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

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Aytac P. S., Durmaz I., Houston D. R., Cetin-Atalay R., TOZKOPARAN KÖPRÜCÜ B.

BIOORGANIC & MEDICINAL CHEMISTRY, cilt.24, sa.4, ss.858-872, 2016 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 24 Sayı: 4
  • Basım Tarihi: 2016
  • Doi Numarası: 10.1016/j.bmc.2016.01.013
  • Dergi Adı: BIOORGANIC & MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.858-872
  • Anahtar Kelimeler: Aminomercaptotriazole, Triazolothiadiazine, Cytotoxic activity, Apoptosis, Oxidative stress, NONSTEROIDAL ANTIINFLAMMATORY DRUGS, QUANTITATIVE STRUCTURE-ACTIVITY, MOLECULAR-MECHANISMS, BLADDER-CANCER, CYCLE ARREST, MOUSE MODEL, GROWTH, DERIVATIVES, PREVENTION, APOPTOSIS
  • Orta Doğu Teknik Üniversitesi Adresli: Evet

Özet

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 similar to 5 mu M (IC50) were further analyzed and showed to induce apoptotic cell death and SubG(1) 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 GSK3 beta, beta-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. (c) 2016 Published by Elsevier Ltd.