Thiosemicarbazone-based lead optimization to discover high-efficiency and low-toxicity anti-gastric cancer agents
| Autor: | Yuan-Yuan Tao, Bing Zhao, Bo-Wang, Zhang-Xu He, Qin Ma, Hong-Min Liu, Haojie Wang, Xin-Hui Zhang, Hui-Pan Wu, Li-Ying Ma, Yi-Han Li |
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| Rok vydání: | 2020 |
| Předmět: |
Thiosemicarbazones
Epithelial-Mesenchymal Transition Cell cycle checkpoint Antineoplastic Agents Apoptosis Structure-Activity Relationship chemistry.chemical_compound Stomach Neoplasms Drug Discovery Tumor Cells Cultured medicine Humans IC50 Cell Proliferation Pharmacology Wound Healing Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Cancer Cell migration Cell Cycle Checkpoints General Medicine medicine.disease Cancer cell Cancer research Drug Screening Assays Antitumor Lead compound Intracellular |
| Zdroj: | European Journal of Medicinal Chemistry. 199:112349 |
| ISSN: | 0223-5234 |
| Popis: | In this paper, a series of thiosemicarbazone derivatives containing different aromatic heterocyclic groups were synthesized and the tridentate donor system of the lead compound was optimized. Most of the target compounds showed improved antiproliferative activity against MGC803 cells. SAR studies revealed that compound 5d displayed significant advantages in inhibition effect with an IC50 value of 0.031 μM, and better selectivity between cancer and normal cells than 3-AP and DpC (about 15- and 5-fold improved respectively). Besides, compound 5d showed selective antiproliferative activity in not only other cancer cells but also different gastric cancer cell lines. In-depth mechanism studies showed that compound 5d could induce mitochondria-related apoptosis which might be related to the elevation of intracellular ROS level, and cause cell cycle arrest at S phase. Moreover, 5d could evidently suppress the cell migration and invasion by blocking the EMT (epithelial–mesenchymal transition) process. Consequently, our studies provided a lead optimization strategy of thiosemicarbazone derivatives which would contribute to discover high-efficiency and low-toxicity agents for the treatment of gastric cancer. |
| Databáze: | OpenAIRE |
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