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

TY - JOUR

T1 - Optimised chemical synthesis of 5-substituted UDP-sugars and their evaluation as glycosyltransferase inhibitors

AU - Tedaldi, Lauren M.

AU - Pierce, Michael

AU - Wagner, Gerd K.

PY - 2012/12/15

Y1 - 2012/12/15

N2 - 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. (C) 2012 Elsevier Ltd. All rights reserved.

AB - 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. (C) 2012 Elsevier Ltd. All rights reserved.

U2 - 10.1016/j.carres.2012.10.009

DO - 10.1016/j.carres.2012.10.009

M3 - Article

SN - 0008-6215

VL - 364

SP - 22

EP - 27

JO - Carbohydrate Research

JF - Carbohydrate Research

ER -