UDP‐GlcNAc Analogues as Inhibitors of O‐GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies

Abstract

A series of glycomimetics of UDP-GlcNAc, in which the β-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures. Their affinities for human O-GlcNAc transferase (hOGT) have been evaluated and studied both spectroscopically and computationally. The binding epitopes of the best ligands have been determined in solution by means of saturation transfer difference (STD) NMR spectroscopy. Experimental, spectroscopic, and computational results are in agreement, pointing out the essential role of the binding of β-phosphate. We have found that the loss of interactions from the β-phosphate can be counterbalanced by the presence of hydrophobic groups at a pyrroline ring acting as a surrogate of the carbohydrate unit. Two of the prepared glycomimetics show inhibition at a micromolar level.

Reactions of Allylmagnesium Reagents with Carbonyl Compounds and Compounds with C═N Double Bonds: Their Diastereoselectivities Generally Cannot Be Analyzed Using the Felkin–Anh and Chelation-Control Models

“…571 In the process of developing inhibitors of glycosyl transferases, the allylations of nitrones 1034 were examined (Scheme 420). 572 In all cases studied in this system, additions were highly stereoselective, even for monocyclic nitrones.…”

Modified Nucleosides, Nucleotides and Nucleic Acids via Click Azide-Alkyne Cycloaddition for Pharmacological Applications

“…A series of glycomimetics of UDP-GlcNAc containing a triazole ring in place of the β-phosphate unit were prepared by using CuAAC chemistry, in order to evaluate their affinities for human O-GlcNAc transferase (hOGT) [ 35 ]. Slightly different reaction conditions were employed for click reaction depending on the anomeric azide/triazole: the classical copper(II) sulfate/sodium ascorbate system performed well for α-anomers 35a , b , while the reactions leading to β-anomers 34a , b showed better results with the system (EtO) 3 P·CuI ( Scheme 7 ).…”

Targeting N‐acetylgalactosaminyltransferase for anticancer therapy

“…Importantly, the dicarbamate moiety prompted the intracellular entry of the molecules by crossing the charged membrane barrier (Jiang, Lazarus, Pasquina, Sliz, & Walker, 2012). Similarly, the replacement of a phosphate group with triazole nucleus provided pyrophosphate mimics that inhibited the target GalNAc‐Ts enzyme in micromolar scale (Ghirardello et al, 2018). Figure 2 demonstrates the contemporary progress in the development of rationally designed inhibitors of GalNAc‐Ts enzyme.…”