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

Nuno M. Xavier
  • Corresponding author
  • Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 2°/5° Piso, Campo Grande, 1749-016 Lisboa, Portugal
  • Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
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, Rita Goncalves-Pereira
  • Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 2°/5° Piso, Campo Grande, 1749-016 Lisboa, Portugal
  • Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
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, Radek Jorda
  • Corresponding author
  • Laboratory of Growth Regulators, Centre of the Region Hana for Biotechnological and Agricultural Research, Palacky University and Institute of Experimental Botany, the Czech Academy of Sciences, Šlechtitelů 27, 78371 Olomouc, Czech Republic
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, Denisa Hendrychová
  • Laboratory of Growth Regulators, Centre of the Region Hana for Biotechnological and Agricultural Research, Palacky University and Institute of Experimental Botany, the Czech Academy of Sciences, Šlechtitelů 27, 78371 Olomouc, Czech Republic
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and M. Conceição Oliveira
  • Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
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Abstract

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 6ʹ-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.

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