Novel phosphate–phosphonate hybrid nanomaterials applied to biology

International audienceA new process for preparing oligonucleotide arrays is described that uses surface grafting chemistry which is fundamentally different from the electrostatic adsorption and organic covalent binding methods normally employed. Solid supports are modified with a mixed organic/inorganic zirconium phosphonate monolayer film providing a stable, well-defined interface. Oligonucleotide probes terminated with phosphate are spotted directly to the zirconated surface forming a covalent linkage. Specific binding of terminal phosphate groups with minimal binding of the internal phosphate diesters has been demonstrated. On the other hand, the reaction of a bisphosphonate bone resorption inhibitor (Zoledronate) with calcium deficient apatites (CDAs) was studied as a potential route to local drug delivery systems active against bone resorption disorders. A simple mathematical model of the Zoledronate/CDA interaction was designed that correctly described the adsorption of Zoledronate onto CDAs. The resulting Zoledronate-loaded materials were found to release the drug in different phosphate-containing media, with a satisfactory agreement between experimental data and the values predicted from the model

Synthèse d'analogues de nucléosides à quatre et six chaînons et incorporation d'analogues cyclobutyliques dans un motif oligonucléotidique antisens (approche vers la synthèse de composés galactosyl-pyrrolo-pyridinones)

Ce travail de thèse, axé sur la thématique des analogues de nucléosides, s est déroulé en trois parties. La synthèse énantiosélective de carbanucléosides cyclobutaniques, en vue de leur incorporation dans des enchaînements oligonucléotidiques, a tout d abord été effectuée. La préparation de nouveaux dérivés nucléosidiques cyclohexéniques a ensuite été réalisée. Enfin, l approche vers la synthèse de composés galactosyl-pyrrolo-pyridinones a été étudiée. Dans le premier chapitre, nous avons mis en évidence la place importante qu occupent les nucléosides, les nucléotides et les acides nucléiques (ADN et ARN) dans les processus physiologiques. Par ailleurs, les différentes modifications structurales ayant abouti au développement de nouveaux analogues nucléosidiques ont été décrites. L intérêt des oligonucléotides en thérapie génique a ensuite été souligné avant d exposer les méthodes de synthèse et les différentes modifications structurales ayant porté sur ces composés. Dans le deuxième chapitre, la synthèse énantiosélective de nouveaux analogues de nucléosides cyclobutaniques, selon une stratégie initialement développée dans notre équipe, a été accomplie. Ces dérivés, après conversion en nucléotides, ont permis la préparation de nouveaux enchaînements oligonucléotidiques originaux. La synthèse de nouveaux analogues de nucléosides cyclohexéniques a été décrite dans le troisième chapitre. Une stratégie impliquant entre autres, une cycloaddition [4+2] asymétrique et l élaboration des bases hétérocycliques, nous a permis d accéder aux analogues cyclohexéniques, dont la structure préfigure l accès à de nouveaux analogues cyclohexaniques contraints. Le dernier chapitre, dans le prolongement de nos travaux sur les analogues de nucléosides, expose l approche vers la synthèse de composés galactosyl-pyrrolo-pyridinones. Les composés clés de la synthèse, à savoir les a-C-acétylènes glycosyl, ont pu être préparés. Ceux-ci devraient nous permettre par la suite d accéder à des pyrrolo-pyridinones diversement substitués via une cycloaddition [4+2] à demande inverse, une régression de cycle et une lactamisation intramoléculaire.This Ph.D thesis focused on the theme of nucleosides analogues. It was divided into three parts. First, the enantioselective synthesis of cyclobutyl nucleosides, and their incorporation into oligonucleotides chains, was performed. The preparation of new cyclohexenyl nucleosides derivatives was then accomplished. Finally, the approach toward the synthesis of galactosyl-pyrrolo pyridinones compounds was studied. In the first chapter we have highlighted the important role of nucleosides, nucleotides and nucleic acids (DNA and RNA) in physiological processes. Furthermore, different structural modifications that led to the development of new nucleosides analogues have been described. The interest of oligonucleotides in gene therapy was then highlighted before outlining the synthesis methods and the different structural modifications performed on these compounds. In the second chapter, the enantioselective synthesis of cyclobutyl nucleosides analogues, using a strategy initially developed in our team, was accomplished. These derivatives, after conversion to nucleotides, allowed the preparation of new and originals oligonucleotides chains. The developpement of new cyclohexenyl nucleosides analogues was described in chapter three. A strategy involving, among others, an asymmetric [4 +2] cycloaddition and the construction of heterocyclic bases, allowed us access to cyclohexenyl derivatives. The structure of those compounds prefigures access to new constrained cyclohexanyl nucleosies analogues. The last chapter, in continuation of our work on nucleoside analogues, outlines the approach toward the synthesis of galactosyl-pyrrolo pyridinones compounds. -C-glycosyl acetylene derivatives were first prepared. Those key compounds in the synthesis should enable us to subsequently access to variously substituted pyrrolo-pyridinones via an inverse demand Diels Alder Reaction, the regression of pyridazine compounds and an intramolecular lactamization.LE MANS-BU Sciences (721812109) / SudocSudocFranceF

(1R,2S,4S,4aS,8S,8aS)-4-Hydroxy-8,8a-dimethyl-10-oxo-2,3,4,7,8,8a-hexahydro-1H-4a,1-(epoxymethano)naphthalen-2-yl acetate

The title compound, C15H20O5, presents a bisnorsesquiterpene skeleton, with a trans-decaline backbone constrained by the lactone bridge. The α-hydroxy substituent and the methyl group belonging to the two decaline rings are in axial positions, whereas the other methyl group and the acyl group occupy the sterically preferred equatorial positions. The molecular structure is stabilized by an intramolecular C—H...O hydrogen bond. In the crystal, molecules are linked into chains along [010] by O—H...O hydrogen bond

New Bitopic Ligands for the Group Actinide Separation by Solvent Extraction

The synthesis and evaluation of solvent extraction performance of N,N,N',N'-tetraalkyl-6,6''-(2,2':6',2''-terpyridine)diamides and N,N'-diethyl-N,N'-diphenyl-6,6''-(2,2':6',2''-terpyridine)diamide are reported here. These new bitopic ligands were found to extract actinides in different oxidation states (U(VI), Np(V and VI), Pu(IV), Am(III), and Cm(III)) from 3 M nitric acid. The presence of three soft nitrogen donors led to the selective extraction of actinides(III) over lanthanides(III) (Ce, Eu) and the presence of two amide functional groups grafted to the terpyridine unit allowed the extraction to occur from a highly acidic medium by minimizing the basicity of the ligand. Ligands bearing long alkyl chains (C4 and C8) or phenyl groups showed increased performances in a polar diluent like nitrobenzene

Hybrid materials for catalysis? Design of new phosphonate-based supported catalysts for the hydrogenation of ketones under hydrogen pressure

International audienceSupported rhodium. and iridium. 2,2 ' -bipyridine complexes were prepared for the hydrogenation of aromatic ketones under hydrogen pressure. The key feature of the immobilization process is the functionalization of the 2,2 ' -bipyridine unit with two phosphonic acid moieties, thus allowing the covalent grafting of the catalytic complex onto in situ generated titanium oxide particles. A very good catalytic activity is observed with the resulting materials that compares well with the homogeneous parent system and gives evidence that the major part of the catalytic sites are readily accessible. Moreover, the catalyst can be reused, and no significant rhodium. leaching is observed

Practical Gram-Scale Synthesis of Either α- or β-Anomer of C-Vinyl Glycosides

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Theoretical Study of the Structures and Hydrogen-Bond Properties of New Alternated Heterocyclic Compounds

International audienceThe conformational preferences of a new his-pyrrole derivative and its his-pyridazine precursor have been investigated through quantum chemistry calculations (HF, DFT(MPWB1K), LMP2) and observations in the solid state. The global energetic minima are planar for both structures, with the conformational preferences being explained by pi-electronic conjugation between the aromatic systems and the occurrence of intramolecular hydrogen bonds (HB). For the bis-pyridazine derivative, the all-anti preferred conformation results front CH center dot center dot Nsp(2) HB whereas the all-syn conformation of the bis-pyrrole is partly due to NH center dot center dot center dot Nsp(2) HB. For both systems, the validity of the theoretical conformational features is confirmed through the excellent agreement with the experimental data available. Calculations of electrostatic potential computed on the molecular surface of the various structures and their building blocks allow the variations to be rationalized in terms of molecular structure and are used to analyze the HB donor and acceptor sites of the compounds. The HB interaction sites predicted from the quantum chemical calculations are confirmed through the FIB interactions observed in relevant crystal structures

Some mechanistic aspects of a nickel-catalyzed electrochemical cross-coupling between aryl halides and substituted chloropyridazines

The nickel-2,2'-bipyridine catalyzed electrochemical cross-coupling reaction between an aryl halide and a chloropyridazine was investigated by an electrochemical study The electrochemical behavior of the divalent nickel complex is affected by the presence of pyridazine rings which act as co-ligands of nickel Cyclic voltammetry indicates that the cross-coupling reaction involves first a rapid oxidative addition of the chloropyridazine on the electrogenerated zerovalent nickel complex. The coupling product is then obtained by reaction with the aryl halide. (C) 2010 Elsevier Ltd. All rights reserved

Tuning the Guest-Binding Ability of a Helically Folded Capsule by In Situ Modification of the Aromatic Oligoamide Backbone

Starting from a previously described aromatic oligoamide helically folded capsule that binds tartaric acid with high affinity and diastereoselectivity, we demonstrate the feasibility of the direct in situ modification of the helix backbone, which results in a conformational change that reduces its affinity for guests by two orders of magnitude. Specifically, ring contraction of the central pyridazine unit into a pyrrole in the full helical sequence was investigated by using electrochemical and chemical processes. The sequence containing the pyrrole was synthesized independently in a convergent manner to ascertain its structure. The conformation of the pyrrolic folded capsule was elucidated in the solid state by X-ray crystallography and in solution by using H-1 and C-13 NMR spectroscopy. Solution studies revealed an unanticipated solvent-dependent equilibrium between the anti-anti and syn-syn conformations of the pyrrole ring with respect to its two adjacent pyridine units. Titrations of the pyrrole-containing sequence monitored by 1H NMR spectroscopy confirmed the expected drop in affinity for tartaric acid and malic acid that arises from the conformation change in the backbone that follows the replacement of the pyridazine by a pyrrole. The reduction of the pyridazine to a pyrrole was characterized by cyclic voltammetry both on the entire sequence and on a shorter precursor. The lower cathodic potential of the precursor made its preparative-scale electroreduction possible. Direct in situ modification of the pyridazine within the entire capsule sequence was achieved chemically by using zinc in acetic acid

Preparation of functionalized aryl- and heteroarylpyridazines by nickel-catalyzed electrochemical cross-coupling reactions

0022-3263International audienceA general efficient electrochemical method for the preparation of aryl- and heteroarylpyridazines in a nickel-catalyzed cross-coupling reaction of 3-chloro-6-methoxypyridazine and 3-chloro-6-methylpyridazine with a range of functionalized aryl or heteroaryl halides is reported