CARB 87

Intracellular postranslational protein glycosylation, through which N-acetylglucosamine (GlcNAc) residues are beta-glycosidically linked to the hydroxy group of serine, has been observed. Furthermore, it has been shown that beta-amyloid precursor protein (APP), which is associated with Alzheimer's disease, is also postranslationally modified by O-GlcNAc residues. The specific functions of O-GlcNAc attachment to proteins have not yet been fully elucidated. Indirect evidence led to the hypothesis that O-GlcNAc linkage has a reciprocal realtionship to the regulatory effect of protein phosphorylation and dephosphorylation. Therefore, access to glycopeptides carrying hydrolytically stable C-linked GlcNAc residues is of great interest.

To this end, C-glycononapeptide 1 – a C-glycosidic analogue of a postranslationally modified RNA polymerase II fragment – has been synthesized using new Fmoc-protected and pentafluorophenol (Pfp) ester activated C-linked D-GlcNAc-L-serine building block 2 in solid phase synthesis (scheme). Thorough conformational analysis of 1 has been carried out by NMR experiments (600 MHz).

C-glycopeptide 1 proved to enhance O-GlcNAc expression in vivo using N2a neuroblastoma cells analysed by Western blot. Therefore, 1 is considered to competitively inhibit O-GlcNAc hydrolase in vivo.