title: Synthesis of novel substituted purine derivatives and identification of the cell death mechanism.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Ankara, Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Demir
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Ebru Bilget
authors.initials: EB
authors.lastname: Guven
authors.affiliation: Department of Engineering Physics, Faculty of Engineering, Hacettepe University, 06800 Beytepe, Ankara, Turkey.
authors.forename: Suheyla
authors.initials: S
authors.lastname: Ozbey
authors.affiliation: Department of Physics, Faculty of Arts and Sciences, Ondokuz Mayıs University, 55139 Kurupelit, Samsun, Turkey.
authors.forename: Canan
authors.initials: C
authors.lastname: Kazak
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey. Electronic address: rengul@bilkent.edu.tr.
authors.forename: Rengul Cetin
authors.initials: RC
authors.lastname: Atalay
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Ankara, Turkey. Electronic address: tuncbile@pharmacy.ankara.edu.tr.
authors.forename: Meral
authors.initials: M
authors.lastname: Tuncbilek
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011687:Purines; C030985:purine
keywords: Adenine; Cytotoxic activity; Hepatocellular carcinoma; Purine derivatives; Senescence