2. Academic Validation
  3. Novel triazolothiadiazines act as potent anticancer agents in liver cancer cells through Akt and ASK-1 proteins

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

  • Bioorg Med Chem. 2016 Feb 15;24(4):858-72. doi: 10.1016/j.bmc.2016.01.013.
Peri S Aytaç 1,  Irem Durmaz 2,  Douglas R Houston 3,  Rengül Çetin-Atalay 4,  Birsen Tozkoparan 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Sıhhiye, 06100 Ankara, Turkey.
  • 2 Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey.
  • 3 Institute of Structural and Molecular Biology, University of Edinburgh, EH9 3JG, UK.
  • 4 Cancer Systems Biology Laboratory, Department of Medical Informatics, Graduate School of Informatics, ODTU, 06800 Ankara, Turkey. Electronic address: rengul@metu.edu.tr.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Sıhhiye, 06100 Ankara, Turkey. Electronic address: tbirsen@hacettepe.edu.tr.
PMID: 26810835 DOI: 10.1016/j.bmc.2016.01.013
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.

Keywords

Aminomercaptotriazole; Apoptosis; Cytotoxic activity; Oxidative stress; Triazolothiadiazine.

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