Synthesis and Molecular Recognition Studies on Small-Molecule Inhibitors for Thioredoxin Reductase

Thioredoxin reductase (TrxR), which is overexpressed in many aggressive cancers, plays a crucial role in redox balance and antioxidant function, including defense of oxidative stress, control of cell proliferation, and regulation of cell apoptosis. Deactivation of TrxR can destroy the homeostasis of the cancer cells, inducing elevation of reactive oxygen species (ROS) levels and the oxidation of enzymatic substrates. Here, we synthesized and identified a new gold­(I) small molecule (D9) that possesses two strong electron-donating moieties, i.e., 4-methylphenyl alkynyl and thionyldiphenyl phosphine, exhibiting an enhanced p−π conjunction effect. The resulting compound shows the increased soft Lewis acids and the stability of gold­(I). And we demonstrated that D9 could efficiently and specifically inhibit the activity of TrxR in vitro and in vivo, and it could effectively avoid the ligand exchange with albumin that was one of the most abundant proteins in blood. We believe that these comprehensive studies on the relationship between the structure and performance will provide inspiring information on the precise synthesis and design of new compounds for targeting TrxR.硫氧还蛋白还原酶（Thioredoxin reductase, TrxR）在多种侵袭性癌症中呈过表达状态，其在氧化还原稳态与抗氧化功能中发挥关键作用，涵盖抵御氧化应激、调控细胞增殖以及调节细胞凋亡。硫氧还蛋白还原酶的失活会破坏癌细胞的稳态，引发活性氧（reactive oxygen species, ROS）水平升高以及酶底物的氧化。本研究合成并鉴定了一种新型金(I)小分子化合物D9，其带有两个强电子给体基团，即4-甲基苯基炔基和硫代二苯基膦，展现出增强的p−π共轭效应。该化合物的软路易斯酸性与金(I)稳定性均有所提升。实验证实，D9可在体内外高效且特异性地抑制硫氧还蛋白还原酶的活性，同时能有效避免与血液中丰度最高的蛋白质之一——白蛋白发生配体交换。我们认为，这些针对结构与性能关系的系统性研究，将为靶向硫氧还蛋白还原酶的新型化合物的精准合成与设计提供富有启发性的参考信息。