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

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 IC(50) values between 5.2 and 9.2 μM. 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 SAβ-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.

• Authors: Meral Tuncbilek, Ebru Bilget Guven, Tugce Onder, Rengul Cetin Atalay
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 7 Pg. 3058-65 (Apr 12 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22409771 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 American Chemical Society

Chemical References

• 6-(4-(4-trifluoromethylphenyl)piperazine-1-yl)-9-(ribofuranosyl)-9H-purine
• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p15
• Piperazines
• Protein Kinase Inhibitors
• Purine Nucleosides
• Retinoblastoma Protein
• Adenosine

Topics

• Adenosine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Carcinoma, Hepatocellular (pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cellular Senescence
• Cyclin-Dependent Kinase Inhibitor p15 (metabolism)
• Drug Screening Assays, Antitumor
• Humans
• Liver Neoplasms (pathology)
• Phosphorylation
• Piperazines (chemical synthesis, chemistry, pharmacology)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Purine Nucleosides (chemical synthesis, chemistry, pharmacology)
• Retinoblastoma Protein (metabolism)
• Structure-Activity Relationship