Structure-Guided optimization of PAO-PDT yields TrxR inhibitors as potential anticancer agent

Thioredoxin reductase (TrxR) is a critical enzyme in maintaining cellular redox balance, and its inhibition has emerged as a promising Anticancer strategy by compromising the antioxidant capacity of tumor cells and inducing oxidative stress-mediated Apoptosis. In our previous work, we identified PAO-PDT as a highly potent organoarsenic TrxR inhibitor, revealing a novel mode of TrxR inhibition at nanomolar concentrations. Building on this discovery, we aim to augment the antitumor efficacy of organoarsenic compounds by incorporating cinnamic acid, a naturally occurring compound derived from cinnamon, which has been reported to exhibit potent Anticancer activity. A series of CA-conjugated organoarsenic derivatives were rationally designed and synthesized. After preliminary screening, As-CA11 demonstrated potent antiproliferative activity against HL-60 cells (IC₅₀ = 0.28 ± 0.05 μM) and exhibited strong inhibition of TrxR in vitro (IC₅₀ = 18.7 ± 0.02 nM). Mechanistic investigations revealed that As-CA11 promotes intracellular ROS accumulation through TrxR inhibition, thereby disrupting redox homeostasis and inducing Apoptosis. These effects were further confirmed in a 4T1 tumor-bearing mouse model. Collectively, our results highlight the potential of structurally modifying organoarsenic scaffolds with bioactive natural product moieties to improve antitumor efficacy, offering promising leads for the development of next-generation organoarsenic-based therapeutics.

Arsenic (III) compounds; Cinnamic acid; Molecular conjugation strategy; Oxidative stress; Thioredoxin reductase; Thioredoxin system.