title: Synthesis and molecular recognition studies on small-molecule inhibitors for thioredoxin reductase.
abstract: 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.
authors.affiliation: CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST) , No. 11 Beiyitiao, Zhongguancun, Haidian District, Beijing, 100190, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.forename: Zhonghe
authors.initials: Z
authors.lastname: Xu
authors.forename: Jia
authors.initials: J
authors.lastname: Yuan
authors.forename: Ying-Xi
authors.initials: YX
authors.lastname: Zhao
authors.forename: Zeng-Ying
authors.initials: ZY
authors.lastname: Qiao
authors.forename: Yu-Juan
authors.initials: YJ
authors.lastname: Gao
authors.forename: Guang-Ao
authors.initials: GA
authors.lastname: Yu
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006046:Gold / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D006046:Gold; D013880:Thioredoxin-Disulfide Reductase