Optimised chemical synthesis of 5-substituted UDP-sugars and their evaluation as glycosyltransferase inhibitors

We have investigated the applicability of different chemical methods for pyrophosphate bond formation to the synthesis of 5-substituted UDP-galactose and UDP-N-acetylglucosamine derivatives. The use of phosphoromorpholidate chemistry, in conjunction with N-methyl imidazolium chloride as the promoter, was identified as the most reliable synthetic protocol for the preparation of these non-natural sugar-nucleotides. Under these conditions, the primary synthetic targets 5-iodo UDP-galactose and 5-iodo UDP-N-acetylglucosamine were consistently obtained in isolated yields of 40–43%. Both 5-iodo UDP-sugars were used successfully as substrates in the Suzuki–Miyaura cross-coupling with 5-formylthien-2-ylboronic acid under aqueous conditions. Importantly, 5-iodo UDP-GlcNAc and 5-(5-formylthien-2-yl) UDP-GlcNAc showed moderate inhibitory activity against the GlcNAc transferase GnT-V, providing the first examples for the inhibition of a GlcNAc transferase by a base-modified donor analogue.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► An optimised chemical synthesis for 5-substituted UDP-sugars was developed. ► NMICl was found to be the optimal promoter for pyrophosphate bond formation. ► Two new derivatives of UDP-GlcNAc were synthesised. ► Both molecules are moderate inhibitors of the GlcNAc transferase GnT-V.