Laboratory of Medicinal Chemistry, University of Antwerp , Universiteitsplein 1, B-2610 Antwerp, Belgium.
Molecular Signaling and Cell Death unit, VIB Inflammation Research Center , 9052 Ghent, Belgium.
J Med Chem. 2016 Mar 10;59(5):2041-53. doi: 10.1021/acs.jmedchem.5b01641. Epub 2016 Feb 8.
Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated necrosis that is critically dependent on glutathione peroxidase 4 (GPX4). It has been shown to contribute to liver and kidney ischemia reperfusion injury in mice. A chemical inhibitor discovered by high-throughput screening displayed inhibition of ferroptosis with nanomolar activity and was dubbed ferrostatin-1 (fer-1). Ferrostatins inhibit oxidative lipid damage, but suffer from inherent stability problems due to the presence of an ester moiety. This limits the application of these molecules in vivo, due to rapid hydrolysis of the ester into the inactive carboxylic acid. Previous studies highlighted the importance of the ethyl ester and suggested steric modifications of the ester for generating improved molecules. In this study, we report the synthesis of novel ferroptosis inhibitors containing amide and sulfonamide moieties with improved stability, single digit nanomolar antiferroptotic activity, and good ADME properties suitable for application in in vivo disease models.
铁死亡是一种非细胞凋亡、铁依赖性的调节性细胞坏死形式，严重依赖于谷胱甘肽过氧化物酶 4（GPX4）。它已被证明可导致小鼠的肝和肾缺血再灌注损伤。一种通过高通量筛选发现的化学抑制剂对铁死亡具有纳摩尔级的抑制活性，并被命名为 ferrostatin-1（fer-1）。铁抑素抑制氧化脂质损伤，但由于存在酯基，存在固有稳定性问题。由于酯基迅速水解为无活性的羧酸，这限制了这些分子在体内的应用。先前的研究强调了乙基酯的重要性，并提出了对酯基的立体修饰，以生成改进的分子。在这项研究中，我们报告了含有酰胺和磺酰胺部分的新型铁死亡抑制剂的合成，这些抑制剂具有改善的稳定性、单个位数纳摩尔级的抗铁死亡活性和良好的 ADME 特性，适合应用于体内疾病模型。
