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

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• 作者：Di Zhang ; Zhonghe Xu ; Jia Yuan ; Ying-Xi Zhao ; Zeng-Ying Qiao ; Yu-Juan Gao ; Guang-Ao Yu ; Jingyuan Li ; Hao Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：57
• 期：19
• 页码：8132-8139
• 全文大小：519K
• ISSN：1520-4804

文摘

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鈭捪€ 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.