Synthesis of bisubstrate analogues targeting α-1,3-fucosyltransferase and their activities

We designed two bisubstrate analogues targeting alpha-1,3-fucosyltransferases, based on the three dimensional structure of Lewis X, which is the product of a alpha-1,3-fucosyltransferase reaction. We selected guanosine-5'-diphospho-L-galactose as a donor mimic and 2-hydroxyethyl P-D-galactoside as an acceptor mimic, and tethered these two mimics with a methylene or ethylene linker. For the synthesis, the 6-position Of L-galactose and the 6-position Of D-galactose were first tethered via a methylene or ethylene linker. The L-galactose moiety was then converted to a GDP derivative. Both bisubstrate analogues were moderate inhibitors against alpha-1,3-fucosyltransferase V and VI. The fact that they were substrates of alpha-1,3-fucosyltransferase VI suggested that these compounds bound to the donor binding site, but not to the acceptor binding site.