Discovery of phenazine derivatives as a new class of non-classical ferroptosis inhibitors and efficacy evaluation on a mouse model of liver injury

Yunjie Wu ¹, Lu Yang ¹, Jing You ²

⁰Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan, 610041, China.

European Journal of Medicinal Chemistry +

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November 18, 2024

View abstract on PubMed

Summary

Researchers discovered phenazine derivatives as novel ferroptosis inhibitors. Compound 13l effectively blocks iron-dependent cell death by inhibiting ferritinophagy, showing promise for treating diseases like acute liver injury.

Area Of Science

Biochemistry
Pharmacology
Cell Biology

Background

Ferroptosis, an iron-dependent regulated cell death, is linked to various diseases.
Current ferroptosis inhibitors (antioxidants, iron chelators) may cause side effects.
Novel non-classical ferroptosis inhibitors are needed for safer therapeutic strategies.

Purpose Of The Study

To discover and characterize a new class of non-classical ferroptosis inhibitors.
To identify potent phenazine derivatives with therapeutic potential.
To elucidate the mechanism of action for novel ferroptosis inhibitors.

Main Methods

Synthesis and structure-activity relationship (SAR) studies of phenazine derivatives.
In vitro assays to determine inhibitory concentrations (EC50) against ferroptosis.
Mechanistic studies involving NCOA4-mediated ferritinophagy.
In vivo testing using an acetaminophen-induced acute liver injury model.

Main Results

Phenazine derivatives were identified as a new class of non-classical ferroptosis inhibitors.
Compound 13l demonstrated high potency with an EC50 of 0.0007 μM.
13l inhibited NCOA4-mediated ferritinophagy, protecting cells from ferroptosis.
13l exhibited significant therapeutic effects in an acute liver injury model.

Conclusions

Phenazine derivatives represent a promising new class of non-classical ferroptosis inhibitors.
Compound 13l is a potent inhibitor of ferroptosis via ferritinophagy inhibition.
13l shows therapeutic potential for treating ferroptosis-associated diseases, including acute liver injury.

Keywords:

Ferroptosis Liver injury Non-classical ferroptosis inhibitor Structure-activity relationship