Scaffold-leaping optimization of naphthoquinone derivatives as ferroptosis inducer against non-small lung cancer

Ferroptosis, an iron-dependent programmed cell death pathway, has emerged as a promising therapeutic target for cancer. Herein, a series of naphthoquinone derivatives were designed via scaffold-leaping optimization from lead compound QD394, synthesized and assessed for their anti-proliferation activity against five cancer cell lines, and the structure-activity relationship (SAR) were described. Of these compounds, I-21 was identified as most active, demonstrating significant anticancer efficacy in vitro (IC₅₀ = 0.76 μM against A549 cell lines). This cytotoxic effect can be counteracted by ferrostatin-1, a ferroptosis inhibitor, indicating that I-21 may acts as a ferroptosis inducer. Mechanistic studies revealed that I-21 triggered ferroptosis by depleting glutathione (GSH), elevating reactive oxygen species (ROS) and malondialdehyde (MDA), and downregulating glutathione peroxidase 4(GPX4) expression in A549 cell lines. Furthermore, I-21 arrested the cell cycle at the G2/M phase and inhibited the migration of A549 cell lines. This study provided the first evidence of naphthoquinone derivatives as ferroptosis inducers, offering a novel leading compound for the non-small cell lung cancer treatment.