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Synthesis and structure-activity optimization of hydroxypyridinones against rhabdomyolysis-induced acute kidney
Jie Cen1, Haiying Zhu2, Chenggang Hong2
1College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Abstract:
The important role of accumulated iron is well recognized in the pathophysiology of rhabdomyolysis-induced acute kidney injury (RM-AKI). Our previous work further confirmed the labile iron triggered iron-dependent ferroptosis thus leading to the renal failure. In view of this, a series of hydroxypyridinones (HOPOs) with excellent iron chelation capability have been designed and synthesized in this study. A lead compound 6k was identified with good ferroptosis inhibition (EC50 = 20 μM) and no obvious cytotoxicity (CC50 > 100 μM), indicating a good therapeutic window (safety index = CC50/EC50 > 5.00). Moreover, intraperitoneal treatment of 6k (10 mg/kg) displayed a superior protective effect than deferiprone (50 mg/kg) in glycerol-induced RM-AKI mice with alleviating kidney dysfunction and pathological injury, decreasing the renal iron level as well as downregulating the mRNA level of ferroptosis associated genes (Acls4 and Ptgs2). Also, 6k exhibited a good in vivo safety profile, even at single high dose up to 1 g/kg without inducing mortality or toxic symptoms. Importantly, 6k could significantly upregulate the protein hypoxia-inducible factor 1α, possibly involving HIF pathway against the ferroptosis. These results collectively highlighted that the strategy of iron chelation and downstream ferroptosis inhibition has a therapeutic potential against RM-AKI.
Insights
New hydroxypyridinones (HOPOs) effectively chelate iron, inhibiting ferroptosis to protect against rhabdomyolysis-induced acute kidney injury (RM-AKI). Compound 6k shows therapeutic potential with a strong safety profile.
Area of Science:
- Biomedical Science
- Medicinal Chemistry
- Nephrology
Background:
- Accumulated iron plays a critical role in rhabdomyolysis-induced acute kidney injury (RM-AKI) pathophysiology.
- Labile iron triggers iron-dependent ferroptosis, leading to renal failure in RM-AKI.
- Developing effective iron chelation therapies is crucial for treating RM-AKI.
Purpose of the Study:
- To design and synthesize novel hydroxypyridinones (HOPOs) as potential therapeutic agents for RM-AKI.
- To evaluate the iron chelation and ferroptosis inhibition capabilities of synthesized HOPOs.
- To assess the in vivo efficacy and safety of a lead HOPO compound in a mouse model of RM-AKI.
Main Methods:
- Synthesis and characterization of a series of hydroxypyridinones (HOPOs).
- In vitro assessment of ferroptosis inhibition (EC50) and cytotoxicity (CC50) of lead compounds.
- In vivo evaluation of a lead compound (6k) in a glycerol-induced RM-AKI mouse model, measuring kidney function, pathology, iron levels, and gene expression.
- Assessment of the in vivo safety profile of compound 6k.
Main Results:
- A lead compound, 6k, was identified with potent ferroptosis inhibition (EC50 = 20 μM) and a wide therapeutic window (CC50 > 100 μM).
- Compound 6k demonstrated superior protective effects against glycerol-induced RM-AKI in mice compared to deferiprone, alleviating kidney dysfunction and injury.
- 6k treatment reduced renal iron levels, downregulated ferroptosis-associated genes (Acls4, Ptgs2), and upregulated HIF-1α protein, suggesting involvement of the HIF pathway.
- Compound 6k exhibited an excellent in vivo safety profile, with no mortality or toxicity observed even at high doses.
Conclusions:
- Hydroxypyridinone 6k is a promising therapeutic candidate for RM-AKI due to its potent iron chelation and ferroptosis inhibition properties.
- The strategy of targeting iron accumulation and downstream ferroptosis offers a viable therapeutic approach for RM-AKI.
- Compound 6k demonstrates significant potential for clinical translation in managing RM-AKI, supported by its efficacy and safety profile.
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