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

Novel dodecyl-containing azido and glucuronamide-based nucleosides exhibiting anticancer potential AbstractThe 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Pure and Applied Chemistry de Gruyter

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

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Publisher
de Gruyter
Copyright
©2019 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/
ISSN
0033-4545
eISSN
1365-3075
DOI
10.1515/pac-2019-0106
Publisher site
See Article on Publisher Site

Abstract

AbstractThe 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.

Journal

Pure and Applied Chemistryde Gruyter

Published: Jul 26, 2019

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