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.