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

Eur J Med Chem. 2015 Jan 7:89:701-20. doi: 10.1016/j.ejmech.2014.10.080. Epub 2014 Oct 30.

Abstract

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 (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.

Keywords: Adenine; Cytotoxic activity; Hepatocellular carcinoma; Purine derivatives; Senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HCT116 Cells
  • Hep G2 Cells
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Purines / chemistry*
  • Purines / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Purines
  • purine