C-6 Modified 2-F-Fucose Derivatives as Inhibitors of Fucosyl Transferases

Abstract

Fluorinated analogs of guanosine-diphosphate-{beta}-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 or slowly transfer 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 biosynthesis 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. Here, we report 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. We also prepared and examined corresponding prodrugs as potential FUT inhibitors of cellular glycosylation. Our findings reveal that two of the inhibitors potently inhibited FUT1, 3, 6, and 9, while displaying minimal activity against FUT8. However, the corresponding prodrugs did 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.