N‐Phenyl‐2‐Pyridone‐Derived Endoperoxide Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis Progression by Three‐Pronged Action

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3‐methyl‐N‐phenyl‐2‐pyridone, thus targeting multiple mechanisms for treating non‐small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half‐life of 8.3 hours without the generation of other by‐products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of HIF‐1α protein, but also inhibits the TGF‐β1 induced fibrosis in vitro. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3‐methyl‐N‐phenyl‐2‐pyridone, and triplet oxygen could downregulate HIF‐1α and relieve tumor hypoxia which is a critical issue in conventional PDT. Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases.