Neuraminic acid analogs

M. Murakami, K. Ikeda, and K. Achiwa, Chemoenzymatic synthesis of neuraminic acid analogs structurally varied at C-5 and C-9 as potential inhibitors of the sialidase from influenza vims, Carbohydr. Res., 280 (1996) 101-110. 

Neuraminic Acid Analogs Non-natural mimics of neuraminic acids which inhibit viral sial-idase have recently emerged as interesting anti-influenza drugs [131]. In this context, 6-thio analogs have been targeted by von Itzstein and co-workers [132] based on the chain exten-... 

Methyl 4,5,7,8,9-penta-(9-acetyl-2-azido-2,3-dideoxy-D-gr/Tccro-a- and p-D-g(a/acro-2-nonulo-pyranosonates (83) were formed by treatment of the p acetate with trimethylsilyl azide in the presence of equimolar amounts of SnCU- The poor yields reported are associated with problems in separation of the catalyst. Formation of the neuraminic acid analog, namely methyl (5-acetamido-4,7,8,... 

The biosynthesis of Kdo and neuraminic acid is known to involve enol-pyruvate phosphate and D-arabinose or 2-acetamido-2-deoxy-D-mannose, respectively. Nothing is known about the biosynthesis of all the other glycu-losonic acids. One interesting problem is, for example, whether the two 5,7-diamino-3,5,7,9-tetradeoxynonulosonic acids are synthesized analogously to neuraminic acid, from a three- and a six-carbon fragment, by modification of neuraminic acid on the sugar nucleotide level, or by a third, less obvious route. 

Addition of pyruvate to Cbz-protected D-mannosamine 194 under NeuA catalysis has furnished an JV-acyl derivative of neuraminic acid 5 from which internal reductive amination yielded an azasugar which could be further elaborated to 195, an analog of the bicyclic, indolizidine type glycosidase inhibitor castanospermine [91]. 

FIGURE 21.16 Sialidase inhibitors 2-deoxy-2,3-didehydro-o-iV-acetyl neuraminic acid 7 and its 4-guanidino analog 8. 

Deoxy analogs of A-protected neuraminic acids were also prepared. The )8-hydrido derivative was obtained by hydrogenation of A-acetyl-A-Boc, 7,8,9-tetra-... 

N-Acetylneuraminic acid aldolase catalyzes the reversible aldol condensation of pyruvate (23) and N-acetylmannosamine (22 ManNAc) to form N-acetylneuraminic acid (24 NeuAc N-acetyl-5-amino-3,5-dideoxy-D-glycerogalacto-2-nonulopyronic acid Scheme 6).80-83 In vivo the enzyme has a catabolic function and the equilibrium for this reaction is near unity the presence of excess pyruvate can shift this equilibrium. NeuAc and other derivatives of neuraminic acid are termed sialic acids. These compounds are found at the termini of mammalian glycoconjugates and play an important role in cellular recognition.84-89 The production of analogs of NeuAc is a point of great interest to synthetic and medicinal chemists. The enzymatic approach has not been fully explored but it may be a practical alternative to the chemical synthesis of certain sialic acids.89... 

CHEMISTRY AND ANTIVIRAL ACTIVITY Zanamivir (4-guanidino-2,4-dideoxy-2, 3-dehydro-/V-acetyl neuraminic acid) is a siaMc acid analog that potently and specifically inhibits the neuraminidases of influenza A and B viruses. Depending on the strain, zanamivir competitively inhibits influenza neuraminidase activity but affects neuraminidases from other pathogens and mammalian sources only at much higher concentrations. Zanamivir inhibits in vitro replication of influenza A and B viruses, including amantadine- and rimantadine-resistant strains and several oseltamivir-resistant variants. 

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