title: Synthesis of Unprecedented Sulfonylated Phosphono-exo-Glycals Designed as Inhibitors of the Three Mycobacterial Galactofuranose Processing Enzymes.
abstract: This study reports a new methodology to synthesize exo-glycals bearing both a sulfone and a phosphonate. This synthetic strategy provides a way to generate exo-glycals displaying two electron-withdrawing groups and was applied to eight different carbohydrates from the furanose and pyranose series. The Z/E configurations of these tetrasubstituted enol ethers could be ascertained using NMR spectroscopic techniques. Deprotection of an exo-glycal followed by an UMP (uridine monophosphate) coupling generated two new UDP (uridine diphosphate)-galactofuranose analogues. These two Z/E isomers were evaluated as inhibitors of UGM, GlfT1, and GlfT2, the three mycobacterial galactofuranose processing enzymes. Molecule 46-(E) is the first characterized inhibitor of GlfT1 reported to date and was also found to efficiently inhibit UGM in a reversible manner. Interestingly, GlfT2 showed a better affinity for the (Z) isomer. The three enzymes studied in the present work are not only interesting because, mechanistically, they are still the topic of intense investigations, but also because they constitute very important targets for the development of novel antimycobacterial agents.
authors.affiliation: University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61, 5000, Namur, Belgium.
authors.forename: Christophe J-M
authors.initials: CJ
authors.lastname: Frédéric
authors.affiliation: University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61, 5000, Namur, Belgium.
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Tikad
authors.affiliation: University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61, 5000, Namur, Belgium.
authors.forename: Jian
authors.initials: J
authors.lastname: Fu
authors.affiliation: The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, 202, Sha-chong South Road, Guiyang, 550002, P. R. China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Chemistry and Alberta Glycomics Centre, University of Alberta, Gunning-Lemieux Chemistry Centre, 11227 Saskatchewan Drive, Edmonton, AB T6G 2G2, Canada.
authors.forename: Ruixiang B
authors.initials: RB
authors.lastname: Zheng
authors.affiliation: Department of Chemistry and Alberta Glycomics Centre, University of Alberta, Gunning-Lemieux Chemistry Centre, 11227 Saskatchewan Drive, Edmonton, AB T6G 2G2, Canada.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Koizumi
authors.affiliation: Department of Chemistry and Alberta Glycomics Centre, University of Alberta, Gunning-Lemieux Chemistry Centre, 11227 Saskatchewan Drive, Edmonton, AB T6G 2G2, Canada.
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Chemistry and Alberta Glycomics Centre, University of Alberta, Gunning-Lemieux Chemistry Centre, 11227 Saskatchewan Drive, Edmonton, AB T6G 2G2, Canada.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Lowary
authors.affiliation: University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61, 5000, Namur, Belgium. stephane.vincent@unamur.be.
authors.forename: Stéphane P
authors.identifier: http://orcid.org/0000-0001-6258-9058
authors.initials: SP
authors.lastname: Vincent
mesh_terms: D002241:Carbohydrates / Q000138:chemical synthesis* / Q000737:chemistry; D004987:Ethers / Q000737:chemistry*; D009161:Mycobacterium / Q000737:chemistry*; D013237:Stereoisomerism; D014530:Uridine Diphosphate / Q000737:chemistry*
chemical_list: D002241:Carbohydrates; D004987:Ethers; D014530:Uridine Diphosphate
keywords: glycals; glycosyltransferase; phosphonates; sulfones; tuberculosis