3-Exomethylene Sialic Acid Disaccharides as Substrate-Type Mechanism-Based Sialidase Inhibitors

Abstract

We designed α(2,3)- and α(2,6)-sialylgalactose analogues bearing an exomethylene unit at C3 of sialic acid (3-exoSia) as a novel type of mechanism-based inhibitors of sialidases. Regio- and stereo-selective substitution by vinylogous activation enabled simultaneous construction of the 3-exomethylene moiety and the O-sialoside linkage. Both types of 3-exoSia disaccharides potently inhibit Clostridium perfringens sialidase NanI and selectively inhibit NEU2 among human sialidases, whereas the corresponding monosaccharide analogue is inactive. These analogues initially work as competitive inhibitors, but are gradually cleaved as substrates to generate a reactive species that forms a covalent bond with sialidase.