Exploitation of new structurally diverse d-glucuronamide-containing N-glycosyl compounds: synthesis and anticancer potential. Issue 21 (18th May 2017)

• Record Type: Journal Article
• Authors: Xavier, Nuno M.; Porcheron, Alexandre; Batista, Daniela; Jorda, Radek; Řezníčková, Eva; Kryštof, Vladimír; Oliveira, M. Conceição
• Is Part Of: Organic & biomolecular chemistry. Volume 15:Issue 21(2017)
• Page Start: 4667
• Page End: 4680
• Publication Date: 2017-05-18
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c7ob00472a
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : The synthesis of noveld -glucuronamide-based N -glycosyl derivatives is described. An N -dodecyl-containing N 9 -glycosylpurine displayed anticancer effects with single-digit micromolar GI50 values. Abstract : 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 N 9 -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.