Synthesis and antiproliferative evaluation of novel azido nucleosides and their phosphoramidate derivatives

0479189 - ÚEB 2018 RIV US eng J - Journal Article
Xavier, N.M. - Goncalves-Pereira, R. - Jorda, Radek - Řezníčková, Eva - Kryštof, Vladimír - Oliveira, M.C.
Synthesis and antiproliferative evaluation of novel azido nucleosides and their phosphoramidate derivatives.
Pure and Applied Chemistry. Roč. 89, č. 9 (2017), s. 1267-1281. ISSN 0033-4545. E-ISSN 1365-3075
R&D Projects: GA MŠMT(CZ) LO1204
Institutional support: RVO:61389030
Keywords : anticancer activity * azido nucleosides * bioactive molecules * ics-28 * N-glycosylation * nucleoside phosphoramidates * nucleoside/nucleotide analogs * Staudinger-phosphite reaction
OECD category: Organic chemistry
Impact factor: 5.294, year: 2017

New xylofuranosyl and glucopyranosyl nucleoside phosphoramidates were synthesized as potential mimetics of nucleoside 5′-monophosphates. Their access involved N-glycosylation of uracil and 2-acetamido-6-chloropurine with 5′/6′-azido-1,2-di-O-acetyl glycosyl donors and subsequent Staudinger-phosphite reaction of the resulting azido nucleosides. The coupling of the purine derivative with the pyranosyl donor furnished N 9 A nd N 7linked nucleosides in 1:1 ratio, whereas with the furanosyl donor, the N 9nucleoside was the major regioisomer formed. When using uracil, only 5′/6′-azido N 1linked nucleosides were obtained. The purine 5′/6′-azido nucleosides were converted into corresponding phosphoramidates in good yields. The antiproliferative effects of the nucleoside phosphoramidates and those of the azido counterparts on cancer cells were evaluated. While the nucleoside phosphoramidates did not show significant activities, the purine 5′/6′-azido nucleosides displayed potent effects against K562, MCF-7 and BT474 cell lines. The 5′-azidofuranosyl N 9 and N 7linked purine nucleosides exhibited highest activity towards the chronic myeloid leukemia cell line (K562) with GI 50 values of 13.6 and 9.7 μM, respectively. Among pyranosyl nucleosides, the N 7linked nucleoside was the most active compound with efficacy towards all cell lines assayed and a highest effect on K562 cells (GI 50 =6.8 μM). Cell cycle analysis of K562 and MCF-7 cells showed that the most active compounds cause G2/M arrest.
Permanent Link: http://hdl.handle.net/11104/0275188