Carbohydrates and Derivatives as Potential Drug Candidates with Emphasis on the Selectin and Linear-B Area

Reinhold      Ohrlein

Abstract

Enzymatic carbohydrate synthesis using glycosyltransferases is highly regio- and stereospecific and does not require extensive protecting group designs. Naturally occurring carbohydrates have been prepared by this biomimetic pathway successfully. As more and more transferases are isolated and get cloned and overexpressed, non-natural substrates were probed with these biocatalysts. Key-polar groups and non-essential residues of the substrates have been determined. Consequently, this technique was employed to generate natural and non-natural carbohydrate libraries for pharmaceutical purposes. The synthesis of sialyl-Lewis a- and sialyl-Lewis x libraries and non-natural Linear-B derivatives applying glycosyltransferases is presented in this article. The respective transferases investigated are α(1-3)galactosyltransferase, β(1-3)galactosyltransferase, β(1-4)galactosyltransferase, α(2-3)sialyltransferase, α(1-3)fucosyltransferase III and α(1-3)fucosyltransferase VI. With respect to the natural acceptors, the aglycon part and the N-acetyl group of the glucosamide have been varied. All enzymes tolerate an unexpected wide range of non-natural acceptors, which is not yet exploited in its full scale. In addition, fucosyltransferase III and VI can be employed to convert also non-natural donors with non-natural acceptors at the same time. Thus sialyl-Lewis a- and sialyl-Lewis x-libraries which differ in three positions compared to the natural tetrasaccharides are generated very efficiently. Also a library of linear-B trisaccharides, a reactive xenoantigen, has been pre pared enzymatically. The aglycon part and the natural N-acetyl group of the glucosamine, which is a part of the acceptor substrate, have been altered widely. This convenient methodology is compared with the evolving solid-phase carbohydrate synthesis using conventional chemistry. The potential use of transferases in solid-phase carbohydrate chemistry is discussed together with the possibility to use these biocatalysts to synthesize carbohydrate mimetics. The presented findings may also be useful to design potential glycosyltransferase inhibitors.

Keywords: Selectin, Glycosyltransferases, Linear-B trisaccharide, Carbohydrate mimetics, Enzymatic glycosylation, E-selectin, Linear-B Trisaccharides, Solid Phase Synthesis, lycosyltransferase Inhibitors