通过诱导GPX4介导的铁铁蛋白的抗癌药，促进敏捷剂的设计，合成和生物学评估是抗癌药
Design, synthesis and biological evaluation of artesunate-Se derivatives as anticancer agents by inducing GPX4-mediated ferroptosis
影响因子:4.70000
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
摘要
合成了一系列基于促数苯乙酸苯酚（ART）支架和SE SE SEE功能（-secn和-secf3）的有机凝胶化合物。静脉 - 苯酸苯酸杆菌-SECN和青蒿琥酯-SECF3衍生物的氧化还原性能是通过2、2-二苯基-1-苯基羟基苯基（DPPH）进行的，结果表明化合物2C，2F和3E具有良好的自由自由基清除活性。对四种类型的癌细胞系（人类结肠腺癌细胞），HCT116（人类结肠直肠腺癌细胞），HEPG2（人类肝细胞癌细胞），MCF-7（MCF-7（人类乳腺癌细胞））评估了它们的细胞毒性。 MTT结果表明，与ART和5-FU相比，化合物2C在SW480，HCT116和MCF-7癌细胞系中表现出有效的体外抗增殖活性，因此选择了进一步的抗肿瘤机制研究。抗肿瘤机制研究表明，化合物2C通过抑制GPX4蛋白的表达，伴随着细胞内ROS水平的上调，诱导了HCT116细胞中的铁凋亡。 HCT116细胞中的线粒体表现出线粒体膜电位（MMP）的去极化和形态学的超微结构变化，这表明2C导致了线粒体功能障碍和铁质肌动症。此外，2C可以增加脂质过氧化和亚铁离子的水平，这进一步证实了化合物2c可以通过铁铁作用发挥其抗肿瘤作用。总体而言，这些结果表明，候选候选者可以提供有希望的新铅衍生物，以进一步潜在的抗癌药物开发。
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.