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Issue 21, 2017
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Exploitation of new structurally diverse d-glucuronamide-containing N-glycosyl compounds: synthesis and anticancer potential

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The synthesis and anticancer evaluation of novel N-glycosyl derivatives containing N-substituted glucuronamide moieties, as nucleoside analogs or as prospective mimetics of glycosyl phosphates or of nucleotides, is reported. These compounds comprise N-anomerically-linked nucleobases or motifs that are surrogates of a phosphate group, such as sulfonamide or phosphoramidate moieties. 1-Sulfonamido glucuronamides containing N-benzyl, N-propargyl or N-dodecyl carboxamide units were synthesized through glycosylation of methanesulfonamide with tetra-O-acetyl glucuronamides. 1-Azido glucuronamides were accessed by microwave-assisted reactions of tetra-O-acetyl glucuronamides with TMSN3 and were further converted into N-glycosylphosphoramidates by treatment with trimethyl phosphite. Potential glucuronamide-based nucleotide mimetics comprising both an anomeric sulfonamide/phosphoramidate group and a benzyltriazolylmethyl amide system at C-5, as nucleobase mimetics, were synthesized via ‘click’ cycloaddition of N-propargyl glucuronamide derivatives with benzyl azide. N-Dodecyl tetra-O-acetyl glucuronamides were converted into uracil and purine nucleosides via N-glycosylation of the corresponding silylated nucleobases. Biological screening revealed significant antiproliferative activities of the N-dodecyl glucuronamide-containing sulfonamide, phosphoramidate and nucleosides in K562 and MCF-7 cells. The highest effect was exhibited by the N9-linked purine nucleoside in the breast cancer cell MCF-7 with a GI50 value similar to that of clinically used 5-fluorouracil. Immunoblotting and cell cycle analysis of K562 cells treated with the most active compound as well as evaluation of the effect of this nucleoside on the activities of caspases 3 and 7 showed induction of apoptosis as the mechanism of cell death.

Graphical abstract: Exploitation of new structurally diverse d-glucuronamide-containing N-glycosyl compounds: synthesis and anticancer potential

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Supplementary files

Article information

24 Feb 2017
08 May 2017
First published
08 May 2017

Org. Biomol. Chem., 2017,15, 4667-4680
Article type

Exploitation of new structurally diverse D-glucuronamide-containing N-glycosyl compounds: synthesis and anticancer potential

N. M. Xavier, A. Porcheron, D. Batista, R. Jorda, E. Řezníčková, V. Kryštof and M. C. Oliveira, Org. Biomol. Chem., 2017, 15, 4667
DOI: 10.1039/C7OB00472A

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