Sialic acids derivatives

K. Ikeda, Y. Ueno, S. Kitani, R. Nishino, and M. Sato, Ferrier glycosylation reaction catalyzed by Bi(OTf)3-Montmorillonite K-10 Efficient synthesis of 3,4-unsaturated sialic acid derivatives, Synlett (2008) 1027-1030. 

M. Wei wer, C.-C. Chen, M. M. Kemp, and R. J. Linhardt, Synthesis and biological evaluation of non-hydrolyzable 1,2,3-triazole-linked sialic acid derivatives as neuramidase inhibitors, Eur. J. Org. Chem. (2009) 2611-2620. 

Azido-N-acetyl sialic acid derivative (SiaNAz)... 

Figure 17.19 An azido-sialic acid derivative that gets incorporated into glycans in cells can be labeled specifically with a biotin-phosphine tag using the Staudinger ligation process. The result is an amide bond linkage with the glycan.

Enolates represent a special class of sp -hybridized C(l) nucleophiles. This is an important and developing aspect of carbohydrate reactivity and the carbonyl function can either be located at C(2), or be external to the sugar ring (as in sialic acid derivatives). Although the latter are not strictly C(l) nucleophiles, both their value in C-glycoside synthesis and relationship to other topics covered in this chapter merit inclusion of these systems. 

Several ganglioside analogs containing an a-thioglycoside of sialic acid, derived for example from (29 c) (Scheme 8), have been found to be potent inhibitors of sialidase activities of different subtypes of influenza virus [64]. 

To facilitate accesses to suitably functionalized sialic acid derivatives and complex sialyloligosaccharides for other usehil neoglycoconjugates, phase transfer catalysis (PTC) has been exploited extensively [for reviews see 42]. This process provided a wide range of carbohydrate derivatives under essentially clean Sn2 transformations. In the case of acetochloroneuraminic acid 1, the PTC reactions always provided inverted a-sialic acid derivatives [43]. para-Formylphenyl sialoside 7 [44], together with many other sialoside derivatives such as 8-10 [43], including thioacetate 12 [45] and azide 14 [46], were thus obtained (Scheme 1). Aldehyde 7 and similar glycosides are of particular interest since they could be directly conjugated to protein by reductive amina-tion after suitable deprotection [44]. 

The sialic acid aldolase-catalyzed condensation of D-mannose 8 and pyruvate led, in an excellent yield, to the synthesis of KDN 9 [33], a natural deaminated neuraminic acid first isolated from rainbow trout eggs [34] and then discovered in other species. The discovery that sialic acid aldolase accepts as substrates D-mannose substituted on the 2-position, even by bulky substituents such as phenyl, azido, or bromine, opened the route to novel unnatural sialic acid derivatives [35-39]. Pentoses also are substrates. N-Substituted neuraminic acids could be prepared either directly from the corresponding Af-substituted mannosamine, such as N-thioacyl derivatives [40], or after reduction and acylation of 5-azido-KDN [41]. Recently, AT-carbobenzyloxy-D-mannosamine was converted, in a good yield, into the N-carbobenzyloxy-neurarninic acid, further used as a precursor of a derivative of castanospermine [42]. 

Table 2 lists 37 sialic acid derivatives and analogues that have been synthesized with sialic acid aldolase by our group and others. This is a nice illustration of the great synthetic potential of the enzyme. In all of these examples, sialic acid derivatives or analogues with equatorial hydroxyl on C-4 are formed, corresponding to a new 45 chiral center and attack of the pyruvate from the si face of the aldehyde. In summary sialic acid aldolase accepts modifications on the 2, 4, 5, and 6 positions of the substrate without any change of its stereoselectivity. 

The position of the bond between the sialic acids was determined by g.l.c.-m.s. of the acetates of partially methylated sialic acid derivatives obtained after methanolysis of the methylated sialoglycolipid, and was confirmed by the periodate-oxidation data. The (2- 9) bond between... 

Vliegenthart JFG, Kamerling JP (1982) Synthesis of sialic acids and sialic acid derivatives, in Schauer R (ed) Sialic acids, chemistry, metabolism and function Springer-Verlag, New York, p 59... 

Oligolysine dendrimers with terminal carbohydrate structures were functionalised by solid-phase synthesis for well-defined construction of glycoclusters . Synthesis proceeded via coupling of lysine molecules. Eight amino groups are attached by peptide bonding to the periphery via a spacer-functionalised sialic acid derivative (Fig. 8.8). 

N. K. Sauter, M. D. Bednarski, B. A. Wurzburg, J. E. Hanson, G. M. Whitesides, J. J. Skehel, and D. C. Wiley, Hemagglutinins from two influenza virus variants bind to sialic acid derivatives with millimolar dissociation constants A 500-MHz proton nuclear magnetic resonance study, Biochemistry, 28 (1989) 8388-8396. 

C. L. White, M. N. Janakiraman, W. G. Laver, C. Philippon, A. Vasella, G. M. Air, and M. Luo, A sialic acid-derived phosphonate analog inhibits different strains of influenza virus neuraminidase with different efficiencies, J. Mol. Biol., 245 (1995) 623-634. 

Extensive research has focused on the synthesis of structurally modified sialic acid derivatives and sialylmimetics as probes or potential inhibitors of specific sialic acid-recognizing proteins, and several comprehensive overviews have been published [26, 30-34], An underlying theme in efforts directed toward the development of novel sialic acid derivatives as biological probes is the complexity of the chemical manipulations associated with sialic acids [30, 32], The chemical strategies and conditions for sialylation are discussed in Chapter 5. 

Kiefel, M.J. et al. Recent Advances in the Synthesis of Sialic Acid Derivatives and Sialylmimetics as Biological Probes. 2002 [63b]... 

Scheme 5.45. Two-pot, triple-aldol condensation catalyzed by DERA and NeuAc, giving deoxy sialic acid derivatives.

Newer agents under investigation include tris(tropolonato) Bi(III) and nitratobis(tropolonato)Bi(in) a host of bis (mercaptoethanol)Bi(III) complexes, which are formed with 0,S-bidentate chelation, with and without deprotonation of the hydroxyl oxygen and usually having an axial fifth ligand and sialic acid derivatives of Bi(III). The interactions of Bi(III) and its compounds with metallothionein, serum albumin and transferrin have been studied by a variety of groups, as have a number of enzymes that may be related to the mechanism(s) of action of bismuth in treating ulcers. 

Ogura H (1992) Sialic acid derivatives as glycolipoids. In Ogura H, Hasegawa A, Suami T (eds) Carbohydrates. Synthetic methods and applications in medicinal chemistry. VCH, Weinheim, p 282 Rothermel J, Faillard H (1990) Carbohydr Res 196 29... 

Colostrum is a richer source of these sialic acid derivatives than milk, and it was from cow colostrum that JV-acetyl-O-acetylneuraminolactose was isolated in about 0.025% yield however, owing to the extreme lability of the 0-acetyl group, most of the subsequent work has been performed on the A "-acetylneuraminolactose. This compound has been split by influenza virus and Vibrio choleras neuraminidase into lactose and A -acetylneura-... 

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