Synthesis and Biological Evaluation of Non‐Hydrolyzable 1,2,3‐Triazole‐Linked Sialic Acid Derivatives as Neuraminidase Inhibitors

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 per-propargylated pentaerythritol acceptor. These novel sialic acid derivatives were then evaluated as potential neuraminidase inhibitors using a 96-well plate fluorescence assay; micromolar IC50 values were observed, comparable to the known sialidase inhibitor Neu5Ac2en.

Application of copper(I)-catalysed azide/alkyne cycloaddition (CuAAC) ‘click chemistry’ in carbohydrate drug and neoglycopolymer synthesis

“…More recently, non-hydrolysable 1,2,3-triazole-linked sialic acid derivatives were synthesised by Linhardt et al 43 as potential neuraminidase inhibitors. Initially, a small library of 1,2,3-triazolelinked sialic acid was prepared by click reaction of a-sialic acid azide 14 and different terminal alkyne-containing molecules, as exemplified for compound 15 (IC 50 ¼28 mM) (Scheme 6).…”

Design and Creativity in Synthesis of Multivalent Neoglycoconjugates

“…7). According to the optimized Sonogashira conditions already described, and using the required di-and tri-iodinated benzene cores and per-O-acetylated 2-propynyl lactoside, they obtained divalent (86) and trivalent (87) glycosides in yields of 90% and 80%, respectively. 102 Complete O-deacetylation resulted in freely water-soluble clusters in almost quantitative yields.…”

Glycotherapy: New Advances Inspire a Reemergence of Glycans in Medicine

“…New methods employing carbohydrate scaffolds are being utilized to screen the glycan chemical space for more potent inhibitors of lectins involved in disease states (Diot et al, 2011; Ferreira et al, 2010; Weïwer et al, 2009). In addition to the compounds reported above, many natural products are glycosylated, which influences their efficacy and specificity.…”