Discovery of novel 2-oximino-2-indolylacetamide derivatives as potent anticancer agents capable of inducing cell autophagy and ferroptosis

[Display omitted] A series of 2-oximino-2-indolylacetamide derivatives were designed, synthesized and evaluated for their antitumour effects. Among them, 4d exhibited the most potent antiproliferative effect in vitro on the tested human cancer cells. Additionally, 4d significantly induced cell apopt...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2023-02, Vol.80, p.117176-117176, Article 117176
Main Authors: Fan, Cai-Wen, Li, Mei-Shan, Song, Xi-Xi, Luo, Li, Jiang, Jing-Chen, Luo, Jia-Zi, Wang, Heng-Shan
Format: Article
Language:English
Subjects:
2-oximino-2-indolylacetamide
Animals
Antineoplastic Agents - pharmacology
Apoptosis
Autophagy
Ferroptosis
Glutathione - metabolism
Humans
Mice
Reactive Oxygen Species - metabolism
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Summary:[Display omitted] A series of 2-oximino-2-indolylacetamide derivatives were designed, synthesized and evaluated for their antitumour effects. Among them, 4d exhibited the most potent antiproliferative effect in vitro on the tested human cancer cells. Additionally, 4d significantly induced cell apoptosis, caused mitochondrial dysfunction, promoted Bax, cleaved-PARP and p53 expression and inhibited Bcl-2 expression in 5-8F cells. Moreover, 4d remarkably promoted autophagosome formation, leading to cell apoptosis. Further investigation indicated that 4d could trigger cell death through cell ferroptosis, including increased ROS generation and lipid peroxidation and decreased glutathione peroxidase 4 (GPx4) expression and glutathione (GSH) levels. More importantly, 4d induced 5-8F cell death by activating ROS/MAPK and inhibiting the AKT/mTOR and STAT3 signalling pathways. Interestingly, 4d significantly suppressed tumour growth in a 5-8F cell xenograft model without obvious toxicity to mice. Overall, these results demonstrate that 4d may be a potential compound for cancer therapy.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2023.117176