Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.
Drug Discovery Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.
Chem Biol Drug Des. 2019 Sep;94(3):1680-1693. doi: 10.1111/cbdd.13572. Epub 2019 Jun 12.
During some investigations into the mechanism of nitric oxide consumption by brain preparations, several potent inhibitors of this process were identified. Subsequent tests revealed the compounds act by inhibiting lipid peroxidation, a trigger for a form of regulated cell death known as ferroptosis. A quantitative structure-activity study together with XED (eXtended Electron Distributions) field analysis allowed a qualitative understanding of the structure-activity relationships. A representative compound N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-10H-phenothiazine-10-carboxamide (DT-PTZ-C) was able to inhibit completely oxidative damage brought about by two different procedures in organotypic hippocampal slice cultures, displaying a 30- to 100-fold higher potency than the standard vitamin E analogue, Trolox or edaravone. The compounds are novel, small, drug-like molecules of potential therapeutic use in neurodegenerative disorders and other conditions associated with oxidative stress.
在对脑制剂中一氧化氮消耗机制的一些研究中，发现了几种强效的该过程抑制剂。随后的测试表明，这些化合物通过抑制脂质过氧化来发挥作用，脂质过氧化是一种已知的调节性细胞死亡形式——铁死亡的触发因素。定量构效关系研究以及 XED（扩展电子分布）场分析允许定性理解结构-活性关系。代表性化合物 N-(3,5-二甲基-4H-1,2,4-三唑-4-基)-10H-吩噻嗪-10-甲酰胺 (DT-PTZ-C) 能够完全抑制器官型海马切片培养物中由两种不同程序引起的氧化损伤，其效力比标准维生素 E 类似物 Trolox 或依达拉奉高 30 到 100 倍。这些化合物是新型的、小的、具有药物样特性的分子，可能在神经退行性疾病和其他与氧化应激相关的疾病中具有治疗用途。
