Synthesis of clickable analogues of ADP-heptose analogues

Student thesis: Doc typesDoctor of Sciences

Abstract

The discovery of new Gram-Negative antivirulence agents via the inhibition of lipopolysaccharide (LPS) biosynthetic pathway which is an important for the virulence factors of Gram-Negative pathogens. The heptosyltransferases such as WaaC represent promising and attractive targets for the discovery of new antibacterial drugs based on anti-virulence mechanisms.
In order to access molecular structures designed to probe the different WaaC binding sites, we synthesized a series of clickable ADP-β-heptose analogues to study the mechanism and the binding properties of WaaC in this thesis. These compounds feature an ADP moiety, a mannose or a heptose subunit for mimicking the natural substrate of WaaC. All these characteristics are essential for the binding with the active site of WaaC. The protected azido-heptose and alkyne-heptose were synthesized from the protected L-heptose scaffolds which could be generated by a multi-step synthesis starting from α-methyl-D-mannoside. Two ADP-azido-mannose and one ADP-azido-heptose have been synthesized using the diallyl chlorophosphate as an effective phosphorylating reagent.
A series of ADP-triazole compounds have been synthesized by click chemistry. The inhibition of profile of ADP-triazole library showed that these molecules are competitive inhibitors of WaaC. The best inhibitor exhibited low micromolar inhibition levels with IC50’s range from 6 μM to 184 μM. Additionally, a series of simple fucose triazoles were also synthesized to explore the inhibition of WaaC, and these simple fucose analogues displayed weak inhibition levels.
Key works: Antibacterial, Antivirulence, LPS biosynthesis, Heptosyltransferase I (WaaC), Click chemistry, Heptose,
Date of Award19 Jan 2015
Original languageEnglish
Awarding Institution
  • University of Namur
SupervisorStéphane Vincent (Supervisor), Johan Wouters (President), Steve Lanners (Jury), Olivier Riant (Jury) & Steven BALLET (Jury)

Cite this

Synthesis of clickable analogues of ADP-heptose analogues
Li, T. (Author). 19 Jan 2015

Student thesis: Doc typesDoctor of Sciences