Chemoenzymatic synthesis of GDP-L-fucose derivatives as potent and selective α-1,3-fucosyltransferase inhibitors

Fucosyltransferases (FucTs) usually catalyze the final step of glycosylation and are critical to many biological processes. High levels of specific FucT activities are often associated with various cancers. Here we report the development of a chemoenzymatic method for synthesizing a library of guanosine diphosphate β-L-fucose (GDP-Fuc) derivatives, followed by in situ screening for inhibitory activity against bacterial and human α-1,3-FucTs. Several compounds incorporating appropriate hydrophobic moieties were identified from the initial screening. These were individually synthesized, purified and characterized in detail for their inhibition kinetics. Compound 5 had a Ki of 29 nM for human FucT-VI, and is 269 and 11 times more selective than for Helicobacter pylori FucT (Ki=7.8 μM) and for human FucT-V (Ki=0.31 μM).