Glycosyltransferases (GTs) are enzymes responsible for the biosynthesis of glycoconjugates such as glycolipids and glycoproteins as well as oligo- and polysaccharides which are crucial factors in bacterial and viral infections. They are also responsible for tumor metastasis. Selective inhibition of the GTs may influence the composition of glycoconjugates and oligosaccharides on the cell surface so that they cannot be recognized by virus or bacteria during infection. Therefore GTs are interesting molecular targets [1-3]. Development of effective inhibitors of these enzymes is very important because it can lead to better understanding of biological pathways implicating glycosyltransferases and also to potential therapeutic applications.

Glycosyltransferase donor type inhibitors are generally designed based on analogies between the three different moieties composing the NDP sugar natural substrates, mimicking either the carbohydrate part [4], the diphosphate linkage, the nucleoside moiety or combination of these [5], while modifications of the uridine sugar have not previously been explored and there is lack of reports on derivatives containing acyclonucleosides.

After studies on modification of sugar motif, pyrophosphate mimicking linker and conformation at anomeric center of the transferred sugar our attention has been directed toward the versatility of the developed methodology in the synthesis of a novel group of analogues of natural donor type substrates of GTs which will be complement to the set synthesized earlier. Herein we present synthesis and biological evaluation of β-D-glucose and β-D-galactose conjugates connected by an amide bond acyclic derivatives of uracil.

Acknowledgement:

Roman Komor received a scholarship under the project DoktoRIS - Scholarship Program for Innovative Silesia.

References:

[1] Dwek, R. A., Chem.Rev., 1996, 96, 683.

[2] Sears, P., Wong, C.-H., Cell. Mol. Life Sci., 1998, 54, 223.

[3] Lowe, J. B., Varki, A. In: Essentials of Glycobiology. Second Edition, Eds.: A. Varki, R. D. Cummings, J. D. Esko, H. H. Freeze, P. Stanley, C. R. Bertozzi, G. W. Hart, M. E. Etzler, CSHL Press, 2009, 784.

[4] Bhattacharya, A. K.; Stolz, F.; Kurzceck, J.; Ruger, W.; Schmidt, R.R., Bioorg. Med. Chem., 2002, 10, 1129.

[5] Schafer, A.; Thiem, J., J. Org. Chem., 2000, 65, 24.

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