Uridine Bisphosphonate-Carbagalactose: A Stabilized α-1,4-Galactosyltransferase Inhibitor.

Methylene and difluoromethylene uridine bisphosphonate carbagalactose were designed and synthesized as stable uridine diphosphate-galactose (UDP-Gal) mimics for probing α-1,4-galactosyltransferase (A4GALT). In these analogues, the labile glycosidic and pyrophosphate linkages of UDP-Gal are replaced by chemically and enzymatically stable motifs, yielding compounds that retain key structural features essential for biological recognition. This work demonstrates the first successful nucleophilic substitution of a secondary triflate with a difluoromethylene bisphosphonate, providing a methodology that should enable efficient access to a range of sugar nucleotide mimics. The CH2 and CF2 UDP-Gal analogues 5 and 6 inhibited A4GALT, displaying IC50 values of 249 and 217 μM, respectively, in the presence of 500 μM UDP-Gal, consistent with efficient recognition by the A4GALT donor-binding site.