Fucosylation is one of the most prevalent modifications on N- and O-
glycans of
glycoproteins, and it plays an important role in various cellular processes and diseases. Small molecule inhibitors of fucosylation have shown promise as therapeutic agents for
sickle cell disease,
arthritis, and
cancer. We describe here the design and synthesis of a panel of fluorinated l-
fucose analogs bearing
fluorine atoms at the C2 and/or C6 positions of l-
fucose as metabolic fucosylation inhibitors. Preliminary study of their effects on cell proliferation revealed that the 6,6-difluoro-l-fucose (3) and 6,6,6-trifluoro-l-fucose (6) showed significant inhibitory activity against proliferation of human
colon cancer cells and human umbilical vein endothelial cells. In contrast, the previously reported
2-deoxy-2-fluoro-l-fucose (1) had no apparent effects on proliferations of all the cell lines tested. To understand the mechanism of cell proliferation inhibition by the fluorinated l-
fucose analogs, we performed chemoenzymatic synthesis of the corresponding
GDP-fluorinated l-
fucose analogs and tested their inhibitory activities against the mammalian α1,6-fucosyltransferase (FUT8). Interestingly, the corresponding
GDP derivatives of 6,6-difluoro-l-fucose (3) and 6,6,6-trifluoro-l-fucose (6), which are the stronger proliferation inhibitors, showed much weaker inhibitory activity against FUT8 than that of the
2-deoxy-2-fluoro-l-fucose (1). These results suggest that FUT8 is not the major target of the 6-fluorinated
fucose analogs (3 and 6). Instead, other factors, such as the key
enzymes involved in the de novo
GDP-fucose biosynthetic pathway and/or other
fucosyltransferases involved in the biosynthesis of
tumor-associated glyco-
epitopes are most likely the targets of the fluorinated l-
fucose analogs to achieve cell proliferation inhibition. To our knowledge, this is the first comparative study of various fluorinated l-
fucose analogs for suppressing the proliferation of human
cancer and primary endothelial cells required for angiogenesis.