Synthesis of novel 6-(4-substituted piperazine-1-yl)-9-(β-dribofuranosyl)purine derivatives, which lead to senescence-induced cell death in liver cancer cells

Date
2012
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Source Title
Journal of Medicinal Chemistry
Print ISSN
0022-2623
Electronic ISSN
Publisher
ACS
Volume
55
Issue
7
Pages
3058 - 3065
Language
English
Type
Article
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Abstract

Novel purine ribonucleoside analogues (9-13) containing a 4-substituted piperazine in the substituent at N-6 were synthesized and evaluated for their cytotoxicity on Huh7, HepG2, FOCUS, Mahlavu liver, MCF7 breast, and HCT116 colon carcinoma cell lines. The purine nucleoside analogues were analyzed initially by an anticancer drug-screening method based on a sulforhodamine B assay. Two nucleoside derivatives with promising cytotoxic activities (11 and 12) were further analyzed on the hepatoma cells. The N-6-(4-Trifluoromethylphenyl)piperazine analogue 11 displayed the best antitumor activity, with IC50 values between 5.2 and 9.2 mu M. Similar to previously described nucleoside analogues, compound 11 also interferes with cellular ATP reserves, possibly through influencing cellular kinase activities. Furthermore, the novel nucleoside analogue 11 was shown to induce senescence-associated cell death, as demonstrated by the SA beta-gal assay. The senescence-dependent cytotoxic effect of 11 was also confirmed through phosphorylation of the Rb protein by p15(INK4b) overexpression in the presence of this compound.

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Keywords
Nucleoside analogs, Carcinoma, Therapy, Fibroblasts, Thiopurines, Hallmarks
Citation
Published Version (Please cite this version)