Synthèse d'inhibiteurs de la glycéraldéhyde-3-phosphate deshydrogénase (étude mécanistique et applications)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Platforms for Bioorthogonal Oligonucleotide-templated Reactions: Translating Concepts into Devices

The exponential improvements made in DNA sequencing technologies, together with the rapidly declining associated costs, has increasingly led to the expansion of the field of personalised genomic medicine. Changes in the sequence or copy number of specific deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules represent key signatures for the diagnosis, prognosis, classification and monitoring of a broad range of pathologies, most notably cancer. Technologies that can detect these changes require analytical tools that can detect DNA or RNA with high sensitivity and high specificity. Sensing based on bioorthogonal oligonucleotide-templated reactions (OTRs) has been recognised as an elegant strategy that satisfies these criteria and was successfully used for the quantitative detection of nucleic acids both in vitro and in vivo. Herein, we will focus on recent efforts to implement bioorthogonal OTRs into clinically useful biosensors using probes immobilised on or embedded in customised materials and platforms

Quadruplexes de guanines et acridines (De la reconnaissance moléculaire au drug design)

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Reversible Synthesis and Characterization of Dynamic Imino Analogues of Trimethine and Pentamethine Cyanine Dyes

International audienc

Nouvelles sondes fluorogéniques supramoléculaires (Preuves de concepts et applications biologiques)

Il existe actuellement un intérêt croissant pour la conception de nouvelles sondes chimiques basées sur des systèmes supramoléculaires qui ont la capacité de reconnaître un métabolite cible avec une grande affinité et spécificité. En réponse à cette interaction, le système subit une rééquilibration se traduisant par un changement des propriétés physiques du milieu. Parmi les sondes chimiques les plus intéressantes, les sondes fluorescentes pour lesquelles le phénomène de reconnaissance moléculaire du métabolite par le capteur s accompagne d un changement des propriétés de fluorescence de l émetteur (longueurs d onde d excitation et d émission) présentent l avantage d une très grande sensibilité et d une grande simplicité de détection du signal. Nous proposons ici de développer un nouveau type de sonde moléculaire fluorescente inspirée des fluorophores de type cyanine dyes couramment utilisés en photographie, en stockage de données optiques ou encore en protéomique. La stratégie générale repose sur la capacité pour deux entités non-fluorescentes de réagir l une avec l autre de façon covalente (réversible ou irréversible) pour donner une molécule de type cyanine (ou analogue) fluorescente. Le système est conçu de telle sorte que la formation de la cyanine est thermodynamiquement fortement défavorisée mais peut être fortement amplifiée en présence d un métabolite capable d induire le rapprochement des deux entités réactives. Dans le cadre de cette thèse, nous nous sommes ainsi intéressés à la mise en évidence et à l étude de nouvelles réactions fluorogéniques biocompatibles puis à leurs applications pour la détection de structures ou séquences d acides nucléiques (ADN) in vitro.[...]Herein, we are reporting the development of original fluorescent and fluorogenic probes which have multiple applications in modern bioresearch. We demonstrate the potential of these systems for sensing nucleic acid structures (e.g. DNA G-quadruplexes, DNA hairpins), nucleic acid sequences (detection of single mutations) and biometabolites (e.g. Malondialdehyde). Most systems rely on the templated synthesis of cyanine dyes (or cyanine dye imino analogues) via either an aldolisation-elimination irreversible reaction or a reversible reaction of imine formation. Of particular interest is the original family of imine-containing cyanine dyes obtained by reaction between a Fisher s base aldehyde and a 2-amino-benzothiazolium derivative. These compounds are shown to form under reversible conditions compatible with the concept of dynamic combinatorial chemistry (DCC). We demonstrate that this fluorogenic system is responsive to external stimuli (such as temperature) and we demonstrate its potential use for monitoring reactions within water-in-oil microdroplets. Dynamic cyanine dyes are also described which are obtained from the reversible reaction between two molecules of 2-amino-benzothiazolium derivative and one molecule of malondialdehyde (MDA). We demonstrate that these compounds can serve as prodrugs for the selective alkylation of cytosines in vitro. Further work will be required to demonstrate whether the same strategy can be applied in vivo. We also use TD-DFT calculations to predict the maximum absorption wavelength of these modified cyanine dyes as well as that of the classical dyes. A very good correlation between theory and calculation was obtained by introducing a zero-point vibrational energy term. Finally, we show that the retro-Knoevenagel reaction is reversible and suitable for the concept of DCC. We demonstrate the reversibility of this C=C exchange reaction and in the future we plan to use this chemistry for developing new dynamic polymers.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Red/NIR G-Quadruplex Sensing, Harvesting Blue Light by a Coumarin-Naphthalene Diimide Dyad

A conceptually new light-up nucleic acid fluorescent probe resulting from the conjugation of a coumarin to a naphthalene diimide exhibits a single wavelength emission at 498 nm when free in solution and an additional red/NIR emission when bound to G-quadruplex DNA. The light-up response centred at 666 nm is highly specific for quadruplex DNA when compared to duplex DNA or to RNA quadruplexes

Selective inhibition of Trypanosoma cruzi GAPDH by “bi-substrate” analogues

International audienceA new series of “bi-substrate” analogues have been synthesized as potential inhibitors of the glyceraldehyde-3-phosphate dehydrogenase and one lead compound has been identified that inhibits the enzyme from Trypanosoma cruzi with good affinity and very high (50-fold) specificity