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Design and synthesis of N-hydroxyalkyl substituted deferiprone: a kind of iron chelating agents for Parkinson's disease chelation therapy strategy

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Abstract

The blood–brain barrier (BBB) permeability of molecules needs to meet stringent requirements of Lipinski’s rule, which pose a difficulty for the rational design of efficient chelating agents for Parkinson's disease chelation therapy. Therefore, the iron chelators employed N-aliphatic alcohols modification of deferiprone were reasonably designed in this work. The chelators not only meet Lipinski’s rule for BBB permeability, but also ensure the iron affinity. The results of solution thermodynamics demonstrated that the pFe3+ value of N-hydroxyalkyl substituted deferiprone is between 19.20 and 19.36, which is comparable to that of clinical deferiprone. The results of 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays indicated that the N-hydroxyalkyl substituted deferiprone also possesses similar radical scavenging ability in comparison to deferiprone. Meanwhile, the Cell Counting Kit-8 assays of neuron-like rat pheochromocytoma cell-line demonstrated that the N-hydroxyalkyl substituted deferiprone exhibits extremely low cytotoxicity and excellent H2O2-induced oxidative stress protection effect. These results indicated that N-hydroxyalkyl substituted deferiprone has potential application prospects as chelating agents for Parkinson's disease chelation therapy strategy.

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Acknowledgments

The authors would like to thank Dr. Heyan Huang (Analytical and Testing Center, Southwest University of Science and Technology) for nuclear paramagnetic resonance measurements.

Funding

The research was funded by the National Natural Science Foundation of China (grant number 51972278), the Project of State Key Laboratory of Environment-friendly Energy Materials, Southwest University of Science and Technology (grant number 19fksy04), and the Natural Science Foundation of Southwest University of Science and Technology (grant number 18zx7136).

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Authors and Affiliations

  1. State Key Laboratory of Environment-Friendly Energy Materials, School of Materials Science and Engineering, Southwest University of Science and Technology, Mianyang, 621010, China

    Qingchun Zhang, Shufan Feng, Bo Jin & Rufang Peng

  2. School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, 621010, China

    Yulian Zhao

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  1. Qingchun Zhang
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  2. Shufan Feng
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  3. Yulian Zhao
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QZ and RP conceived and designed the experiments; QZ, SF and YZ performed the experiments; QZ, and BJ analyzed the data; QZ and RP wrote and edited the manuscript.

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Correspondence to Qingchun Zhang or Rufang Peng.

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Zhang, Q., Feng, S., Zhao, Y. et al. Design and synthesis of N-hydroxyalkyl substituted deferiprone: a kind of iron chelating agents for Parkinson's disease chelation therapy strategy. J Biol Inorg Chem 26, 467–478 (2021). https://doi.org/10.1007/s00775-021-01863-x

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  • DOI: https://doi.org/10.1007/s00775-021-01863-x

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