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.