Design, synthesis and in vitro anticancer research of novel tetrandrine and fangchinoline derivatives
| Autor: | Yu-kai Zhang, Chen Jiashu, Sun Bin, Chao Liu, Wang Muxuan, Zhang Ruirui, Xiu-zheng Gao, Yu-fa Liu, Xu-tao Lv, Yang Luo, Jin-yue Sun |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cell Survival
Cell Antineoplastic Agents Apoptosis Benzylisoquinolines 01 natural sciences Biochemistry Stephania tetrandra HeLa chemistry.chemical_compound Cell Line Tumor Drug Discovery medicine Humans Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation A549 cell Molecular Structure biology 010405 organic chemistry Cell growth Organic Chemistry Cell Cycle Checkpoints biology.organism_classification 0104 chemical sciences Tetrandrine 010404 medicinal & biomolecular chemistry medicine.anatomical_structure chemistry Drug Design Cancer research |
| Zdroj: | Bioorganic Chemistry. 109:104694 |
| ISSN: | 0045-2068 |
| Popis: | Cancer treatment is one of the major public health issues in the world. Tetrandrine (Tet) and fangchinoline (d-Tet) are two bis-benzyl isoquinoline alkaloids extracted from Stephania tetrandra S. Moore, and their antitumor activities have been confirmed. However, the effective dose of Tet and d-Tet were much higher than that of the positive control and failed to meet clinical standards. Therefore, in this study, as a continuation of our previous work to study and develop high-efficiency and low-toxic anti-tumor lead compounds, twenty new Tet and d-Tet derivatives were designed, synthesized and evaluated as antitumor agents against six cancer cell lines (H460, H520, HeLa, HepG-2, MCF-7, SW480 cell lines) and BEAS-2B normal cells by CCK-8 analysis. Ten derivatives showed better cytotoxic effects than the parent fangchinoline, of which 4g showed the strongest cell growth inhibitory activity with an IC50 value of 0.59 μM against A549 cells. Subsequently, the antitumor mechanism of 4g was studied by flow cytometry, Hoechst 33258, JC-1 staining, cell scratch, transwell migration, and Western blotting assays. These results showed that compound 4g could inhibit A549 cell proliferation by arresting the G2/M cell cycle and inhibiting cell migration and invasion by reducing MMP-2 and MMP-9 expression. Meanwhile, 4g could induce apoptosis of A549 cells through the intrinsic pathway regulated by mitochondria. In addition, compound 4g inhibited the phosphorylation of PI3K, Akt and mTOR, suggesting a correlation between blocking the PI3K/Akt/mTOR pathway and the above antitumor activities. These results suggest that compound 4g may be a future drug for the development of new potential drug candidates against lung cancer. |
| Databáze: | OpenAIRE |
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