Synthesis and Evaluation of Iminosugar-Based Analogs of UDP-GlcNAc as Putative OGT Inhibitors

O-GlcNAc transferase (OGT) is an essential mammalian enzyme that regulates numerous cellular processes through the attachment of O-linked N-acetylglucosamine (O-GlcNAc) residues to nuclear and cytoplasmic proteins. Inhibitors of OGT are needed as research tools and for evaluating the potential of OGT as a therapeutic target. As little effort has been made to incorporate mimicry of the glycosyl oxocarbenium character of the OGT transition state, we report herein the synthesis of a series of glycomimetics of the OGT substrate UDP-GlcNAc, in which the GlcNAc motif has been replaced by an imino-C-glycoside and the pyrophosphate moiety has been either conserved, replaced by a squaramide linker, or truncated to remove the terminal phosphate and base. While their affinity for human OGT both in vitro and in cells proved modest (>300 µM), an imino-C-glycoside of α-D-GalNAc-1-phosphate showed, surprisingly, micromolar noncompetitive inhibition of OGT (IC₅₀ = 50 µM).