Synthesis of UDP-carbasugars as inhibitors of UDP-GALACTOPYRANOSE MUTASE

Tuberculosis, caused by Mycobacterium tuberculosis (TB), one of the most contagious diseases, threatens the world population because of the emergence of pathogenic strains highly resistant to known antibiotics. UDP-Galactopyranose mutase (UGM) is a validated target for the discovery of new therapeutic agents to fight TB. This enzyme can catalyze the interconversion of UDP-Galactopyranose (UDP-Galp) into UDPGalactofuranose (UDP-Galf). The contribution of UGM in the biosynthesis of Galf containing glycoconjugates and its absence in mammals push the community to synthesize novel inhibitors in order to elucidate the modes of action and binding of this enzyme. The design of new mechanistic probes that mimick UDP-Galf or the transition states of this reaction will help to better understand its mechanism and then may allow the development of new drugs to cure TB. The aim of this thesis is to synthesize a series of UDP-carbasugars analogues of UDP-Galf in order to study the mechanism and the binding properties of UGM. These compounds feature a UDP moiety, a galactitol chain for mimicking high-energy intermediates of the enzymatic reaction. All these characteristics are essential for the binding within the active site of UGM. Cyclohexene derivatives could be obtained by ring-closing metathesis from the corresponding diene which would be generated by a multi-step synthesis starting from D-galactose. Two different categories of UDP-Galf analogues have been synthesized using the carbocycle (cyclohexene) as precursor: compounds with a phosphonate moiety or with a phosphate group. From these two scaffolds, a divergent synthesis has been carried out by functionalizing the double bond of the carbocycle. These products have then been coupled with uridine monophosphate to provide the different UDPcarbasugars. The inhibition profile of UDP-carbasugars showed that these compounds are competitive inhibitors of UGM. UDP-cyclohexene and UDP-cyclohexane provides the best inhibition profile of this series due to the hydrophobic character present on the anomeric position of the carbocycle. Interestingly, UDP-polyol phosphates can bind UGM better than UDP-polyol phosphonates due to the presence of an oxygen atom between the anomeric position and the UDP.