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.
Original language | English |
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Pages (from-to) | 858-872 |
Number of pages | 15 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 24 |
Issue number | 4 |
DOIs | |
Publication status | Published - 15 Feb 2016 |
Keywords / Materials (for Non-textual outputs)
- 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