Exploitation of new structurally diverse d-glucuronamide-containing: Nglycosyl compounds: Synthesis and anticancer potential

0476598 - ÚEB 2018 RIV GB eng J - Journal Article
Xavier, N.M. - Porcheron, A. - Batista, D. - Jorda, Radek - Řezníčková, Eva - Kryštof, Vladimír - Oliveira, M.C.
Exploitation of new structurally diverse d-glucuronamide-containing: Nglycosyl compounds: Synthesis and anticancer potential.
Organic & Biomolecular Chemistry. Roč. 15, č. 21 (2017), s. 4667-4680. ISSN 1477-0520. E-ISSN 1477-0539
R&D Projects: GA MŠMT(CZ) LO1204
Institutional support: RVO:61389030
Keywords : ACUTE MYELOID-LEUKEMIA * PYRIMIDINE NUCLEOSIDES * PURINE NUCLEOSIDES
OECD category: Organic chemistry
Impact factor: 3.423, year: 2017

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 TMSN 3 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 N 9linked purine nucleoside in the breast cancer cell MCF-7 with a GI 50 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.
Permanent Link: http://hdl.handle.net/11104/0273070