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Herein we present the methodology for obtaining glycosyltransferase inhibitors, analogues of natural enzyme substrates of donor-type: UDP-glucose and UDP-galactose. The synthesis concerned glycoconjugates, nucleoside analogues containing an acyclic ribose mimetic linked to a uracil moiety in their structure. The biological activity of the synthesised compounds was determined on the basis of their ability to inhibit the model enzyme action of β-1,4-galactosyltransferase from bovine milk. The obtained results allowed to expand and supplement the existing library of synthetic compounds that are able to regulate the biological activity of enzymes from the GT class.

A series of UDP-sugar analogues was synthesized and their preliminary biological activity was evaluated. Glycoconjugates of uridine 1 and 2 were synthesized by condensation of uridine-5'-carboxylic acid and 1-amino sugars derivatives of d-glucose and d-galactose, glycoconjugates 3 and 4 were synthesized by azide-alkyne 1,3-dipolar cycloaddition (CuAAC) of 1-azido sugars and propargylamide derivatives of uridine while glycoconjugates 5 and 6 were synthesized by CuAAC of propargyl β-O-glycosides and 5'-azido uridine. Evaluation of inhibitory activity of compounds 1-6 against commercially available β-1,4-galactosyltransferase I (β4GalT) show that compound 5 inhibited the enzyme in µmolar range. Additionally, the antitumor activity of the obtained glycoconjugates 1-6 were tested using MTT assay., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The synthesis of (5-nitro-2-pyridyl) 2-deoxy-1-thioglycosides is presented. Obtained compounds were used in the synthesis of uridine derivatives, potential glycosyltransferases inhibitors. In the first stage of the research 2-deoxyglucose and 2-deoxygalactose were connected to aglycone (nitropyridine derivative) via alpha-1-thioglycosidic bond. Therefore, protected 1.2-unsaturated D-glucose or D-galactose derivatives were treated with 2-thio-5-nitropyridine in the presence of the catalyst. In the next step nitro group in the aglycone was reduced in the reaction with the use of zinc dust in acetic acid. Then, these compounds were connected to selectively protected uridine derivatives by amide bond with or without succinic spacer. The obtained glycoconjugates differ in the protecting group of the carbohydrate part and in the presence of the spacer between the sugar and uridine moiety.

The title compounds, variously protected 2.3-anhydrosugars linked with genistein through an alkyl chain, were synthesized in a sequence of reactions. First step involved Ferrier rearragement of 3,4-di-O-acetyl-L-rhamnal with 3-bromopropanol to obtain 2,3-unsaturated bromoalkylglycosides. The next step was epoxidation with m-CPBA and finally these compounds were connected with genistein in reaction of 7-O-genistein tetra-butylamonium salt with 2,3-anhydro bromoalkylglycosides. Obtained glycoconjugates differ in orientation of an oxirane ring and the protecting group in a sugar moiety. All compounds were tested in vitro for antiproliferative potential in cancer cells.