Ces travaux de recherche décrivent la synthèse d’architectures hélicoïdales et twistées à partir de briques moléculaires hétérocycliques. D’abord, la première partie est consacrée aux structures hélicéniques à savoir les carbohélicènes, oxahélicènes et fluorénones hélicoïdales.La deuxième partie du travail est dédiée à la préparation des architectures moléculaires twistées. Pour cela, nous avons mis au point une méthodologie simple et courte qui mène à des édifices hétérocycliques étendus à base du motif acridino-acridines et phénanthrolines à partir de la condensation entre des β-chlorovinylaldéhydes d’anilines diversement substituées. / The intertest of our research is the synthesis of helical and twisted architectures from heterocyclic molecular bricks. The first part is devoted to helicenic structures named carbohelicenes, oxahelicenes and helical fluorenones.The second part of the work describes the preparation of twisted molecular architectures. For this, we have developed a short and simple methodology that leads to twisted molecular architectures included acridines, acridino-acridines and phenanthrolines. This synthesis is accessible from the condensation between β-chlorovinylaldehydes and variously substituted anilines.

The regulation of systemic immune responses is dependent on individual cell responses that will concur to induce a coherent response against a stimulus. In turn, cell response is dependent on the processing of intracellular signals generated at the cell membrane and transmitted through successive protein modifications to the nucleus in order to activate gene transcription. This is referred to as intracellular signalling. Tight control of these mechanisms is required to generate an appropriate cell response to environmental stimulations and globally to establish an appropriate immune response. Among protein modifications used to transmit a signal to the nucleus, protein tyrosine phosphorylation represents a pivotal method used by immune cells to rapidly induce signalling. While protein tyrosine kinases (PTKs) phosphorylate proteins, protein tyrosine phosphatases (PTPs) regulate the signalling by removing the phosphate group. The goal of this study was to better characterize intracellular signalling events involved in allergic asthma, a chronic inflammatory disease involving a Th2 immune response. In a first time, we investigated the role of PTPs in the development of asthma. We show that inhibition of global PTP activity in mice, during either the allergen sensitization or the allergen challenge phase, reduces asthma development and is linked to an increased Th1 response in the spleen and lung. Secondly, we revealed that TC-PTP inhibition reduces asthma development, while PTP-1B inhibition exacerbates inflammatory cells recruitment to the lung. Inhibition of either SHP-1 or PTP-PEST activity did not significantly modulate asthma development in our model. In a third set of experiments, we got interested in the signalling pathways triggered by the pro-inflammatory molecules myeloid-related proteins (MRPs) 8 and 14. MRPs are small cytosolic proteins recently described to have extracellular functions. MRP8 expression is resistant to corticosteroid treatment, and potentially promotes inflammation in corticosteroid-treated patients. We identified that MRPs induce signal through the action of TLR-4 and trigger the activation of MEK/ERK and JNK pathways that lead to NF-kappaB translocation. Collectively, our data provide a new characterization of signalling pathways engaged in allergic asthma. This should be helpful in the elaboration of new therapeutic approaches targeting precise pathways to inhibit mechanisms of inflammation.

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