The biosynthesis of polysaccharides and glycoconjugates mediated by glycosyltransferases (GTs) has attracted increasing interest. Modulation of GTs activity by selective inhibitors  has become a tool for investiagation of biochemical pathways and also a new field for a novel therapeutics discovery.

The natural donor substrates for the majority of glycosyltransferases are UDP-sugars. They are bound to the active site of enzyme by coordination to divalent metal ion through diphosphate group. The aim of this work was to synthesize potential β-1,4-galactosyltransefrase inhibitors that are analogues of natural donor substrate (UDP-Gal). A variety of pyrophosphate analogues that can mimic pyrophosphate-metal interactions have been developed[1-6]. We decided to replace the diphosphate unit with β-ketoenol group which is known to coordinate to divalent metal ion. The designed compounds were composed of uridine unit connected to substituted aromatic ring through different linkages. Structures of all final products were confirmed by ¹H and ¹³C NMR spectroscopy.

All synthesized compounds were tested as potential inhibitors in a competition assay against bovine milk β-1,4-galactosyltransferase. We have applied the fluorescence assay developed by Praly and co-workers to measure GTs activity[4]. This method utilizes fluorescent-labeled acceptor β-GlcNAc-O-(CH₂)₆-dansyl instead of the natural substrate. The samples were analyzed using reversed-phase HPLC with fluorescent detector. Synthesis of target compounds and evaluation of their activity will be presented.

Acknowledgement

Research studies part-financed by European Union within the European Regional Development Fund (POIG 01.01.02-14-102/09)

References

[1] K.-H. Jung, R.R. Schmidt, Glycosyltransferase Inhibitors in Carbohydrate-Based Discovery (C.-H. Wong, Ed.), Wiley-VCH Verlag, Weinheim, 2003, 2, 609–659.

[2] M.M. Vaghefi, R.J. Bernacki, W.J. Hennen, R.K. Robins, J. Med. Chem., 1987, 30, 1383–1391.

[3] M.M. Vaghefi, R.J. Bernacki, W.J. Hennen, R.K. Robins, J. Med. Chem., 1987, 30, 1391–1399.

[4] S. Vidal, I. Bruyere, A. Malleron, C. Augé, J.-P. Praly, Bioorg. Med. Chem.,  2006, 14, 7293–7301

[5] R. Wang, D.H. Steensma, Y. Takaoka, J.W. Yun, T. Kajimoto, C-H. Wong, Bioorg. Med. Chem., 1997, 5, 661–672.

[6] I. Wandzik, T. Bieg, M. Czaplicka, Bioorg. Chem., 2009, 37, 211-216.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/28034 must be provided.

1. Synthesis and biological evaluation of 5’-glycine derivatives of uridine
2. Evaluation of anti-denaturation activity of C-5' - substituted uridine derivatives.
3. Study on lipophilicity of selected uridine derivatives
4. Uridine derivatives of 1-thioglycosides as analogs of glycosyltransferases natural substrates
5. Interactions between glycosyltransferases and 2-deoxy glycosyl derivatives of uridine simulated by molecular docking
6. VIRTUAL SCREENING - SOFTWARE TOOLS AND SUCCESSFUL APPLICATIONS
7. SYNTHESIS OF URIDINE DERIVATIVES OF 2-DEOXY SUGARS AND THEIR BIOLOGICAL ACTIVITY