Heptose glycomimetics: synthesis and biological evaluations

Session: 
S10.1 Lipopolysaccharides
Code: 
OL10.1.4
Location (hall): 
Glucose
Start/end time: 
Thursday, July 4, 2019 - 18:00 to 18:15
Stéphane
Vincent

Stéphane Vincent1

1University Of Namur, Namur, Belgium

The glycero-D-mannoheptose core structure is exclusively found in bacteria, either with the 6-D configuration as in 1 or with a 6-L configuration as in ADP-heptose 3. Nucleotide-sugar 3 is the substrate of bacterial heptosyltransferases that play a key role in the biosynthesis of Lipopolysaccharide (LPS). From a medical prospective this bacterial biosynthetic pathway is important because: 1) the inhibition of the heptose processing enzymes leads to a dramatic phenotypic change that blocks the virulence of some major pathogenic gram-negative bacteria 2) It has been recently shown that heptose metabolites such as 1-3 can activate the innate immune response through a TIFA-dependent pathway.[1]

Based on the biological relevance of the bacterial heptosides, our laboratory has synthesized different types of heptose glycomimetics illustrated in Figure 1: multivalent species based on a glycofullerene core structure 4,[2]  highly fluorinated D-heptoside 5 and heptosyltransferase inhibitor 6.[3] Novel heptose scaffolds are now available in our laboratory and their biological evaluations will be discussed.

Figure 1. Natural bacterial heposides 1-3 and synthetic heptose analogues 4-6.

References: 
  1. Gaudet, R. G.; Sintsova, A.; Buckwalter, C. M.; Leung, N.; Cochrane, A.; Li, J.; Cox, A. D.; Moffat, J.; Gray-Owen, S. D., Science 2015, 348, 1251-5 ; P. Zhou, F. Shao et al. Nature 2018, 561, 122-6
  2. M. Durka, K. Buffet, J. Iehl, M Holler, J.-F. Nierengarten, S.P. Vincent Chem. Eur. J. 2012, 18, 641-651.
  3. M. Durka, A. Tikad,  R. Périon,  M. Bosco, M. Andaloussi, S. Floquet,  E. Malacain, F. Moreau, M. Oxoby, V. Gerusz, S.P. Vincent    Chem. Eur. J. 2011, 17, 11305-13 ; H. Dohi, R. Périon, M. Durka, M. Bosco, Y. Roué, F. Moreau, S. Grizot, A. Ducruix, S. Escaich, S. P. Vincent Chem. Eur. J. 2008, 14, 9530-39.

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