title: Novel triazolothiadiazines act as potent anticancer agents in liver cancer cells through Akt and ASK-1 proteins.
abstract: Newly designed triazolothiadiazines incorporating with structural motifs of nonsteroidal analgesic anti-inflammatory drugs were synthesized and screened for their bioactivity against epithelial cancer cells. Compounds with bioactivities less then ∼5μM (IC50) were further analyzed and showed to induce apoptotic cell death and SubG1 cell cycle arrest in liver cancer cells. Among this group, two compounds (1g and 1h) were then studied to identify the mechanism of action. These molecules triggered oxidative stress induced apoptosis through ASK-1 protein activation and Akt protein inhibition as demonstrated by downstream targets such as GSK3β, β-catenin and cyclin D1. QSAR and molecular docking models provide insight into the mechanism of inhibition and indicate the optimal direction of future synthetic efforts. Furthermore, molecular docking results were confirmed with in vitro COX bioactivity studies. This study demonstrates that the novel triazolothiadiazine derivatives are promising drug candidates for epithelial cancers, especially liver cancer.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Sıhhiye, 06100 Ankara, Turkey.
authors.forename: Peri S
authors.initials: PS
authors.lastname: Aytaç
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey.
authors.forename: Irem
authors.initials: I
authors.lastname: Durmaz
authors.affiliation: Institute of Structural and Molecular Biology, University of Edinburgh, EH9 3JG, UK.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Houston
authors.affiliation: Cancer Systems Biology Laboratory, Department of Medical Informatics, Graduate School of Informatics, ODTU, 06800 Ankara, Turkey. Electronic address: rengul@metu.edu.tr.
authors.forename: Rengül
authors.initials: R
authors.lastname: Çetin-Atalay
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Sıhhiye, 06100 Ankara, Turkey. Electronic address: tbirsen@hacettepe.edu.tr.
authors.forename: Birsen
authors.initials: B
authors.lastname: Tozkoparan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017433:Protein Structure, Secondary; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D015398:Signal Transduction; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C512806:NIN protein, human; D009687:Nuclear Proteins; D013829:Thiadiazines; D014230:Triazoles; D051176:beta Catenin; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human
keywords: Aminomercaptotriazole; Apoptosis; Cytotoxic activity; Oxidative stress; Triazolothiadiazine