Synthesis and biological evaluation of celastrol derivatives as potent antitumor agents with STAT3 inhibition
| Autor: | Shaohua Xu, Ruolan Fan, Lu Wang, Weishen He, Haixia Ge, Hailan Chen, Wen Xu, Jian Zhang, Wei Xu, Yaqian Feng, Zhimin Fan |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular STAT3 Transcription Factor structural modification Pharmacology Dose-Response Relationship Drug Molecular Structure STAT3 inhibitor Cell Cycle Antineoplastic Agents Apoptosis RM1-950 General Medicine Celastrol Structure-Activity Relationship Drug Discovery Tumor Cells Cultured Humans Therapeutics. Pharmacology anti-tumour Drug Screening Assays Antitumor Pentacyclic Triterpenes colorectal cancer organoid Cell Proliferation Research Article Research Paper |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry article-version (VoR) Version of Record Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 37, Iss 1, Pp 236-251 (2022) |
| ISSN: | 1475-6374 1475-6366 |
| DOI: | 10.1080/14756366.2021.2001805 |
| Popis: | Using STAT3 inhibitors as a potential strategy in cancer therapy have attracted much attention. Recently, celastrol has been reported that it could directly bind to and suppress the activity of STAT3 in the cardiac dysfunction model. To explore more effective STAT3 inhibiting anti-tumour drug candidates, we synthesised a series of celastrol derivatives and biologically evaluated them with several human cancer cell lines. The western blotting analysis showed that compound 4 m, the most active derivative, could suppress the STAT3’s phosphorylation as well as its downstream genes. SPR analysis, molecular docking and dynamics simulations’ results indicated that the 4m could bind with STAT3 protein more tightly than celastrol. Then we found that the 4m could block cell-cycle and induce apoptosis on HCT-116 cells. Furthermore, the anti-tumour effect of 4m was verified on colorectal cancer organoid. This is the first research that discovered effective STAT3 inhibitors as potent anti-tumour agents from celastrol derivatives. |
| Databáze: | OpenAIRE |
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