Synthesis of N-Acyl-Glucosaminyl Derivatives for Inhibition of Human OGA

O-GlcNAcylation is a dynamic post-translational modification by adding and removing a single β-N-acetylglucosamine (GlcNAc) moiety to and from serine/threonine residues of nucleocytosolic and mitochondrial proteins. The dynamic cycling of O-GlcNAc modification on numerous, functionally diverse set of proteins is catalyzed by two enzymes: O-linked β-N-acetylglucosamine transferase (OGT) and β-N-acetylglucosaminidase (OGA) in response to cellular signals or cellular stages, similarly to phosphorylation. In many cases, phosphorylation and O-GlcNAcylation target the same serine/threonine residues in a reciprocal manner.[1,2] Human OGA is a promising therapeutic target in diseases where aberrant low level of O-GlcNAc is experienced.

PUGNAC (1) is one of the first inhibitors of OGA, NAG-thiazoline (2) is a transition-state mimicry inhibitor. Longer chains in the C-2 position can improve the inhibition and also the selectivity. Thus, Thiamet-G (3) has a dramatic 37 000-fold selectivity over the lysosomal β-hexosaminidase.[3] Also, the triazole compounds 4 have shown acceptable inhibition in case of aromatic substituents. Here we present the synthesis of some PUGNAC analog compounds (5), as well as C-(glucosaminyl)-heterocycles (6) among which tight-binding nanomolar inhibitors of human OGA were found.