合成了一系列基于青蒿琥酯（ART）支架和硒官能团（-SeCN和-SeCF3）杂交的有机硒化合物。采用2, 2-二二苯基-1-三硝基苯肼(DPPH)对青蒿琥酯-SeCN和青蒿琥酯-SeCF3衍生物进行氧化还原性能测试，结果表明化合物2c、2f和3e具有良好的自由基清除活性。针对四种类型的癌细胞系 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）评估了它们的细胞毒性。 MTT结果显示，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，因此被选择用于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，并上调细胞内ROS水平，诱导HCT116细胞铁死亡。 HCT116 细胞中的线粒体表现出线粒体膜电位 (MMP) 去极化和超微结构形态变化，表明 2c 导致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的水平，这进一步证实化合物2c可能通过铁死亡发挥抗肿瘤作用。总体而言，这些结果表明青蒿琥酯-硒候选物可以为进一步潜在的抗癌药物开发提供有前景的新先导衍生物。版权所有 © 2024。由 Elsevier Inc. 出版。

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.Copyright © 2024. Published by Elsevier Inc.