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

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 4; pp. 858 - 872
• Main Authors: Aytaç, Peri S., Durmaz, Irem, Houston, Douglas R., Çetin-Atalay, Rengül, Tozkoparan, Birsen
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.02.2016; Elsevier
• Subjects: Aminomercaptotriazole; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; beta Catenin - genetics; beta Catenin - metabolism; Biochemistry & Molecular Biology; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Cytotoxic activity; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; HCT116 Cells; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; MAP Kinase Kinase Kinase 5 - genetics; MAP Kinase Kinase Kinase 5 - metabolism; MCF-7 Cells; Molecular Docking Simulation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oxidative stress; Oxidative Stress - drug effects; Pharmacology & Pharmacy; Physical Sciences; Protein Structure, Secondary; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Quantitative Structure-Activity Relationship; Science & Technology; Signal Transduction; Thiadiazines - chemical synthesis; Thiadiazines - pharmacology; Triazoles - chemical synthesis; Triazoles - pharmacology; Triazolothiadiazine; Oxidative stress; Aminomercaptotriazole; Triazolothiadiazine; Cytotoxic activity; Apoptosis; BLADDER-CANCER; CYCLE ARREST; PREVENTION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; QUANTITATIVE STRUCTURE-ACTIVITY; MOUSE MODEL; GROWTH; DERIVATIVES; MOLECULAR-MECHANISMS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.01.013

[Display omitted] 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.