title: Selectfluor and NFSI exo-glycal fluorination strategies applied to the enhancement of the binding affinity of galactofuranosyltransferase GlfT2 inhibitors.
abstract: Two complementary methods for the synthesis of fluorinated exo-glycals have been developed, for which previously no general reaction had been available. First, a Selectfluor-mediated fluorination was optimized after detailed analysis of all the reaction parameters. A dramatic effect of molecular sieves on the course of the reaction was observed. The reaction was generalized with a set of biologically relevant furanosides and pyranosides. A second direct approach involving carbanionic chemistry and the use of N-fluorobenzenesulfonimide (NFSI) was performed and this method gave better diastereoselectivities. Assignment of the Z/E configuration of all the fluorinated exo-glycals was achieved based on the results of HOESY experiments. Furthermore, fluorinated exo-glycal analogues of UDP-galactofuranose were prepared and assayed against GlfT2, which is a key enzyme involved in the cell-wall biosynthesis of major pathogens. The fluorinated exo-glycals proved to be potent inhibitors as compared with a series of C-glycosidic analogues of UDP-Galf, thus demonstrating the double beneficial effect of the exocyclic enol ether functionality and the fluorine atom.
authors.affiliation: University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique rue de Bruxelles 61, B-5000 Namur (Belgium), Fax: (+32) 81-72-45-17.
authors.forename: Lidia
authors.initials: L
authors.lastname: Dumitrescu
authors.forename: Guillaume
authors.initials: G
authors.lastname: Eppe
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Tikad
authors.forename: Weidong
authors.initials: W
authors.lastname: Pan
authors.forename: Sandy
authors.initials: S
authors.lastname: El Bkassiny
authors.forename: Sudagar S
authors.initials: SS
authors.lastname: Gurcha
authors.forename: Ana
authors.initials: A
authors.lastname: Ardá
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Stéphane P
authors.initials: SP
authors.lastname: Vincent
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003979:Diazonium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005690:Galactose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054879:Halogenation; D006801:Humans; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy; D014530:Uridine Diphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000995:Antitubercular Agents; D003979:Diazonium Compounds; D004791:Enzyme Inhibitors; D005690:Galactose; D005700:Galactosyltransferases; D013449:Sulfonamides; D014530:Uridine Diphosphate; C104136:uridine diphosphate galactofuranose; C523711:N-fluorobenzenesulfonimide; D000096926:Benzenesulfonamides; C408750:selectfluor
keywords: NMR spectroscopy; fluorination; glycosyltransferase; phosphonates; structure elucidation; tuberculosis