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SYNTHESIS OF URIDINE DERIVATIVES OF 2-DEOXY SUGARS AND THEIR BIOLOGICAL ACTIVITY

Ilona Wandzik 1Grzegorz Grynkiewicz 2Wiesław Szeja 1Bogusław Szewczyk 3Ewelina Król 3

1. Silesian University of Technology, Department of Organic Chem., Bioorganic Chem. and Biotechnol., Krzywoustego 4, Gliwice 44-100, Poland
2. Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland
3. University of Gdansk, Department of Molecular Virology, Kładki 24, Gdańsk 80-822, Poland

Abstract

Glycosyltransferases (GTS) are enzymes responsible for processing variety of biomacromolecules, generating higher saccharides such as glycolipids, glycoproteins and other glycoconjugates. They regulate many cellular functions and therefore are important targets in medicinal chemistry. Inhibitors of GTS have already found application in various therapeutic categories [1].

GST catalyse sugar unit transfer from a sugar nucleotide donor to an unprotected sugar acceptor. We report herein the synthesis of several analogues of sugar nucleotides, which were designed to act as inhibitors by binding in the active site of the enzyme in competition with natural donor substrates.

In order to construct analogues of uridine diphospho sugars we have chosen glycal chemistry. First, uridine and glycals were selectively protected. Afterwards addition of uridine derivative to a glycal, catalysed by triphenylphosphine hydrobromide, was performed [2]. In this way we have synthesized, in totally stereoselective manner, several uridine derivatives of 2-deoxy sugars in high yields.

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Biological activity studies with these inhibitors were divided into two parts. First, using the neutral red cytotoxicity assay, we established the optimal doses of inhibitors when the viability of swine kidney cells (SK6) was higher than 50%. In the next experiments, we examined the effect of concentration of inhibitors on penetration and propagation of classical swine fever virus (CSFV). The best results were observed for IW3 inhibitor. Even low doses of this inhibitor (20 µg/mL), when the viability of SK6 cells was higher than 90%, inhibition the propagation of CSFV virus and the viral yield was decreased by over 80%.

Acknowledgement

Financial support from the Polish State Committee for Scientific Research (Grant No. 3 T09 A 01226) is gratefully acknowledged.

  1. K. H. Jung, R. R. Schmidt Glycosylotransferase Inhibitors in: "Carbohydrate-Based Drug Discovery", C.-H. Wong (Ed.), Wiley - VCH, ch. 2, 609-659 (2003).
  2. V. Bolitt., Ch. Mioskowski, S.-G. Lee, and J. R. Falck, J. Org. Chem., 1990, 55, 5812-1813.
 

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Submitted: 2006-02-07 11:32
Revised:   2009-06-07 00:44