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

Bioorg Med Chem. 2023 Feb 15:80:117176. doi: 10.1016/j.bmc.2023.117176.

Cai-Wen Fan ¹, Mei-Shan Li ², Xi-Xi Song ², Li Luo ², Jing-Chen Jiang ², Jia-Zi Luo ³, Heng-Shan Wang ⁴

Affiliations

1 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China; Scientific Experiment Center, Guilin Medical University, Guilin 541199, China.
2 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
3 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China. Electronic address: LJZ20220118@163.com.
4 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China. Electronic address: whengshan@163.com.

PMID: 36709571 DOI: 10.1016/j.bmc.2023.117176

Abstract

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.

Keywords

2-oximino-2-indolylacetamide; Apoptosis; Autophagy; Ferroptosis.

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