Design of Glycosyltransferase Inhibitors: Pyridine as a Pyrophosphate Surrogate

A series of ten glycosyltransferase inhibitors has been designed and synthesized by using pyridine as a pyrophosphate surrogate. The series was prepared by conjugation of carbohydrate, pyridine, and nucleoside building blocks by using a combination of glycosylation, the Staudinger-Vilarrasa amide-bond formation, and azide-alkyne click chemistry. The compounds were evaluated as inhibitors of five metal-dependent galactosyltransferases. Crystallographic analyses of three inhibitors complexed in the active site of one of the enzymes confirmed that the pyridine moiety chelates the Mn2+ ion causing a slight displacement (2 angstrom) from its original position. The carbohydrate head group occupies a different position than in the natural uridine diphosphate (UDP)-Gal substrate with little interaction with the enzyme.