Glycosyltransefrases (GTs) are enzymes responsible for transfer of activated monosaccharide units in the form of their nucleotide diphosphate derivatives (NDP-sugar) to a specific free hydroxyl group of the acceptor molecule e.g. growing oligosaccharide, a protein or a lipid. Oligosaccharides that are present on cell surface participate in many intracellular and extracellular events such as viral or bacterial infection, tumor metastasis or immune response [1]. Therefore GTs represent an interesting molecular targets for development of novel therapeutic agents.

The aim of this work was to synthesize a set of uridine derivatives as GTs donor substrate analogues. Several peptidyl derivatives of nucleosides such as nikkomycines or polioxines are known antibiotics. They are potent GT inhibitors acting against chitin synthase [2]. This motivated us to introduce aminoacid to the structure of target compounds. Glycine motif was used as a replacement of diphosphate linkage present in NDP-sugars. Such approach was based on the fact that glycine is known to form complex with divalent metal cation [3-4], so that designed compounds could interact with Mn²⁺ in the active site of enzyme. Moreover uridine part should ensure proper orientation of a compound and thus enabling binding with the enzyme active site. The general structure of target compounds is presented in Figure 1.

All synthesized compounds were tested as potential inhibitors in a competition assay against chosen GTs and evaluated for antifungal properties against Aspergillus fumigatus and Candida albicans. Synthesis of target compounds and evaluation of their activity will be presented.

Acknowledgement

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

References:

[1] Essentials of Glycobiology Second Edition, Eds.: A. Varki, R. D. Cummings, J. D. Esco, H. H. Freeze, P. Stanley, C. R. Bertozzi, G. W. Hart, M. E. Etzler, CSHL Press, 784pp. (2009).

[2] K. E. Jackson, P. K. Pogula, S. E. Patterson, Heterocycl. Commun., 19, 375-386 (2013).

[3] H. N. Aliyu, J. Na’aliya, Bayero Journal of Pure and Applied Sciences, 2, 191-193 (2009).

[4] M. H. Khodabandeh, M. D. Davari, M. Zahedi, G. Ohanessian, Int. J. Mass Spectrom., 291, 73–83 (2010).

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