1,721,080 research outputs found
Synthesis and studies of new chelators for the detoxification of d10 metal ions in organisms
No full textCe travail de thèse a consisté à synthétiser de nouveaux chélateurs pour la complexation des ions métalliques d10 toxiques en milieu biologique, comme le cuivre (I), lorsqu'il est présent en excès dans les cellules, et le mercure (II), délétère à l'état de traces. En particulier, des tripodes à trois soufres, inspirés de tripodes fonctionnalisés par trois dérivés cystéine, développés antérieurement au laboratoire, ont été élaborés et leur propriétés de complexation avec le cuivre (I) ont été examinées. Comme les tripodes cystéines, les nouveaux tripodes fonctionnalisés par d'autres dérivés soufrés, en particulier des dérivés de D-Pénicillamine (D-PEN), sont capables de complexer le cuivre (I) dans des environnements CuS3 avec de fortes affinités et sélectivités par rapport au zinc (II) présent dans les milieux biologiques. Des études structurales approfondies effectuées par spectroscopie d'absorption des rayons X (XAS) ont permis de caractériser complètement les complexes et clusters de cuivre (I) formés, de corréler les mesures d'affinités effectuées en utilisant différentes techniques et de rationaliser les relations structure/ affinité observées. L'un des nouveaux tripodes a ensuite été fonctionnalisé pour être ciblé vers les cellules du foie, où une accumulation de cuivre est observée chez les patients atteints de la maladie de Wilson. Les premiers tests biologiques réalisés sur des cellules hépatiques ont montré que l'architecture fonctionnalisée ainsi conçue (CHEL4) est capable de complexer le cuivre (I) en excès in cellulo. Cette étude conforte les résultats obtenus antérieurement au laboratoire avec le tripode cystéine fonctionnalisé (CHEL2) et valide donc le système de vectorisation vers les hépatocytes. Les propriétés de complexation des nouveaux tripodes avec l'ion toxique mercure (II), plus gros et plus mou que l'ion cuivre (I), ont aussi été étudiées. Il a ainsi été établi que les nouveaux tripodes thiolates peuvent aussi stabiliser un environnement trigonal autour du mercure (II). Notre étude a donc montré comment des tripodes soufrés de faible poids moléculaire, judicieusement fonctionnalisés, peuvent accommoder des environnements trigonaux très stables autour des ions mous cuivre (I) et mercure (II). De tels environnements miment plus ou moins les sites trigonaux du cuivre (I) et du mercure (II) trouvés dans les protéines à cuivre (I) (Ctr1, Mac1, Ace 1, COX…), les protéines bactériennes de détoxification du mercure (II) (Mer-R), et les métallothionéines (MTs), petites protéines riches en cystéines qui complexent les ions métalliques en excès ou toxiques dans les cellules. Ces analogies avec les complexes métalliques biologiques permettent de rationnaliser les fortes affinités des nouveaux tripodes pour les ions mous cuivre (I) et mercure (II). Plus généralement, notre étude apporte des règles de design moléculaires pour concevoir des architectures efficaces dédiées à la détoxification des métaux mous en milieu biologiques. Mots clés : cuivre (I), zinc (II), mercure (II), maladie de Wilson, foie, surcharges métalliques, toxicité, chélateurs, tripodes soufrés, cystéine, D-pénicillamine (D-PEN), environnements trigonaux, protéines du cuivre (I), métallothionéines (MTs), Mer-R, Spectroscopie d'Absorption des rayons X (XAS).This work consisted in the syntheses of new chelators for the binding of soft d10 metal ions in biological media, such as the copper (I) ion, toxic at high levels in the cells, and the mercury (II) ion, deleterious even at low concentrations. In particular, new suphur-based tripodal architectures, derived from the cysteine-based architectures previously designed at the laboratory, have been synthetized and their binding properties with the copper (I) ion have been looked into. As the cysteine-based scaffolds, the new chelators, based on new sulphur compounds, in particular D-Penicillamine (D-PEN) derivatives, complex the copper (I) ion in trigonal CuS3 environments with high affinities and high selectivities with respect to the bioavailable zinc (II) ion. In depth structural studies have been performed by X-Ray Absorption Spectroscopy (XAS) to fully characterize the copper (I) complexes and the copper (I) clusters formed in solution, to correlate the affinity measurements performed using different analytical techniques and to rationalize structure/ affinity relationships. One of the new chelators has been functionalized to be targeted to the liver cells, where copper (I) overloads are observed when people suffer from the Wilson's disease. The first biological experiments carried out in hepatocytes, have shown that the functionalized chelator (CHEL4) complexes excess copper (I) in cellulo. This study supports the results previously obtained with the functionalized cysteine-based architecture (CHEL2) and thus validates the targeting system. The binding properties of the new tripodal architectures with the mercury (II) ion, bulkier and softer than the copper (I) ion, have also been studied. It has been established that the new chelators also stabilize trigonal environments around the mercury (II) ion. Thus this study has shown how low molecular weight sulphur-based tripodal architectures, judiciously functionalized, are able to adapt stable sulphur-only trigonal environments around the soft metal ions, copper (I) and mercury (II). Such environments reproduce more or less the trigonal binding sites found in copper (I) proteins (Crt1, Mac1, Ace1, COX…), bacteria proteins dedicated to mercury (II) detoxification (Mer-R) and metallothioneins (MTs), which are small cysteine-rich proteins in charge of the detoxification of toxic metal ions in cells. Those structural analogies shared with the biological metallic complexes allow us to rationalize the high affinities of the new tripodal architectures for soft metal ions. In a more extended point of view, this study brings some guidelines of molecular design to elaborate efficient chelators dedicated to the detoxification of soft metal ion in biological media. Keywords: copper (I), zinc (II), mercury (II), Wilson's disease, liver, metal overloads, toxicity, chelators, sulphur-based tripods, cysteine, D-penicillamine (D-PEN), trigonal environments, copper (I) proteins, metallothioneins, Mer-R, X-Ray Absorption Spectroscopy (XAS)
DNA recognition by lanthanides peptides complexes
No full textL'auteur n'a pas fourni de résumé en françaisL'auteur n'a pas fourni de résumé en anglai
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Keynote Lecture: Bioinspired Cu chelators or How bioinorganic chemistry may help treating the Wilson’s disease
No full textInternational audienc
Invited Lecture: Targeting intrahepatocyte copper overload thanks to the asialoglycoprotein receptors
No full textInternational audienc
Plenary Lecture: How does bioinorganic chemistry contribute to current challenges in biology, toxicology or medicine?
No full textInternational audienc
Deciphering and mimicking metal binding sites in biology through peptide design approaches
No full textInternational audienc
Invited oral communication: Deciphering and mimicking metal binding sites in life
No full textInternational audienc
- …
