2. Academic Validation
  3. Synthesis and structure-activity optimization of hydroxypyridinones against rhabdomyolysis-induced acute kidney injury

Synthesis and structure-activity optimization of hydroxypyridinones against rhabdomyolysis-induced acute kidney injury

  • Eur J Med Chem. 2023 Nov 10:263:115933. doi: 10.1016/j.ejmech.2023.115933.
Jie Cen 1,  Haiying Zhu 2,  Chenggang Hong 2,  Xi Zhang 1,  Shuangrong Liu 1,  Bo Yang 3,  Yongping Yu 1,  Yuanmei Wen 4,  Ji Cao 5,  Wenteng Chen 6
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 2 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 3 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China; Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, China.
  • 4 The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China.
  • 5 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China; Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, China; Cancer Center of Zhejiang University, Hangzhou, China. Electronic address: caoji88@zju.edu.cn.
  • 6 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Electronic address: wentengchen@zju.edu.cn.
PMID: 37976703 DOI: 10.1016/j.ejmech.2023.115933
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.

Keywords

Ferroptosis inhibition; Hydrophilicity; Iron chelation; Lipophilicity; SAR optimization.

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