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Structure-Guided optimization of PAO-PDT yields TrxR inhibitors as potential anticancer agent
Suntao Shi1, Jingwen Tu1, Miao Zhong1
1State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
European Journal of Medicinal Chemistry
|December 3, 2025
Summary
New organoarsenic compounds conjugated with cinnamic acid show potent anticancer activity by inhibiting thioredoxin reductase (TrxR). This strategy enhances antitumor efficacy and induces cancer cell apoptosis via oxidative stress.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Oncology
Background:
- Thioredoxin reductase (TrxR) is crucial for cellular redox balance.
- TrxR inhibition is a promising anticancer strategy inducing oxidative stress and apoptosis.
- Previous work identified PAO-PDT as a potent organoarsenic TrxR inhibitor.
Purpose of the Study:
- To enhance the antitumor efficacy of organoarsenic compounds.
- To synthesize and evaluate cinnamic acid (CA)-conjugated organoarsenic derivatives.
- To explore novel therapeutic leads for cancer treatment.
Main Methods:
- Rational design and synthesis of CA-conjugated organoarsenic derivatives.
- In vitro antiproliferative activity assays against HL-60 cells.
- In vitro TrxR inhibition assays.
- Mechanistic studies on reactive oxygen species (ROS) and apoptosis.
- In vivo evaluation in a 4T1 tumor-bearing mouse model.
Main Results:
- As-CA11 demonstrated potent antiproliferative activity (IC50 = 0.28 ± 0.05 μM) and TrxR inhibition (IC50 = 18.7 ± 0.02 nM).
- As-CA11 induced intracellular ROS accumulation by inhibiting TrxR, disrupting redox homeostasis.
- The compound promoted apoptosis and showed antitumor effects in a mouse model.
Conclusions:
- Structurally modifying organoarsenic scaffolds with natural product moieties like cinnamic acid can improve antitumor efficacy.
- As-CA11 is a promising lead compound for developing next-generation organoarsenic-based therapeutics.
- Targeting TrxR with novel organoarsenic derivatives offers a viable anticancer strategy.
