Development of α-Fucosyltransferase Inhibitors by Structure- and Mechanism-Based Design
Date Issued
2009
Date
2009
Author(s)
Chen, Ying-Chu
Abstract
α-Fucosyltransferases (FucTs) usually catalyze the final steps in the biosynthesis of fucose-containing oligosaccharides. Owing to the related biological significance (such as tumor metastasis and bacterial infection), these enzymes are considered as the targets for therapeutic intervention. This thesis is mainly focused on the design, synthesis and evaluation of FucT inhibitors. On the basis of the reported x-ray crystal structures and mechanistic studies, the molecules were designed to include guanosine diphosphate (GDP) that offers major binding affinity, a negative-containing group to mimic the positive-charge character of the transition state, and a hydrophobic group to acquire additional affinity. Several GDP-conjugated pyrrolidines, piperidines and imidazoles were prepared and evaluated as the inhibitors against the FucTs from Helicobacter pylori and human. The structure and activity relationship was also discussed. Furthermore, a series of GDP- and triazole-containing compounds were also developed as FucT inhibitors previously. Because 2’-(phenylsulfonyl-methyl)benzyl group was found to be the best hydrophobic group attached to the triazole, the same group was hens coupled with GDP-pyrrolidine to give YCC-7 (61). YCC-7 was found to be a potent inhibitor against H. pylori alpha-1,3-FucT. The corresponding IC50 abd Ki values are 44.1 and 29.5 micromolar, respectively. Computational modeling was further empoyled for the explanation at molecular basis.
Subjects
fucosyltransferase
Helicobacter pylori
GDP inhibitor
Type
thesis
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