A new methodology for the synthesis of fluorinated exo-glycals and their time-dependent inhibition of UDP-galactopyranose mutase.
Fluorinated carbohydrates constitute a very important class of mechanistic probes for glycosyl-processing enzymes. In this study, we describe the first synthesis of fluorinated and phosphonylated exo-glycals and their corresponding nucleotide sugars in the galactofuranose series. The synthetic protocol that we have developed is a Selectfluor-mediated fluorination/elimination sequence on phosphonylated exo-glycals, and it offers a new entry into fluorinated carbohydrate chemistry. The challenging E/Z stereochemical assignment of the resulting tetrasubstituted alkenes, which bear an alkoxy, an alkyl, a fluoro, and a phosphonyl group, has been achieved through NMR experiments. The corresponding (E)- and (Z)-nucleotide fluorosugars have been prepared and tested as inhibitors of UDP-galactopyranose mutase (UGM). UGM is a flavoenzyme that catalyzes the isomerization of uridine diphosphate(UDP)-galactopyranose into UDP-galactofuranose, a key step of the biosynthesis of important mycobacterial cell-wall glycoconjugates. The two diastereomeric molecules were found to display time-dependent inactivation of UGM, as expected from preliminary results using non-fluorinated exo-glycal nucleotides. The inhibitory properties of the two fluorinated molecules led us to suggest that the inactivation mechanism proceeds through two-electron processes, despite the presence of the flavin cofactor within the UGM catalytic site.
Caravano
Audrey
A
Ecole Normale Supérieure, Département de Chimie, Institut de Chimie Moléculaire (FR 2769), UMR 8642: CNRS-ENS-UPMC Paris 6, 24 rue Lhomond, 75231 Paris Cedex 05, France.
Dohi
Hirofumi
H
Sinaÿ
Pierre
P
Vincent
Stéphane P
SP
D005461:Fluorine / Q000737:chemistry*; D005690:Galactose / Q000737:chemistry*; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D009711:Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology
D009711:Nucleotides; D005461:Fluorine; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase; D005690:Galactose