Chemoenzymatic Synthesis of GDP-L-Fucose Derivatives as Potent and Selective alpha-1,3-Fucosyltransferase Inhibitors
Resource
ADVANCED SYNTHESIS & CATALYSIS, 354(9), 1750-1758
Journal
ADVANCED SYNTHESIS & CATALYSIS
Journal Volume
354
Journal Issue
9
Pages
1750-1758
Date Issued
2012
Date
2012
Author(s)
Lin, Yu-Nong
Stein, Daniel
Lin, Sheng-Wei
Chang, Sue-Ming
Lin, Ting-Chien
Chuang, Yu-Ruei
Gervay-Hague, Jacquelyn
Narimatsu, Hisashi
Lin, Chun-Hung
Abstract
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 K i of 29 nM for human FucT-VI, and is 269 and 11 times more selective than for Helicobacter pylori FucT (K i=7.8 μM) and for human FucT-V (K i=0.31 μM). Copyright ? 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Subjects
enzyme catalysis; enzymes; guanosine diphosphate β- L -fucose (GDP-Fuc) derivatives; inhibitors; transferases
SDGs
Type
journal article