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Synthesis and Biological Evaluation of Non‐Hydrolyzable 1,2,3‐Triazole‐Linked Sialic Acid Derivatives as Neuraminidase Inhibitors
Author(s) -
Weïwer Michel,
Chen ChiChang,
Kemp Melissa M.,
Linhardt Robert J.
Publication year - 2009
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200900117
Subject(s) - sialic acid , chemistry , neuraminidase , sialidase , click chemistry , azide , triazole , propargyl , disaccharide , carboxylic acid , combinatorial chemistry , organic chemistry , biochemistry , stereochemistry , enzyme , catalysis
Abstract α‐Sialic acid azide 1 has 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‐natural N‐glycosides of sialic acid that are resistant to neuraminidase‐catalyzed hydrolysis as opposed to the natural O‐glycosides. These N‐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 azide 1 and a C‐8 propargyl sialic acid acceptor in 68 % yield. A model sialic acid coated dendrimer was also synthesized from a perpropargylated pentaerythritol acceptor. These novel sialic acid derivatives were then evaluated as potential neuraminidase inhibitors using a 96‐well plate fluorescence assay; micromolar IC 50 values wereobserved, comparable to the known sialidase inhibitorNeu5Ac2en.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)