Novel triazolothiadiazines act as potent anticancer agents in liver cancer cells through Akt and ASK-1 proteins

Peri S Aytaç, Irem Durmaz, Douglas R Houston, Rengül Çetin-Atalay, Birsen Tozkoparan

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)858-872
Number of pages15
JournalBioorganic and Medicinal Chemistry
Issue number4
Publication statusPublished - 15 Feb 2016


  • Antineoplastic Agents
  • Apoptosis
  • Cell Line, Tumor
  • Cyclin D1
  • Cytoskeletal Proteins
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Hepatocytes
  • Humans
  • Inhibitory Concentration 50
  • MAP Kinase Kinase Kinase 5
  • MCF-7 Cells
  • Molecular Docking Simulation
  • Nuclear Proteins
  • Oxidative Stress
  • Protein Structure, Secondary
  • Proto-Oncogene Proteins c-akt
  • Quantitative Structure-Activity Relationship
  • Signal Transduction
  • Thiadiazines
  • Triazoles
  • beta Catenin
  • Journal Article
  • Research Support, Non-U.S. Gov't


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