C-6-Modified 2-F-Fucose Derivatives as Inhibitors of Fucosyltransferases.

Abstract

Fluorinated analogs of guanosine-diphosphate-β-L-fucose (GDP-Fuc) have received considerable attention for the development of inhibitors of fucosyltransferases (FUTs). These compounds can be recognized by FUTs but do not transfer or transfer slowly the fluorinated fucosyl residue because the electron-withdrawing fluorine(s) destabilize the oxocarbenium-like transition state. Fluorinated GDP-Fuc analogs can also act as feedback inhibitor of the de novo biosynthetic pathway of GDP-Fuc. To investigate the biological significance of distinct glycoconjugate classes, it is important to develop inhibitors that can selectively target specific FUT enzymes. The design, synthesis, and biological evaluation of a series of GDP-2-F-Fuc analogs modified at C-6 of Fuc by various amides and ethers are reported. Corresponding prodrugs are also prepared and examined as potential FUT inhibitors of cellular glycosylation. The findings reveal that two of the inhibitors potently inhibited FUT1, 3, 6, and 9, while displaying minimal activity against FUT8. However, the corresponding prodrugs do not inhibit cellular fucosylation, which is probably due to a lack of GDP-fucose pyrophosphorylase activity. The results demonstrate that modifications at the C-6 position of Fuc can confer selectivity, although further investigations of alternative functional groups are required to enhance cellular tolerance and efficacy.