Abstract : In the context of the search for active molecules that would act specifically on pathogenic microorganisms such as mycobacteria, galactofuranose biosynthesis has become a challenging new drug target. Our approach consists in designing and synthesizing original iminosugars that could act as mechanistic probes and/or inhibitors of the enzymes involved: UDP-Galp mutase (UGM) and Galf transferases (GlfT). Consequently, we investigated two stereodivergent approaches to imino-C-galactosides.
We developed a methodology based on the Lewis-Acid mediated addition of silylated nucleophiles onto protected N-glucosylamine which lead to alpha-1-C-substituted 1,4-dideoxy-1,4-imino-D-galactitol derivatives with a diversity of functionalized groups at C-1 position. Following convergent synthetic sequences such as cross-metathesis reactions we then synthesized iminosugar-based UDP-Galf mimics linked to UMP by structurally various tethers.
On the other hand, 1,3-dipolar cycloaddition of functionalized phosphonate with a D-galacto-configured cyclic nitrone provided an isoxazolidine with high regio- and stereoselectivity. This bicyclic compound is an original UDP-Galf analog and a precursor of beta-linked 1,4-iminogalactitol-UMP conjugates. This methodology also provided a concise and convergent approach to various Galf-disaccharide mimics. We also found that unprotected polyhydroxylated nitrone reacted readily, in water, with sugars olefins to provide the corresponding cycloadducts as imino-disaccharides precursors.
Biological evaluation of these compounds as potential inhibitors of UGM and GlfT2 showed that one UDP-Galf analog exhibited interesting activity toward GlfT2.