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

We designed α(2,3)- and α(2,6)-sialylgalactose analogs bearing an exomethylene unit at C3 of sialic acid (3-exoSia) as a novel type of mechanism-based inhibitors of sialidases. Regio- and stereoselective substitution via vinylogous activation enabled the 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 analog is inactive. These analogs initially work as competitive inhibitors, but are gradually cleaved as substrates to generate a reactive species that forms a covalent bond with sialidase.