Non-isosteric C-glycosyl analogues of natural nucleotide diphosphate sugars as glycosyltransferase inhibitors.
A series of C-glycosyl ethylphosphonophosphate analogues of UDP-Glc, UDP-Gal, UDP-GlcNAc and GDP-Fuc were synthesized from the corresponding C-glycosyl ethylphosphonic acids. Analogues were obtained as alpha-anomers through either diastereoselective photo-induced radical addition of glycosyl bromides (D-Glc, D-Gal and L-Fuc) to diethyl vinylphosphonate, or a multi-step sequence (D-GlcNAc), with subsequent coupling with morpholidate-activated nucleotide monophosphates. The in vitro inhibitory activity of UDP-Gal, GDP-Fuc and UDP-GlcNAc analogues towards glycosyltransferases (beta-1,4-GalT, FUT3 and LgtA) was evaluated through a competition fluorescence assay and IC(50) values of 40 microM, 2 mM and 3.5 mM were obtained, respectively.
Vidal
Sébastien
S
Laboratoire de Chimie Organique 2, UMR-CNRS 5181, Université Claude Bernard Lyon 1, CPE-Lyon Bâtiment 308, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France.
Bruyère
Isabelle
I
Malleron
Annie
A
Augé
Claudine
C
Praly
Jean-Pierre
JP
D002241:Carbohydrates / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016695:Glycosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D018629:Spectrometry, Mass, Secondary Ion; D013379:Substrate Specificity
D002241:Carbohydrates; D004791:Enzyme Inhibitors; D016695:Glycosyltransferases