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

Article abstract of DOI:10.1021/jm3001532

Novel purine ribonucleoside analogues (9-13) containing a 4-substituted piperazine in the substituent at N⁶ 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 N⁶-(4- Trifluoromethylphenyl)piperazine analogue 11 displayed the best antitumor activity, with IC₅₀ 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.