Synthèse asymétrique d' a-acides aminés conformationnellement contraints et de lactames dipeptidiques avec incorporation dans les peptides bioactifs

Les peptides jouent un rôle primordial dans divers systèmes biologiques en tant qu'hormones, neurotransmetteurs et neuromodulateurs... ce qui leur confère un intérêt considérable. Néanmoins, certaines caractéristiques intrinsèques empêchent leur développement en médicaments. Certains de ces inconvénients peuvent être évités dans les composés peptidomimétiques. Ces composés peuvent être obtenus par l'introduction de contraintes conformationnelles dans les peptides bioactifs. Beaucoup de peptides bioactifs prennent la conformation en coude qui joue un rôle important dans la reconnaissance du récepteur peptidique et dans la détermination de l'antigène. Dans le chapitre I, un rappel bibliographique sur les peptidomimétiques et sur la conformation en coude est présenté. De plus, nous nous sommes intéressés à l'AcSDKP, peptide bioactif, inhibiteur de la prolifération des cellules souches hématopoïétiques. Afin d'induire un coude, nous avons voulu incorporer un pont entre la chaîne latérale d'un acide aminé et le squelette peptidique. Dans le chapitre II, nous abordons la synthèse de lactames dipeptidiques de type 4-alkyl- 3-aminopipéridin-2-one, ainsi que l'étude conformationnelle de ce type de composé par la modélisation moléculaire et par des études en spectrométrie de RMN et en spectroscopie IR. Cette synthèse étant basée sur l'addition diastéréosélective en 1,4 d'un organocuprate sur un ester a,b insaturé, fait l'objet d'un rappel bibliographique. Dans le chapitre III, la synthèse de cis-3-alkyl-L-proline est présentée, chimère d'acides aminés. Cette synthèse a été effectuée suivant deux voies et les excès diastéréomériques contrôlés par CLHP. Le chapitre IV présente la synthèse d'analogues de l'AcSDKP obtenus par incorporation de lactame dipeptidique et de L-proline 3-cis-substituée synthétisés dans les parties précédentes.The peptides play a critical role in the various biological systems, i.e. hormones, neurotransmitters, and neuromodulators... Therefore, they are of considerable interests to the medicinal chemists. However, the use of peptides as drugs is limited by the following factors: their low metabolic stability towards proteolysis and their poor bioavailability. Some of the disadvantages could be overcome in the peptidomimetic compounds in which the modified structures retain the essential functionalities and then the three-dimensional structures of the native peptide. These peptidomimetics can be obtained by introducing the conformational constraints in the bioactive peptides. Numerous bioactive peptides have the turn conformations. In the chapter I, the progress in the literature on the peptidomimetics and on the turn conformation mimics reviewed. The turn is one of the essential conformations of peptides. Moreover, we are interested in the bioactive tetrapeptide AcSDKP, an inhibitor of the proliferation of the hematopoietic primitive stem cells. In order to introduce a turn structure, the incorporation of a "bridge" between the side chain of an amino acid and the peptide backbone is postulated. In fact, the cyclization is a well-known method for inducing a conformational constraint. In the chapter II, the synthesis of dipeptide lactams, 4-alkyl-3-amino-2-piperidinones is described. The key step of this synthesis is the diastereoselective 1,4-addition of an organocuprate onto an a, b-unsaturated ester. In this chapter, the conformation of the lactam 3-amino-4-methyl-2-piperidinone is also studied by molecular medeling and NMR and IR analyses. In the chapter III, two synthetic strategies of cis-3-alkyl-L-proline, chimeras of two amino acides, are presented. The diastereomeric excesses are determined by HPLC analysis. The chapter IV presents the synthesis of the analogues of the AcSDKP by incorporating the dipeptide lactam and the cis-3- substituted proline.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Qsat: A Mission Proposal for Profiling Water Vapour from Space

International audienceIn many important respects climate and weather rely heavily on the distribution of water vapour in the atmosphere. In terms of climate change, water vapour leads to the largest feedback, as it more than doubles the surface warming from atmospheric CO2. In the tropics, lower tropospheric water vapour is the best predictor of vertical motion and precipitation, thus making it central for understanding tropical weather, the climate of the tropics, and tropical climate change, as well as cloud feedbacks. But also in the extra-tropics, the poleward transport of water vapour in the storm track regions, e.g., in the form of "atmospheric rivers", which often accompany the rapid intensification of extra-tropical cyclones, is frequently associated with important weather events and extremes. Some of the questions related to the distribution of water vapour in the atmosphere, in particular in the upper troposphere, are longstanding and have been targeted by previous measurement systems, albeit not satisfactorily. To make progress with regard to these open questions the authors proposed to ESA the idea for a future mission, Qsat, to globally measure profiles of tropospheric water vapour with high vertical resolution and low bias from a satellite in a lower Earth orbit. Using the differential absorption lidar (DIAL) technique in combination with a scanning microwave radiometer Qsat would resolve the distribution of water vapor, also in the lower troposphere, over a broad area. Its measurements would close a long-standing gap in the observing system and provide crucial new information for climate research and weather forecasting. We will present the mission idea, the instrument concept and show simulations of the expected performance under various atmospheric conditions. Measurement examples from an airborne demonstrator for Qsat will be used to highlight the deficits of current global water vapour profiling and the possible benefits of Qsat

Qsat: A Mission Proposal for Profiling Water Vapour from Space

International audienceIn many important respects climate and weather rely heavily on the distribution of water vapour in the atmosphere. In terms of climate change, water vapour leads to the largest feedback, as it more than doubles the surface warming from atmospheric CO2. In the tropics, lower tropospheric water vapour is the best predictor of vertical motion and precipitation, thus making it central for understanding tropical weather, the climate of the tropics, and tropical climate change, as well as cloud feedbacks. But also in the extra-tropics, the poleward transport of water vapour in the storm track regions, e.g., in the form of "atmospheric rivers", which often accompany the rapid intensification of extra-tropical cyclones, is frequently associated with important weather events and extremes. Some of the questions related to the distribution of water vapour in the atmosphere, in particular in the upper troposphere, are longstanding and have been targeted by previous measurement systems, albeit not satisfactorily. To make progress with regard to these open questions the authors proposed to ESA the idea for a future mission, Qsat, to globally measure profiles of tropospheric water vapour with high vertical resolution and low bias from a satellite in a lower Earth orbit. Using the differential absorption lidar (DIAL) technique in combination with a scanning microwave radiometer Qsat would resolve the distribution of water vapor, also in the lower troposphere, over a broad area. Its measurements would close a long-standing gap in the observing system and provide crucial new information for climate research and weather forecasting. We will present the mission idea, the instrument concept and show simulations of the expected performance under various atmospheric conditions. Measurement examples from an airborne demonstrator for Qsat will be used to highlight the deficits of current global water vapour profiling and the possible benefits of Qsat

Qsat: A Mission Proposal for Profiling Water Vapour from Space

International audienceIn many important respects climate and weather rely heavily on the distribution of water vapour in the atmosphere. In terms of climate change, water vapour leads to the largest feedback, as it more than doubles the surface warming from atmospheric CO2. In the tropics, lower tropospheric water vapour is the best predictor of vertical motion and precipitation, thus making it central for understanding tropical weather, the climate of the tropics, and tropical climate change, as well as cloud feedbacks. But also in the extra-tropics, the poleward transport of water vapour in the storm track regions, e.g., in the form of "atmospheric rivers", which often accompany the rapid intensification of extra-tropical cyclones, is frequently associated with important weather events and extremes. Some of the questions related to the distribution of water vapour in the atmosphere, in particular in the upper troposphere, are longstanding and have been targeted by previous measurement systems, albeit not satisfactorily. To make progress with regard to these open questions the authors proposed to ESA the idea for a future mission, Qsat, to globally measure profiles of tropospheric water vapour with high vertical resolution and low bias from a satellite in a lower Earth orbit. Using the differential absorption lidar (DIAL) technique in combination with a scanning microwave radiometer Qsat would resolve the distribution of water vapor, also in the lower troposphere, over a broad area. Its measurements would close a long-standing gap in the observing system and provide crucial new information for climate research and weather forecasting. We will present the mission idea, the instrument concept and show simulations of the expected performance under various atmospheric conditions. Measurement examples from an airborne demonstrator for Qsat will be used to highlight the deficits of current global water vapour profiling and the possible benefits of Qsat