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

Abstract

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 N 7 -linked purine nucleoside and glucofuranuronamide derivatives comprising N 1 -linked uracil and N 7 -linked purine units with activities in the single-digit micromolar order of concentration against both cell lines. Their GI 50 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.