Synthesis of unprecedented electron-deficient exo-glycals targeting the mycobacterium tuberculosis cell call

Student thesis: Doc typesDoctor of Sciences

Abstract

Due to the fact that Mycobacterium tuberculosis, the causative agent of tuberculosis, remains a major threat for public health worldwide, the development of new drugs provides an interesting challenge. In this context, the biosynthesis of the mycobacterial cell wall has received a lot of attention. The main cell wall component is the mycolyl-ArabinoGalactan-Peptidoglycan (mAGP) complex which is composed of an arabinogalactan complex linked to a peptidoglycan backbone and mycolic acids. This mAGP constitutes a true Achilles heel of the bacterium since the inhibition of its formation will prevent M. tuberculosis to survive within the infected host. Therefore, the arabinogalactan complex still presents a major target for the development of anti-tubercular drugs because of its essential role for the viability of mycobacteria. The enzymes involved in the formation of the arabinogalactan complex are mainly UDP-galactopyranose mutase (UGM), two galactofuranose-transferases (GlfT1 and GlfT2) and several arabinosyltransferases (Arab-Ts). Their inhibition would prevent the biosynthesis of arabinogalactan complex and thus dramatically weaken the M. tuberculosis cell wall.
In this context, we propose the use of electron-deficient exo-glycals as inhibitors or inactivators of enzymes involved in the cell wall biosynthesis of M. tuberculosis. This thesis started with the development of a synthetic methodology for the synthesis of electron-poor exo-glycals bearing a sulfonyl group phosphonate. Applied to galactofuranose, this strategy allowed us to synthesize the sulfonylated-phosphono-exo-glycals (E) and (Z) as new UDP (uridine diphosphate)-galactofuranose analogues. The (E)-isomer was found to efficiently inhibit UGM in a reversible manner and was the first characterized inhibitor of GlfT1. Interestingly, for GlfT2, a better affinity was found for the (Z)-isomer. Then, several tetrasubstituted exo-glycals was synthesized through a directed metalation of phosphono-exo-glycals followed by electrophilic neutralization. This method also allowed to obtain the UDP-cyano-exo-glycals (E) and (Z). Finally, we developed the highly (Z)-diastereoselective synthesis of trifluoromethylated exo-glycals via photoredox catalysis.
Date of Award19 Dec 2018
Original languageEnglish
Awarding Institution
  • University of Namur
SponsorsFund for Research Training in Industry and Agriculture (FRIA)
SupervisorStéphane Vincent (Supervisor), Carmela Aprile (President), Guillaume Berionni (Jury), Raphaël Robiette (Jury) & Géraldine Masson (Jury)

Cite this

Synthesis of unprecedented electron-deficient exo-glycals targeting the mycobacterium tuberculosis cell call
Frederic, C. (Author). 19 Dec 2018

Student thesis: Doc typesDoctor of Sciences