Laboratory of Medicinal Chemistry , University of Antwerp , Universiteitsplein 1 , 2610 Antwerp , Belgium.
Molecular Signalling and Cell Death Unit , VIB Center for Inflammation Research , Technologiepark 927 , 9052 Ghent , Belgium.
J Med Chem. 2018 Nov 21;61(22):10126-10140. doi: 10.1021/acs.jmedchem.8b01299. Epub 2018 Nov 6.
Ferroptosis is an iron-catalyzed, nonapoptotic form of regulated necrosis that results in oxidative lipid damage in cell membranes that can be inhibited by the radical-trapping antioxidant Ferrostatin-1 (Fer-1). Novel inhibitors derived from the Fer-1 scaffold inhibited ferroptosis potently but suffered from solubility issues. In this paper, we report the synthesis of a more stable and readily soluble series of Fer-1 analogues that potently inhibit ferroptosis. The most promising compounds (37, 38, and 39) showed an improved protection compared to Fer-1 against multiorgan injury in mice. No toxicity was observed in mice after daily injection of 39 (UAMC-3203) for 4 weeks. UAMC-3203 inserts rapidly in a phospholipid bilayer in silico, which aligns with the current understanding of the mechanism of action of these compounds. In conclusion, these analogues have superior properties compared to Fer-1, show in vivo efficacy, and represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models.
铁死亡是一种铁催化的、非细胞凋亡形式的细胞程序性死亡，其结果是细胞膜上的氧化脂质损伤，这种损伤可以被自由基捕获抗氧化剂 Ferrostatin-1（Fer-1）抑制。源自 Fer-1 支架的新型抑制剂能够强烈抑制铁死亡，但存在溶解度问题。在本文中，我们报告了一系列更稳定、更易溶的 Fer-1 类似物的合成，这些类似物能够强烈抑制铁死亡。最有前途的化合物（37、38 和 39）在对抗小鼠多器官损伤方面显示出比 Fer-1 更好的保护作用。在小鼠中，连续 4 周每天注射 39（UAMC-3203）后未观察到毒性。UAMC-3203 在计算机模拟中迅速插入磷脂双层，这与目前对这些化合物作用机制的理解一致。总之，与 Fer-1 相比，这些类似物具有更好的性质，在体内有效，并代表具有治疗潜力的新型先导化合物，可用于相关的铁死亡驱动疾病模型。
