NOVEL SYNTHESIS OF TRI- AND TETRASUBSTITUTED EXO-GLYCALS TARGETING THE MYCOBACTERIAL CELL WALL BIOSYNTHESIS

  • Guillaume Eppe

    Student thesis: Doc typesDoctor of Sciences

    Abstract

    Each year, Mycobacterium tuberculosis is responsible for 8 million human infections and 2 million deaths. Today’s therapies are more and more obsolete with the emergence of new resistant strains thus urging the need for novel therapeutic targets in the fight against tuberculosis. The inhibition of the biosynthesis of the mycobacterial cell wall is now a validated approach to develop novel antitubercular agents. In this prospect, the three galactofuranose processing enzymes (UGM, GlfT1, GlfT2) have recently emerged as important targets. In particular: the UDP Galacto-pyranose mutase (UGM) and two Galactofuranosyl transferases (GlfTs). Their common substrate, UDP-Galf, is essential for the growth of the pathogen. Phosphono-exo-glycals and fluoro-phosphono-exo-glycals are analogs of UDP-Galf, shared by the three aforementioned enzymes. More importantly, those molecules are irreversible inhibitors of UGM. The restrictions inherent to the synthetic methods available today for the preparation of exo-glycals limit both the available diversity of substituent on the double bond and the stereocontrol of the double bond. In particular, exo-glycals bearing two electronwithdrawing groups, despite being highly desirable for the biochemical relevance, are not accessible by the methodologies described in the literature. In this thesis, we report the development of a new methodology allowing the functionalization of exo-glycals. This methodology allows the preparation of both diastereoisomers from a stereo defined trisubstituted exo-glycal by a new process of cyclic enol ether isomerization never reported to date, to the best of our knowledge. Furthermore, this methodology allowed us to prepare new exo-glycals with two electronwithdrawing substituents in modest to good yields and mixed diastereoselectivities. Finally, biochemical studies on the UGM were performed, including Kd measurement for non natural substrate and competition assays against a novel E-exo-glycal analog of UDP-Galf.
    Date of Award17 Dec 2012
    Original languageFrench
    Awarding Institution
    • University of Namur
    SupervisorStephane Vincent (Supervisor), Davide BONIFAZI (Jury), Carmela APRILE (President), Robert FIELD (Jury) & Daniel WERZ (Jury)

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