Novel anticancer paeonol derivatives possessing a nitric oxide donor moiety as TrxR inhibitors: design, synthesis, biological evaluation.

The tumor microenvironment (TME) plays a pivotal role in determining tumor progression and treatment response. Within the TME, redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) are critically involved in regulating intercellular and intracellular signaling. In this study, we hypothesized that conjugating an NO-releasing moiety to paeonol derivatives and introducing a chalcone structure to enhance thioredoxin reductase (TrxR) targeting would yield compounds with potent anticancer activity. Accordingly, a series of mono- and di-substituted nitrate derivatives were synthesized. The inhibitory activities of all synthesized compounds were evaluated against BGC823, HCT116, Hep G2, and MCF-7 cell lines using the CCK-8 assay. Among the paeonol chalcone derivatives, compound 11f exhibited significant antiproliferative activity across the tested cancer cell panel. It was identified as a promising candidate with potent TrxR inhibitory activity (IC50 = 0.26 ± 0.17 μM in vitro; IC50 = 0.33 μM in vivo). Furthermore, compound 11f induced S-phase arrest and promoted apoptosis in MCF-7 cells. These findings underscore the enhanced anticancer potential of paeonol chalcone derivatives, attributable to the synergistic effects of NO and ROS.