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.