Synthesis of novel oxazol-5-one derivatives containing chiral trifluoromethyl and isoxazole moieties as potent antitumor agents and the mechanism investigation

• Published in: Bioorganic chemistry 2023-06, Vol.135, p.106505-106505, Article 106505
• Main Authors: Wang, Mengqi, Li, Luyao, Yang, Shuping, Guo, Fangyuan, Zhu, Gongming, Zhu, Bo, Chang, Junbiao
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Apoptosis; Carcinoma, Hepatocellular - drug therapy; Cell Line, Tumor; Cell Proliferation; Cytotoxic activities; Hepatocellular carcinoma; Liver Neoplasms - pathology; Mechanism; Mice; Molecular Docking Simulation; Molecular target; Peroxiredoxin 1; Reactive Oxygen Species - metabolism; Tumor growth
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106505

[Display omitted] •Oxazol-5-one derivatives containing chiral trifluoromethyl and isoxazole moieties as potent antitumor agents were designed through the molecular hybridization approach and synthesized.•Compound 5t showed high activity against HepG2 cells, which effectively inhibited liver cancer growth both in vitro and in vivo and may have therapeutic efficacy.•Compound 5t targeted peroxiredoxin 1 (PRDX1) and inhibited its antioxidant activity, leading to ROS accumulation and apoptosis in HepG2 cells. In this study, a series of novel oxazol-5-one derivatives containing a chiral trifluoromethyl and isoxazole moiety were synthesized and evaluated for cytotoxic activities. Among them, 5t was the most effective compound against HepG2 liver cancer cells with an IC50 of 1.8 μM. 5t inhibited cell proliferation, migration, invasion, and induced cell cycle arrest and apoptosis in vitro. Nevertheless, the potential anti-hepatocellular carcinoma (HCC) target and mechanism of 5t were unclear. This work aimed to seek the molecular target of 5t against HCC and investigate its mechanism. Liquid chromatography tandem-mass spectrometry was used to identify peroxiredoxin 1(PRDX1) as a possible target of 5t. Cellular thermal shift assay, drug affinity responsive target stability, and molecular docking provided conclusive evidence that 5t targeted PRDX1 and inhibited its enzymatic activity. 5t augmented the level of reactive oxygen species (ROS) and led to ROS-dependent DNA damage, endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis in HepG2 cells. Silencing PRDX1 also resulted in ROS-mediated apoptosis in HepG2 cells. In vivo, 5t inhibited mouse tumor growth by increasing oxidative stress. Briefly, our studies revealed that compound 5t targeted PRDX1 through a ROS-dependent mechanism, highlighting the future development of compound 5t as a novel therapeutic drug for HCC.