针对癌细胞中过度表达的硫氧还蛋白还原酶（TrxR）来诱导氧化应激已被证明是癌症治疗的有效策略。然而，TrxR抑制剂的低效和频繁给药阻碍了治疗，因此迫切需要更有效的TrxR抑制剂。在此，我们设计并合成了一系列基于砷的TrxR抑制剂。其中，化合物1d在低微摩尔浓度下抑制多种癌细胞的增殖，并且对正常细胞表现出低毒性。重要的是，化合物1d通过抑制TrxR活性诱导活性氧（ROS）积累，进一步导致氧化还原系统崩溃、线粒体功能障碍、内质网（ER）应激和DNA损伤，进而诱导细胞氧化应激细胞凋亡。体内数据显示，与临床TrxR抑制剂金诺芬（AUR）相比，化合物1d在1.5mg/kg的剂量下可以更有效地消除肿瘤90%，且没有任何明显的副作用。这些结果表明化合物 1d 是一种有效的 TrxR 抗癌抑制剂。版权所有 © 2023。由 Elsevier Inc. 出版。

Targeting overexpressed thioredoxin reductase (TrxR) in cancer cells to induce oxidative stress has been proved to be an effective strategy for cancer therapy. However, the treatment was hindered by the low efficiency and frequent administration of TrxR inhibitors, and hence more potent TrxR inhibitors were urgently needed. Herein, we designed and synthesized a series of TrxR inhibitors based on arsenicals. Among these, compound 1d inhibited the proliferation of a variety of cancer cells at low micromolar concentrations and exhibited low toxicity to normal cells. Importantly, compound 1d induced the accumulation of reactive oxygen species (ROS) by inhibiting the TrxR activity, further causing the collapse of the redox system, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and DNA damage, followed by oxidative stress-induced cell apoptosis. In vivo data showed that, compared with the clinical TrxR inhibitor auranofin (AUR), compound 1d could more effectively eliminate tumors by 90 % at a dose of 1.5 mg/kg without any obvious side effects. These results indicated that compound 1d was a potent TrxR inhibitor against cancer.Copyright © 2023. Published by Elsevier Inc.