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Synthesis and molecular recognition studies on small-molecule inhibitors for thioredoxin reductase
Di Zhang1, Zhonghe Xu, Jia Yuan
1CAS 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.
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.
Insights
A novel gold(I) compound, D9, effectively inhibits thioredoxin reductase (TrxR) in cancer cells. This targeted approach disrupts cancer cell homeostasis by increasing reactive oxygen species (ROS) and offers a promising new strategy for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Biochemistry
Background:
- Thioredoxin reductase (TrxR) is overexpressed in aggressive cancers, regulating redox balance, cell proliferation, and apoptosis.
- Inhibition of TrxR disrupts cancer cell homeostasis, increasing reactive oxygen species (ROS) and leading to cell death.
Purpose of the Study:
- To synthesize and characterize a novel gold(I) small molecule (D9) targeting TrxR.
- To evaluate the efficacy and specificity of D9 in inhibiting TrxR activity both in vitro and in vivo.
- To assess the stability of D9 against ligand exchange with albumin.
Main Methods:
- Synthesis and structural identification of the gold(I) compound D9.
- In vitro and in vivo assays to measure TrxR inhibition.
- Assessment of D9's interaction with albumin.
Main Results:
- D9, featuring electron-donating moieties, demonstrated enhanced stability and soft Lewis acidity.
- D9 efficiently and specifically inhibited TrxR activity in vitro and in vivo.
- D9 showed minimal ligand exchange with albumin, suggesting good pharmacokinetic properties.
Conclusions:
- The novel gold(I) compound D9 is a potent and specific inhibitor of thioredoxin reductase.
- D9's unique structure and properties make it a promising candidate for targeted cancer therapy.
- Structure-activity relationship studies provide insights for designing new TrxR-targeting agents.
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