JBIC Journal of Biological Inorganic Chemistry ( IF 2.7 ) Pub Date : 2021-05-08 , DOI: 10.1007/s00775-021-01863-x Qingchun Zhang 1 , Shufan Feng 1 , Yulian Zhao 2 , Bo Jin 1 , Rufang Peng 1
|
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.
Graphic abstract
中文翻译：
N-羟烷基取代去铁酮的设计与合成：一种用于帕金森病螯合治疗策略的铁螯合剂
分子的血脑屏障（BBB）通透性需要满足利平斯基规则的严格要求，这给合理设计用于帕金森病螯合治疗的高效螯合剂带来了困难。因此，本工作合理设计了使用去铁酮的N-脂肪醇修饰的铁螯合剂。螯合剂不仅满足利平斯基对血脑屏障通透性的规则，而且保证了铁的亲和力。溶液热力学结果表明，N-羟烷基取代去铁酮的pFe 3+值在19.20～19.36之间，与临床去铁酮相当。2,2-diphenyl-1-picrylhydrazyl 自由基清除实验结果表明，N与去铁酮相比，-羟烷基取代的去铁酮还具有类似的自由基清除能力。同时，神经元样大鼠嗜铬细胞瘤细胞系的Cell Counting Kit-8分析表明，N-羟烷基取代的去铁酮表现出极低的细胞毒性和优异的H 2 O 2诱导的氧化应激保护作用。这些结果表明，N-羟烷基取代的去铁酮作为帕金森病螯合治疗策略的螯合剂具有潜在的应用前景。
京公网安备 11010802027423号