; Metal overload is involved in several diseases; some are due to toxic metal poisoning whereas others can be the result of disrupted homeostasis due to a genetic disorder. This is the case for copper in Wilson's disease and for iron in hemochromatosis. This chapter focuses on these two genetic disorders and the strategies that the medicinal inorganic chemist may apply to design novel chelation therapies to treat these iron or copper overloads. In particular, the emphasis will be put on the requirement of having a good understanding of the biology of metals to design more effective and more specific chelating drugs. The basic principles of coordination chemistry, which are used for designing appropriate chelating agents, will be first briefly described. Then, recent and specific developments in the field will be presented in relation with copper or iron regulation.

DC-SIGN is a dendritic cell-specific C-type lectin receptor that recognizes highly glycosylated ligands expressed on the surface of various pathogens. This receptor plays an important role in the early stages of many viral infections, including HIV, which makes it an interesting therapeutic target. Glycomimetic compounds are good drug candidates for DC-SIGN inhibition due to their high solubility, resistance to glycosidases, and nontoxicity. We studied the structural properties of the interaction of the tetrameric DC-SIGN extracellular domain (ECD), with two glycomimetic antagonists, a pseudomannobioside (1) and a linear pseudomannotrioside (2). Though the inhibitory potency of 2, as measured by SPR competition experiments, was 1 order of magnitude higher than that of 1, crystal structures of the complexes within the DC-SIGN carbohydrate recognition domain showed the same binding mode for both compounds. Moreover, when conjugated to multivalent scaffolds, the inhibitory potencies of these compounds became uniform. Combining isothermal titration microcalorimetry, analytical ultracentrifugation, and dynamic light scattering techniques to study DC-SIGN ECD interaction with these glycomimetics revealed that 2 is able, without any multivalent presentation, to cluster DC-SIGN tetramers leading to an artificially overestimated inhibitory potency. The use of multivalent scaffolds presenting 1 or 2 in HIV trans-infection inhibition assay confirms the loss of potency of 2 upon conjugation and the equal efficacy of chemically simpler compound 1. This study documents a unique case where, among two active compounds chemically derived, the compound with the lower apparent activity is the optimal lead for further drug development

WOS: 000321737700033, Three resorcinarene-cavitands bearing a 3-R-1-imidazolylium substituent (R = alkyl) grafted to the wider rim of the cavitand (1-3) were assessed in the Kumada-Tamao-Corriu cross-coupling of aryl halides with arylmagnesium halides. Their combination with [Ni(cod)(2)] (cod = 1,5-cyclooctadiene; 1:1 stoichiometry) resulted in highly efficient catalysts, the activities of which varied in the following order: R = n-propyl (1) < isopropyl (2) approximate to benzyl (3). A remarkable turnover frequency of 60400 mol(ArX) mol(Ni)(-1) h(-1) was obtained in the coupling of 2-bromo-6-methoxynaphthalene with PhMgBr (100 degrees C in dioxane, with precursor 2). The high activities of the cavitand derivatives were attributed to steric effects that facilitate the reductive-elimination/product decoordination step. Comparative experiments carried out with a structurally modified resorcinarene, as well as cavity-free imidazolium salts bearing 2-methoxyaryl substituents, suggest that the efficiency of the catalysts mainly relies on steric interactions between the metal and the flexible substituents attached to two methine carbon atoms. These steric interactions are probably reinforced each time the metal binds one of the two oxygen atoms located next to the catalytic centre., Scientific and Technological Research of Turkey (TUBITAK-BIDEB); French Agence Nationale de la Recherche (ANR) [ANR-12-BS07-0001-01-RESICAT], The authors thank the Scientific and Technological Research of Turkey (TUBITAK-BIDEB), International Research Fellowship Programme for a grant to N. S., and the French Agence Nationale de la Recherche (ANR) (ANR-12-BS07-0001-01-RESICAT) for financial support.

International audience; Hypertension, diabetes and metabolic syndrome are important risk factors for cardiovascular morbidity and mortality. Angiotensin II plays an important role in blood pressure regulation and angiotensin II type 1 receptors (AT1) blockers are widely used in the treatment of hypertension. Some, such as telmisartan, and at a lesser degree, losartan, also exhibit activity at the Peroxisome Proliferator Activated Receptor gamma (PPAR-gamma), a nuclear receptor involved in the control of glucose metabolism. This represents a new therapeutic approach for the treatment of hypertension and diabetes, which are often concomitant and difficult to treat by one-target molecules. In this context, instead of pharmacomodulations on telmisartan (already done by Mizuno et al.), we preferably choose to modify the structure of losartan, in order to build-up new PPAR-gamma/AT1 dual molecules. The losartan structure was linked to a 4'-hydroxy-5-benzilidenethizolidinedione moiety, which is found in many PPAR-gamma agonists. Many chemical modulations were done on the resulting molecule, in order to get structure-activity relationships to both targets. In parallel, we realized docking experiments, with the aim of predicting the activities of the compounds. The molecules were docked into the PPAR-gamma receptor by the Autodock software, using a set of various PPAR-gamma X-ray structures from the Protein Data Bank. In order to validate the method, we first applied this procedure for rosiglitazone, a well-known PPAR-gamma agonist. In vitro AT1 activity was evaluated by displacement of fluorescent angiotensin II in cells overexpressing AT1 receptors. In vivo AT1 antagonistic activity was evaluated in anesthetized normotensive Wistar rats via the blunted hypertensive response to acute angiotensin II (10-10 mol/kg; intravenously). In vitro PPAR-gamma activity was evaluated in MCF-7 cells by co-transfection of (PPRE)3-TK-Luc and hPPAR-gamma vectors. As a result, many molecules showed in vitro potency on AT1 or PPAR-gamma receptors. Furthermore, some exhibited strong in vivo antihypertensive activity.

International audience; (R)- and (S)-4,4′-diaminomethyl-BINAP were prepared in three steps from enantiomerically pure BINAPO in a global yield of 52 %. A regioselective bromination of BINAPO with NBS in HMimPF6 gave the desired 4,4′-dibromo-BINAPO in quantitative yield, and the recyclability of the ionic liquid was demonstrated. Copper cyanide cyanation of 4,4′-dibromo-BINAPO gave the 4,4′-dicyano-BINAPO in 70 % yield. Both enantiomers were characterized by NMR spectroscopy and HPLC analysis, and the structures were confirmed by X-ray crystallography. The cyano and phosphane oxide groups of the resulting 4,4′-dicyano-BINAPO were reduced in one step to the corresponding 4,4′-diaminomethyl-BINAP by using tetramethyldisiloxane/Ti(OiPr)4 in 75 % yield.

International audience; Four different regioselective double capping reactions were applied either to alpha- or beta-cyclodextrin (CD) scaffolds. The first, which relied on the use of a rigid, bulky dialkylating reagent containing two trityl-like subunits, gave access to an A,B,D,E-tetra-functionalised beta-CD regioisomer in large scale reactions. Two further capping reactions, involving the dianions PhP2- and S2-, led to the synthesis of new C-1-symmetrical beta-cyclodextrins in which pairs of neighbouring glucose units are linked by very short spacers. The last double capping reaction described allowed the high-yield preparation of unprecedented alpha- and beta-cyclodextrins containing two sulfate handles. Proximal capping turned out to be favoured for each of the above difunctional reagents. The structural characterisation of the capped species was achieved by thorough NMR investigations as well as by single-crystal X-ray diffraction studies.

A straightforward synthesis of homoallyl- and allylphosphanes has been developed using nBuLi-mediated hydrophosphination of conjugated dienes. In all the cases the phosphorus atom of the reacting phosphane attacked the sterically less demanding side of the diene exclusively. In addition, high regioselectivities towards 1,2- or 1,4-addition products were observed depending on the nature of the dienes. This hydrophosphination reaction was extended to a variety of substrates such as styrene derivatives, alkynes and 1,3,5-cycloheptatriene. The structures of three hydrophosphination products were confirmed by X-ray diffraction studies.

La découverte des propriétés catalytiques des ARN a bouleversé nos conceptions en biologie moléculaire sur les rôles des ARN au cours de l’évolution, des origines de la vie jusqu’à main- tenant. Du point de vue biochimique, on commence seulement à comprendre dans le détail la catalyse des ribozymes. L’enzymologie moléculaire offre des approches expérimentales pour étu- dier la catalyse par les ARN ; les méthodes de mécanique quantique permettent de modéliser les réactions qualitativement et quantitativement et d’essayer de comprendre l’origine du pouvoir catalytique des enzymes. C’est dans cette optique que nous avons modélisé la réaction chimique qui intervient dans le ribozyme à tête marteau qui est considéré comme un prototype dans la catalyse par les ARN car il est un des plus petits ribozymes naturels que l’on connaisse. Nous avons proposé le 1er modèle à 2 cations métalliques pour un ribozyme auto-clivable. A ce jour, le mécanisme réactionnel et les changements conformationnels associés à la catalyse ne sont pas complètement élucidés. Pour y contribuer, nous cherchons à comparer de façon théorique les catalyses de type "metallo-enzyme" et "nucléobase" ou hybrides.Des découvertes récentes ont mis en évidence l’existence de nombreux ARN non-codant im- pliqués dans de nombreuses et diverses fonctions biologiques. Dans cette thématique, nous nous sommes focalisés sur un domaine du vivant encore peu étudié : les archaea. Nous avons développé et mis en œuvre une approche bio-informatique pour rechercher des gènes d’ARN non-codant dans ces génomes qui a été largement validée expérimentalement sur une classe particulière d’ARN non-codant que sont les ARN guides de modifications à boîtes H/ACA. Des développe- ments permettant d’améliorer la sensibilité de la méthode sont prévus. D’autre part, les connais- sances acquises sur les ARN à boîtes H/ACA ouvrent des perspectives dans la compréhension d’une maladie humaine (la dyskeratose) reliée à un dysfonctionnement associée à cette famille d’ARN non-codant chez l’homme. Le prolongement de cette thématique abordée à l’aide d’outils bio-informatiques s’appuiera sur l’utilisation de méthodes de modélisation 3D développées par ailleurs.Les travaux menés sur les ribozymes et l’essor de la RNomics démontrent la versatilité de fonction et de structure des ARN. La biologie structurale a permis d’acquérir beaucoup de connais- sances sur la structuration des ARN et leurs interactions. La conception assistée par ordinateur de ligands dirigée contre des ARN comme cibles thérapeutiques est dès lors possible. La modéli- sation 3D de macromolécules offre une approche possible d’étude des liens structure/fonction en l’absence de données structurales mais aussi d’étude théorique de la flexibilité conformationnelle qui joue un rôle primordial dans le repliement des ARN et leur interaction avec des ligands. Les travaux présentés ici s’inscrivent dans le cadre d’un développement d’approches de modélisation de complexes ARN/protéines et ARN/ligand adaptées au mode d’interaction étudié, selon que l’ARN est structuré ou non. Dans le premier cas, une approche de docking classique est utilisée où l’ARN peut être considéré comme une cible pour un ligand protéique ou autre. Dans le se- cond cas, une approche de docking "par fragment" (SELEX in silico) inspirée des méthodes de conception de drogues est utilisée pour prédire la reconnaissance par des protéines de liaison à l’ARN et éventuellement concevoir d’autres ligands ARN. La méthode est en cours de validation et sera appliquée à des cibles d’intérêt impliquées dans les dystrophies myotoniques.

4 pages; International audience; A polydentate ligand, H4L, based on adjacent 1,3-diketone and phenol functions has been used in combination with a strong base for the assembly of four Ni(II) ions into molecular species, [Ni4L2(py)6] (1), featuring a targeted linear [Ni-Ni⋯Ni-Ni] sequence. Weak antiferromagnetic exchange is observed within pairs of closest Ni(II) centers, of J = −5.04 cm−1 (in the H = −2JS1S2 convention). An unusual combination of coordination geometries (square pyramidal + octahedral) is observed within each [Ni2] moiety in the molecule, attributed to the geometrical constraints imposed by L4−.

6 pages; International audience; A novel ligand featuring one phenol and two pyrazole groups in a linear fashion was prepared. This donor facilitates the assembly of a mixed-valence chain of Mn ions in the [MnIIMnIIIMnII] sequence, with formula [Mn3(Hpbpz)2(OAc)3- (MeOH)3] (1). Complex 1 exhibits dominant antiferromagnetic coupling between adjacent pairs of Mn ions. A fit of the magnetic susceptibility data using the Hamiltonian H = –2J1(S1S2 + S2S3) – 2J2(S1S3) yields coupling constants of J1 = –3.14 cm–1 and J2 = –0.39 cm–1, which leads to a spin ground state of ST = 3

The increasing structural and functional knowledge of proteins gives us a clearer idea of how they interact. This information could be used to design new compounds, able to interact with a wide variety of interesting targets, as well as improve our comprehension of this phenomenon. This work presents the development of a new method enabling the design of protein ligands based on the transfer of a set of amino acids of a known ligand, contributing to the binding of a chosen target on a host protein, containing less than 100 residues (mini-proteins). These host proteins, able to reproduce the interaction after motif insertion, are identified in a systematic manner from the PDB. This approach has been applied to the development of new ligands of the Kv1.2 channel using the structural and functional knowledge of the interaction with the BgK toxin. Three ligands have been designed with inhibition constants in the micro molar range. Those results demonstrate the possibility of designing new ligands with a method based on the transfer of a functional motif of residues on a new scaffold which is sterically and electrostatically compatible with the interaction targeted., L'accroissement des connaissances, structurales et fonctionnelles, des protéines nous donne désormais une vision plus précise des phénomènes d'interaction. L'utilisation de ces informations pour le développement de ligands permettrait d'obtenir de nouveaux composés, capables d'interagir avec diverses cibles d'intérêt, et d'améliorer notre compréhension de ces interactions. Ce travail présente le développement d'une nouvelle méthode de conception de ligands protéiques, laquelle repose sur le transfert d'un groupe de résidus, appartenant à un ligand connu et contribuant de façon importante à la liaison avec une cible d'intérêt, sur une protéine hôte, de moins de 100 résidus (mini-protéines). L'identification de protéines hôtes, aptes à reproduire l'interaction après transfert du motif, est réalisée de manière systématique à partir des structures présentes dans la PDB. L'approche a été appliquée pour le développement de ligands du canal Kv1.2, à partir de connaissances structurales et fonctionnelles de l'interaction de ce même canal avec la toxine BgK. Trois ligands, possédant des constantes d'inhibition micro molaires, ont été ainsi conçus. Ces résultats démontrent la possibilité de mettre en application une méthode de conception de ligands, basée sur le transfert de motifs de « hotspots », sur une plateforme structurale de nature protéique, dont les aspects stérique et électrostatique sont compatibles avec une interaction donnée.