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DTSTART;TZID=Europe/Paris:20261020T140000
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DTSTAMP:20260927T170156
CREATED:20260922T091427Z
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UID:206357-1792504800-1792504800@www.bordeaux-neurocampus.fr
SUMMARY:Thesis defense - Adrien Denizet
DESCRIPTION:Venue : BBS \nThesis defended in french \n \n\nIMN\nTeam: Purinergic mediated neuroinflammation and brain disorders\nThesis directed by Philippe Peixoto (ISM).\nCo-directed by Sandrine Bertrand (INCIA) and Eric Boué-Grabot (IMN) \nTitle\nTotal syntheses of Securinega alkaloids and study of their biological activities \nAbstract\nSecurinega alkaloids constitute a family of tetracyclic metabolites isolated from subtropical plants of the Phyllanthaceae family. Since the identification of the first members of this class in the mid-XXth century\, more than 170 compounds have been described to date. Over the years\, these molecules have attracted increasing interest because of their diverse biological activities. Among them\, the activity at GABAA receptors of (–)-securinine\, the first isolated entity of this family\, was demonstrated approximately forty years ago\, paving the way for the study of these alkaloids in the context of central nervous system disorders. Despite these initial observations\, the molecular mechanisms underlying their neurobiological effects remain largely unknown\, leaving unresolved their pharmacological positioning among currently available GABAA receptor ligands. Limited access to these compounds from natural sources has long hindered their investigation. However\, advances in organic synthesis now make it possible to explore them in greater depth using modern neurobiological tools. In this context\, the main objective of this thesis was to characterize the activity of several Securinega alkaloids at GABAA receptors and to determine which structural features of both the natural products and the receptor influence their activity. \nThe first stage of this work consisted in producing several members of this family in sufficient quantities through total synthesis\, relying on expertise developed and mastered within my research group. Electrophysiological studies performed on Xenopus laevis oocytes and mouse brain slices revealed structure–activity relationships within this series of alkaloids\, as well as an influence of GABAA receptor subunit composition on their activity. These results were further supported by molecular modeling studies\, providing a rationale for the observed selectivity profiles. Beyond the central nervous system\, the potential application of these compounds was also explored in the field of phytopathology through the evaluation of their activity against grapevine downy mildew\, a major socio-economic challenge in the Bordeaux region. Finally\, a second component of this thesis\, developed in parallel with the main project\, led to the first asymmetric total synthesis of (+)- and (–)-myrioneurinols through the combination of two transformations developed within the laboratory: a chlorinative alkynyl-Prins reaction and a late-stage resolution strategy based on the Barton–McCombie reaction. \nKey words\nOrganic chemistry\, Neurobiology\, Securinega alkaloids\, Natural products\, GABAA receptors\, Total synthesis\, Myrioneurinol \nJury\n\nThomas GRUTTER\, Directeur de recherche\, CNRS-UMR 7199\, Strasbourg – Rapporteur\nYung-Sing WONG\, Directeur de recherche\, CNRS-UMR 5063\, Grenoble – Rapporteur\nMme Stéphanie CLUZET\, Professeure\, CNRS-UMR 1366\, Bordeaux – Examinatrice\nYannick LANDAIS\, Professeur\, CNRS-UMR 5255\, Bordeaux – Examinateur\nAntoine TALY\, Directeur de recherche\, CNRS-UPR 9080\, Paris – Examinateur\nPhilippe A. PEIXOTO\, Chargé de recherche\, CNRS-UMR 5255\, Bordeaux – Directeur de thèse\nMme Sandrine BERTRAND\, Directrice de recherche\, CNRS-UMR 5287\, Bordeaux – Co-encadrante\nM. Éric BOUÉ-GRABOT\, Directeur de recherche\, CNRS-UMR 5293\, Bordeaux – Co-encadrant\n\n
URL:https://www.bordeaux-neurocampus.fr/en/event/soutenance-de-these-adrien-denizet/
CATEGORIES:IMN,Thesis
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