2,2-Di-Fluoro-Derivatives of Fucose Can Inhibit Cell Surface Fucosylation Without Causing Slow Transfer to Acceptors

Abstract

ABSTRACTFucosyltransferases (FUTs) are enzymes that transfer fucose (Fuc) from GDP-Fuc to acceptor substrates resulting in fucosylated glycoconjugates that are involved in myriad of physiological and disease processes. Previously, it has been shown that per-O-acetylated 2-F-Fuc can be taken up by cells and converted into GDP-2-F-Fuc which is a competitive inhibitor of FUTs. Furthermore, it can act as a feedback inhibitor ofde-novobiosynthesis of GDP-Fuc resulting in reduced glycoconjugate fucosylation. GDP-2-F-Fuc and several other reported analogs are slow substrates, which can result in unintended incorporation of unnatural fucosides. Here, we describe the design, synthesis, and biological evaluation of GDP-2,2-di-F-Fuc and corresponding prodrugs as inhibitor of FUTs. This compound lacks the slow transfer activity observed for the mono-fluorinated counterpart. Furthermore, it was found that GDP-2-F-Fuc and GDP-2,2-di-F-Fuc have similar Kivalues for the various human fucosyl transferases while the corresponding phosphate prodrugs exhibit substantial differences in inhibition of cell surface fucosylation. Quantitative sugar nucleotides analysis by LC-MS indicates that the 2,2-di-F-Fuc prodrug has substantial greater feedback inhibitory activity. It was also found that by controlling the concentration of the inhibitor, varying degrees of inhibition of the biosynthesis of different types of fucosylatedN-glycan structures can be achieved. These findings open new avenues for the modulation of fucosylation of cell surface glycoconjugates.