The alteration of redox homeostasis is a hallmark of cancer cells. As a critical player in regulating cellular redox signaling, thioredoxin reductase (TrxR) enzymes are increasingly recognized as attractive targets for anticancer drug development. We reported herein the natural product sanguinarine (SAN) as a potent inhibitor of TrxR with a new chemical scaffold. Inhibition of TrxR leads to accumulation of the oxidized thioredoxin, elicits oxidative stress, and finally promotes apoptosis of cancer cells. Further synthesis of different model compounds of SAN demonstrated that the phenanthridinium unit is responsible for the TrxR inhibition. The core structure of SAN, e.g., the phenanthridinium moiety, is different from those of known TrxR inhibitors, and thus SAN is a new chemical entity of TrxR inhibitors and may serve a lead for further development. In addition, as the phenanthridinium scaffold is widely present in natural products, the disclosure of TrxR inhibition by such unit sheds light in understanding the pharmacological actions of these molecules.

中文翻译：

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血红素作为硫氧还蛋白还原酶抑制剂的新化学实体，可引起氧化应激并促进肿瘤细胞凋亡。

氧化还原稳态的改变是癌细胞的标志。作为调节细胞氧化还原信号的关键因素，硫氧还蛋白还原酶（TrxR）酶已被越来越多地认为是抗癌药物开发的有吸引力的靶标。我们在本文中报道了天然产物sanguinarine（SAN）与新的化学支架一起作为TrxR的有效抑制剂。TrxR的抑制导致氧化的硫氧还蛋白的积累，引起氧化应激，并最终促进癌细胞的凋亡。SAN的不同模型化合物的进一步合成表明，菲啶鎓单元负责TrxR抑制。SAN的核心结构（例如菲啶鎓部分）不同于已知的TrxR抑制剂，因此，SAN是TrxR抑制剂的新化学实体，并可能为进一步开发提供线索。另外，由于菲啶鎓支架广泛存在于天然产物中，因此通过这种单元抑制TrxR的公开为理解这些分子的药理作用提供了启示。