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 α-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 (β-1,4-GalT, FUT3 and LgtA) was evaluated through a competition fluorescence assay and IC50 values of 40 μM, 2 mM and 3.5 mM were obtained, respectively.

A series of glycosyltransferase inhibitors were synthesized through photo-induced radical addition of glycosyl bromides to diethyl vinylphosphonate followed by deprotection then coupling with activated nucleoside monophosphates. Inhibition of each analogue was tested through a competition assay using a fluorescent acceptor substrate and analysis by RP-HPLC. Each analogue displayed reasonable inhibition towards the corresponding glycosyltransferase with a noticeable inhibition (similar to the Km of the natural substrate) for the UDP-Gal analogue.Figure optionsDownload as PowerPoint slide