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Scaffold-leaping optimization of naphthoquinone derivatives as ferroptosis inducer against non-small lung cancer
Hua Yang1, Xiaoya Wu1, Mengyu Li1
1School of Pharmaceutical Science and Pingyuan Laboratory, Zhengzhou University, Zhengzhou, Henan 450001, China.
Abstract:
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.
Insights
New naphthoquinone derivatives show promise as ferroptosis inducers for cancer therapy. Compound I-21 effectively reduced cancer cell proliferation by triggering ferroptosis, offering a novel treatment strategy for non-small cell lung cancer.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Ferroptosis, an iron-dependent cell death, is a potential cancer treatment target.
- Developing novel ferroptosis inducers is crucial for effective cancer therapy.
Purpose of the Study:
- To design, synthesize, and evaluate novel naphthoquinone derivatives as potential ferroptosis inducers.
- To identify potent anticancer agents with a specific mechanism of action against cancer cell lines.
Main Methods:
- Scaffold-leaping optimization of lead compound QD394 to generate new naphthoquinone derivatives.
- In vitro anti-proliferation assays against five cancer cell lines.
- Mechanistic studies including ferroptosis inhibition assays, glutathione (GSH) depletion, reactive oxygen species (ROS) and malondialdehyde (MDA) level assessment, and glutathione peroxidase 4 (GPX4) expression analysis.
- Cell cycle analysis and cell migration assays.
Main Results:
- A series of naphthoquinone derivatives were synthesized and their structure-activity relationship (SAR) was established.
- Compound I-21 exhibited potent in vitro anticancer activity (IC50 = 0.76 μM against A549 cells) and was identified as the most active compound.
- I-21's cytotoxic effect was reversed by ferrostatin-1, confirming its role as a ferroptosis inducer.
- Mechanistic studies showed I-21 depletes GSH, increases ROS and MDA, and downregulates GPX4 in A549 cells, inducing ferroptosis.
- I-21 also caused G2/M cell cycle arrest and inhibited cell migration.
Conclusions:
- Naphthoquinone derivatives can act as effective ferroptosis inducers.
- Compound I-21 represents a novel leading compound for non-small cell lung cancer treatment due to its potent ferroptosis-inducing activity.
- This study opens new avenues for developing naphthoquinone-based ferroptosis inducers for cancer therapy.
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