Rational design and synthesis of chemical probes for O-GlcNAcase and OGT

Attachment of GlcNAc via a β-O-linkage to serine or threonine residues of various nucleocytoplasmic proteins is a posttranslational modification in multicellular eukaryotes. A glycosyl transferase, UDP-N-acetyl-D-glucosamine: polypeptide-N-acetylglucosaminyl transferase (OGT) installs O-GlcNAc while a β-N-acetylglucosaminidase, O-GlcNAcase, removes this modification from proteins. A dynamic relationship between O-GlcNAc and phosphorylation has been proposed and is implicated in cellular signalling and disorders such as Alzheimer disease. In this thesis, the facile syntheses of two series of inhibitors of O-GlcNAcase are described. The potency of these compounds toward O-GlcNAcase is also detailed. Several of these compounds are highly potent and selective inhibitors of O-GlcNAcase. Additionally, 2-acetamido-2-deoxy-5-thio-D-glucopyranosose was synthesized as an analogue of GlcNAc. This compound was used for cell studies and to synthesize para-methoxyphenyl 2-acetamido-2-deoxy-5-thio-D-glucopyranoside as a potential substrate for O-GlcNAcase. Together, these compounds should serve as useful chemical probes to study the function of O-GlcNAc in cells and in vivo.