Sialic acid mimetics

Woodhall, T., Williams, G., Berry, A. and Nelson, A. (2005) Creation of a tailored aldolase for the parallel synthesis of sialic acid mimetics. Angewandte Chemie-International Edition, 44, 2109-2112. 

A convenient chemoenzymatic access to sialic acid mimetics as important inhibitors of influenza sialidases has been established by Nelson et al. (Fig. 35b) [191, 192]. Application of a pyruvate-dependent sialic acid aldolase improved by directed evolution disclosed a new route to the core structure of important pharmaceuticals, such as zanamivir (Relenza ). 

A-acetyl neuraminic acid lyase (NAL) catalyzes the reversible aldol addition of N-acetylmannosamine to pyruvate to produce A-acetylneuraminic acid, a sialic acid. Sialic acid is an essential component of complex carbohydrates which are of paramount importance as recognition signals in a variety of biological process, such as parasite invasion, infectivity and survival of the invading organism in the host. Hence, sialic acids mimetics, such as the commercial Oseltamavir, Relenza and... 

The fairly broad tolerance of NAL for stereochemically related N-acetylmannosamine allowed the synthesis of a number of natural and unnatural sialic acid derivatives (Fessner and Helaine 2001). Recently, a pair of stereocom-plementary R- and 5-stereoselective NAL variants for the synthesis of sialic acid mimetics has been described, using a combination of stmcture-guided mutagenesis and directed evolution (Williams et al. 2006). 

A similar approach was used in the synthesis of the sialyl Lewis X mimetics of type 85 (Scheme 13.22).66 Protein crystallization,67 conformational studies of sLex in solution68 and in bound form to E- and P-selectin69 as well as the study of structure-function relationships70,71 gave information about the functional groups of the sLex-epitope essential for the binding to the selectins. Synthesized mimetics must contain the three essential hydroxyl functions of the fucose. Sialic acid, galactose, and... 

P. Florio, R. J. Thomson, A. Alafaci, S. Abo, and M. von Itzstein, Synthesis of 8 4-P-d-glucopyranosiduronic acids as mimetics of 2,3-unsaturated sialic acids for sialidase inhibition, Bioorg. Med. Chem. Lett., 9 (1999) 2065-2068. 

---