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Sialic Acid Derivatives (sialic + acid_derivative)

Distribution by Scientific Domains

Chemistry	100%

Selected Abstracts

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

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 16 2009
Michel Weïwer
Abstract ,-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 ,-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 IC50 values wereobserved, comparable to the known sialidase inhibitorNeu5Ac2en.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source]

Combining crystallographic information and an aspherical-atom data bank in the evaluation of the electrostatic interaction energy in an enzyme,substrate complex: influenza neuraminidase inhibition

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 5 2009
Paulina M. Dominiak
Although electrostatic interactions contribute only a part of the interaction energies between macromolecules, unlike dispersion forces they are highly directional and therefore dominate the nature of molecular packing in crystals and in biological complexes and contribute significantly to differences in inhibition strength among related enzyme inhibitors. In the reported study, a wide range of complexes of influenza neuraminidases with inhibitor molecules (sialic acid derivatives and others) have been analyzed using charge densities from a transferable aspherical-atom data bank. The strongest interactions of the residues are with the acidic group at the C2 position of the inhibitor (,,300,kJ,mol,1 for ,COO, in non-aromatic inhibitors, ,,120,210,kJ,mol,1 for ,COO, in aromatic inhibitors and ,,450,kJ,mol,1 for ,PO32,) and with the amino and guanidine groups at C4 (,,250,kJ,mol,1). Other groups contribute less than ,100,kJ,mol,1. Residues Glu119, Asp151, Glu227, Glu276 and Arg371 show the largest variation in electrostatic energies of interaction with different groups of inhibitors, which points to their important role in the inhibitor recognition. The Arg292,Lys mutation reduces the electrostatic interactions of the enzyme with the acidic group at C2 for all inhibitors that have been studied (SIA, DAN, 4AM, ZMR, G20, G28, G39 and BCZ), but enhances the interactions with the glycerol group at C6 for inhibitors that contain it. This is in agreement with the lower level of resistance of the mutated virus to glycerol-containing inhibitors compared with the more hydrophobic derivatives. [source]