Synthesis and Biological Evaluation of Non-Hydrolizable 1,2,3-Triazole Linked Sialic Acid Derivatives as Neuraminidase Inhibitors.
α-Sialic acid azide1has been used as a substrate for the efficient preparation of 1,2,3-triazole derivatives of sialic acid using the copper-catalyzed azide-alkyne Huisgen cycloaddition ("click chemistry"). Our approach is to generate non-naturalN-glycosides of sialic acid that are resistant to neuraminidase catalyzed hydrolysis as opposed to the naturalO-glycosides. TheseN-glycosides would act as neuraminidase inhibitors to prevent the release of new virions. As a preliminary study, a small library of 1,2,3-triazole-linked sialic acid derivatives has been synthesized in 71-89% yield. A disaccharide mimic of sialic acid has also been prepared using the α-sialic acid azide1and a C-8 propargyl sialic acid acceptor in 68% yield. A model sialic acid coated dendrimer was also synthesized from a per-propargylated pentaerythritol acceptor. These novel sialic acid derivatives were then evaluated as potential neuraminidase inhibitors using a 96-well plate fluorescence assay; micromolar IC50values were observed, comparable to the known sialidase inhibitor Neu5Ac2en.
Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, 110, 8th Street, Troy, NY 12180 (USA).
Michel
M
Weïwer
Chi-Chang
CC
Chen
Melissa M
MM
Kemp
Robert J
RJ
Linhardt
Cycloaddition; Influenza virus; N-glycosides; Neuraminidase inhibitors; Sialic acids