Syntheses of C-3-modified sialylglycosides as selective inhibitors of influenza hemagglutinin and neuraminidase

In an effort to develop new structures as inhibitors of both influenza viru s proteins hemagglutinin and neuraminidase, a series of sialic acid derivat ives, including those with one of the hydrogen atoms at the C-3 position re placed by either OH or F, were synthesized, The sialic acid derivative with a 3-eq-OH group was first synthesized by means of a new process and used a s the key intermediate for further derivatization at the C-3 position. The stability of these compounds under acid- and sialidase-catalyzed hydrolysis conditions was studied, and the results showed that these compounds exhibi t stronger resistance towards both conditions than their parent p-nitrophen yl alpha-sialoside. Further inhibition assay indicated that the 3-ax-OH or F derivatives 4, 5, and 24, the 4-epimer of 4, are effective specific inhib itors of the sialidases from Clostridium perfringens, among other bacterial sialidases tested. The 3-eq-OH derivative 3, however, showed little inhibi tion. The same tendency was observed for the inhibition of human influenza sialidases N1 and N2. Compounds 3-5 and sialic acid were then converted int o the distealoylphosphatidylethanolamine conjugates. Of these liposome-like compounds, the ones from 4 and 5 showed potent and selective inhibitory ac tivities against the hemagglutinin H3 subtype, but displayed resistance to the influenza virus neuraminidases N1 and N2.