Novel Hybrids of 3‑Substituted Coumarin and Phenylsulfonylfuroxan as Potent Antitumor Agents against Wild-Type and Drug-Resistant Nonsmall Cell Lung Cancer Cell Lines

Lung
cancer represents a major global health challenge, and the development
of new therapeutic agents remains a serious task. This study designed
and synthesized 27 novel coumarin-furoxan hybrids. Among them, compound 6o exhibited potent nanomolar-level antiproliferative activity
against six nonsmall cell lung cancer (NSCLC) cell lines, including
both wild-type and drug-resistant models. Mechanistic investigations
revealed that 6o downregulates the expression of ferroptosis-related
factors SLC7A11 and GPX4, thereby disrupting redox homeostasis, depleting
glutathione, and accumulating lipid peroxides, which collectively
trigger ferroptosis. Furthermore, 6o elevated mitochondrial
nitric oxide (NO) and reactive oxygen species (ROS) levels, exacerbating
cellular damage. 6o also displayed low hERG channel toxicity,
favorable in vivo safety, and acceptable solubility. In summary, 6o demonstrates high efficacy against both wild-type and drug-resistant
NSCLC cells via a ferroptosis-mediated mechanism, along with a promising
safety profile, supporting its potential as a candidate for further
development.