Novel dodecyl-containing azido and glucuronamide-based nucleosides exhibiting anticancer potential

0507563 - ÚEB 2020 RIV DE eng J - Journal Article
Xavier, N.M. - Goncalves-Pereira, R. - Jorda, Radek - Hendrychová, Denisa - Oliveira, M. C.
Novel dodecyl-containing azido and glucuronamide-based nucleosides exhibiting anticancer potential.
Pure and Applied Chemistry. Roč. 91, č. 7 (2019), s. 1085-1105. ISSN 0033-4545. E-ISSN 1365-3075
R&D Projects: GA MŠMT(CZ) EF16_019/0000868
Institutional support: RVO:61389030
Keywords : anticancer activity * apoptosis * azido nucleosides * glucuronamide-based nucleosides * ics-29 * nucleoside analogs
OECD category: Hematology
Impact factor: 1.919, year: 2019
Method of publishing: Open access
http://dx.doi.org/10.1515/pac-2019-0106

The synthesis and anticancer evaluation of new series of nucleosides constructed on 5/6-azidoglycosyl or glucuronamide moieties and containing an O- or an N-dodecyl chain, respectively, are disclosed. Based on our previous results, their structures were planned to preclude them to act via a similar metabolic pathway than that of clinically used nucleoside antimetabolites, against which cancer cells frequently acquire resistance. Xylo and gluco-configured 5/6-azido-1,2-di-O-acetyl furanosyl and pyranosyl donors containing a 3-O-dodecyl group were synthesized from diacetone-d-glucose and were subsequently coupled with silylated uracil or 2-acetamido-6-chloropurine. N-Dodecyl glucuronamide-based nucleosides were accessed from acetonide-protected glucofuranurono-6,3-lactone, which was converted in few steps into O-benzylated 1,2-di-O-acetyl furanuronamide or pyranuronamide derivatives to undergo further N-glycosylation. Both types of nucleosides demonstrated notorious antiproliferative effects in chronic myeloid leukemia (K562) and in breast cancer (MCF-7) cells. The most potent molecules were a 6′-azidoglucopyranosyl N7-linked purine nucleoside and glucofuranuronamide derivatives comprising N1-linked uracil and N7-linked purine units with activities in the single-digit micromolar order of concentration against both cell lines. Their GI50 values in MCF-7 cells were similar or ca. 3-fold lower than that of the standard drug 5-fluorouracil. Cell cycle studies and immunoblotting analysis of apoptosis-associated proteins in treated K562 cells indicated that the antiproliferative effect of the most effective nucleosides is based on apoptosis induction.
Permanent Link: http://hdl.handle.net/11104/0298544