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report herein the synthesis of a series of glycomimetics of the OGT substrate UDP‐GlcNAc, in which the GlcNAc motif has been replaced by an imino‐ C ‐glycoside and the pyrophosphate moiety has been either conserved, replaced by a squaramide linker, or truncated to remove the terminal phosphate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 (IC 50 = 50 µM).