Complex oligosaccharides present in different classes of glycoconjugates are involved in numerous cell-cell recognition and communication processes. They are also responsible for intercellular adhesion in inflammation, bacterial or viral infection and activation of the immunity system. Formation of glycosidic linkage in biosynthesis of oligosaccharides usually occurs under action of glycosyltransferases (GTs). They catalyze sugar-transfer reaction in a regio- and stereospecific manner. Inhibition of GTs leads to the modulation of oligosaccharide biosynthesis and enables us to study their biological functions. Therefore some GTs inhibitors might be of therapeutic interest. GTs inhibitors are generally designed based on analogies between the three different moieties composing NDP sugar natural substrates: carbohydrate part, the diphosphate linkage and the nucleoside moiety [1].

We present herein a part of our current program on the synthesis of some kind of analogues of sugar nucleotides, which were designed to act as GTs inhibitors particularly donor substrate analogues. Such inhibitors contain a glycosyl unit (usual glucose or galactose) and a nucleoside diphosphate mimic, which is essential for binding to the enzyme. We construct analogues of GTs inhibitors using aryl and heteroaryl 1-thioglycosides as glycosyl units which are connected to uridine with or without a spacer. We used succinic, glutaric and malonic acid as a spacer. We believe that presence of sulfur atom instead of glycosidic oxygen atom increases the stability of sugar-aglycon linkage against enzymatic cleavage [2]. This way we obtained several uridine derivatives containing different types of diphosphate mimic linkers.

Acknowledgement

Financial support from the Polish State Committee for Scientific Research (Grant No. 1 T09A 08630) is gratefully acknowledged.

[1] Jung, K. H.; Schmidt, R. R. Glycosyltransferase Inhibitors in: „Carbohydrate-Based Drug Discovery”, C.-H. Wong (Ed.), Wiley-VCH, 2003, 23, 609-659.
[2] Zhu, X.; Stolz, F.; Schmidt, R. R. J. Org. Chem. 2004, 69, 7367-7370.

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