Synthesis of novel substituted purine derivatives and identification of the cell death mechanism

Novel 9-(substituted amino/piperazinoethyl)adenines ( 4 – 12 ), 6-(substituted piperazino/amino)purines ( 15 – 27 ), 9-( p -toluenesulfonyl/cyclopentyl/ethoxycarbonylmethyl)-6-(substituted amino/piperazino)purines ( 28 – 34 , 36, 37 , 38 – 41 ) were synthesized and evaluated initially for their cytotoxic activities on liver Huh7, breast T47D and colon HCT116 carcinoma cells. N 6 -(4-Trifluoromethylphenyl)piperazine derivative ( 17 ) and its 9-(p-toluene-sulfonyl)/9-cyclopentyl analogues ( 28 , 36 ) had promising cytotoxic activities. Compounds 17 , 28 and 36 were further analysed for their cytotoxicity in a panel of a liver cancer cell lines. The compound 36 had better cytotoxic activities (IC 50 ≤ 1 μM) than the nucleobase 5-FU and nucleosides fludarabine, cladribine, and pentostatine on Huh7 cells. Cytotoxicity induced by 36 was later identified as senescence associated cell death by SA-β-Gal assay. Novel substituted adenine, purine analogues were synthesized. 36 Triggered a time-, dose-dependent decrease in cell growth indexes in all HCC cells. 36 treated Huh7 cells showed senescence associated morphology. • Novel substituted adenine and purine derivatives were designed and synthesized. • Compound 36 displayed the greatest cytotoxic activity with IC 50 less than 1 μM. • 36 induces senescence associated cell death, which was demonstrated with SAβ-Gal assay.