Structural Optimization of Dithiaarsanes-Enhanced Cytotoxicity to Leukemia Cells With Improved Thioredoxin Reductase Inhibition.

Herein, we report the rational design and optimization of dithiaarsane-based organoarsenicals that target thioredoxin reductase (TrxR), a selenoenzyme essential for maintaining cellular redox balance and often upregulated in various cancers. Guided by structure-activity relationship (SAR) analysis, refinement of the arsenic-sulfur heterocyclic scaffold afforded compound 37, which exhibits potent cytotoxicity against HL-60 leukemia cells. Mechanistic studies revealed that compound 37 efficiently inhibits TrxR activity, increases intracellular reactive oxygen species, and triggers apoptosis. Collectively, these results, together with the chemically versatile dithiaarsane scaffold established herein, provide a solid foundation for the development of next-generation TrxR-targeted therapeutics and redox-responsive functional molecules.