Inhibition of Dermatan Sulfate Epimerase 1 by Substituted Glucuronic Acids

Abstract Dermatan sulfate epimerase 1 (DS-epi1) is a key enzyme in the biosynthesis of the glycosaminoglycan chondroitin sulfate/dermatan sulfate, catalyzing the conversion of glucuronic acid to iduronic acid at the polymer level. Chondroitin sulfate/dermatan sulfate chains are found on at least 32 proteoglycans, many of which are implicated in human diseases and syndromes, as well as in both malignant and normal cell development. DS-epi1 therefore represents a promising target for drug development, and recent structural studies have provided insights into its active site and catalytic mechanism. Here, we report the synthesis and biological evaluation of inhibitors based on 1,4-disubstituted glucuronic acids. These compounds were synthesized from glucose through a divergent approach, yielding 19 derivatives that were tested in a functional assay. To explore the importance of the carboxylic acid moiety, we also tested the methyl ester analog and the analogous xylose derivative. The most potent compound exhibited an IC50 of 42 ± 4 μM. Molecular dynamics simulations showed a strong interaction with the active site of DS-epi1.