艺参素-硒衍生物的设计、合成与抗癌评估：通过诱导GPX4介导的铁死亡

Design, synthesis and biological evaluation of artesunate-Se derivatives as anticancer agents by inducing GPX4-mediated ferroptosis

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BIOORGANIC CHEMISTRY

影响因子:4.7

分区:医学2区 / 有机化学1区生化与分子生物学2区

发表日期:2024 Nov

作者: Meilin Ren, Simin Liang, Sitong Lin, Rizhen Huang, Yanyan Chen, Ye Zhang, Yanli Xu

DOI: 10.1016/j.bioorg.2024.107733

摘要

合成了一系列基于艺参素（ART）骨架与硒官能团（-SeCN和-SeCF3）杂化的有机硒化合物。利用2,2-二苯基-1-吡咯烷酮-5-基自由基清除剂（DPPH）检测艺参素-SeCN及艺参素-SeCF3衍生物的氧化还原性能，结果显示化合物2c、2f和3e具有良好的自由基清除能力。对四种癌细胞系（SW480人结肠腺癌细胞、HCT116人结直肠腺癌细胞、HepG2人肝细胞癌细胞、MCF-7人乳腺癌细胞）进行细胞毒性评价。MTT实验结果表明，与艺参素和5-FU相比，化合物2c在SW480、HCT116和MCF-7细胞中表现出强效的体外抗增殖活性，因此被选中用于后续抗肿瘤机制研究。研究发现，化合物2c通过抑制GPX4蛋白的表达，诱导HCT116细胞的铁死亡，同时伴有细胞内反应性氧（ROS）水平升高。线粒体表现出线粒体膜电位（MMP）去极化和超微结构变化，表明2c引起线粒体功能障碍和铁死亡。此外，2c还能增加脂质过氧化和亚铁离子水平，进一步确认其抗肿瘤作用可能通过铁死亡机制实现。综上所述，艺参素-硒候选化合物有望成为新型抗癌药物开发的潜在先导分子。

Abstract

A series of organoselenium compounds based on the hybridization of artesunate (ART) scaffolds and Se functionalities (-SeCN and -SeCF3) were synthesized. The redox properties of artesunate-SeCN and artesunate-SeCF3 derivatives were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), and the results showed that compounds 2c, 2f and 3e have a good free radical scavenging activity. Their cytotoxicity was evaluated against four types of cancer cell lines, SW480 (human colon adenocarcinoma cells), HCT116 (human colorectal adenocarcinoma cells), HepG2 (human hepatocellular carcinoma cells), MCF-7 (human breast cancer cells). The MTT results showed that compared with ART and 5-FU, compound 2c exhibited potent in vitro antiproliferative activity in SW480, HCT116, and MCF-7 cancer cell lines, and was thus chose for further antitumor mechanism investigation. The antitumor mechanism study revealed that compound 2c induced ferroptosis in HCT116 cells by inhibiting the expression of GPX4 protein, accompanying by the up-regulation of intracellular ROS levels. Mitochondria in HCT116 cells exhibit depolarization of mitochondrial membrane potential (MMP) and ultrastructural changes in morphology, which indicated that 2c resulted in mitochondrial dysfunction and ferroptosis. Moreover, 2c could increase the levels of lipid peroxidation and ferrous ion, which further confirm that compound 2c may exert its antitumor effect through ferroptosis. Overall, these results suggest that the artesunate-Se candidates could provide promising new lead derivatives for further potential anticancer drug development.