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

•Novel substituted adenine and purine derivatives were designed and synthesized.•Compound 36 displayed the greatest cytotoxic activity with IC50 less than 1 μM.•36 induces senescence associated cell death, which was demonstrated with SAβ-Gal assay.

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. N6-(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 (IC50 ≤ 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.

Graphical abstractNovel 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.Figure optionsDownload full-size imageDownload as PowerPoint slide