We synthesized new aroyl diheterocyclic pyrrole (ARDHEP) 15 that exhibited the hallmarks of ferroptosis. Compound 15 strongly inhibited U-87 MG, OVCAR-3, and MCF-7 cancer cells, induced an increase of cleaved PARP, but was not toxic for normal human primary T lymphocytes at 0.1 μM. Analysis of the levels of lactoperoxidase, malondialdehyde, lactic acid, total glutathione, and ATP suggested that the in vivo inhibition of cancer cell proliferation by 15 went through stimulation of oxidative stress injury and Fe²⁺ accumulation. Quantitative polymerase chain reaction analysis of the mRNA expression in U-87 MG and SKOV-3 tumor tissues from 15-treated mice showed the presence of Ptgs2/Nfe2l2/Sat1/Akr1c1/Gpx4 genes correlated with ferroptosis in both groups. Immunofluorescence staining revealed significantly lower expressions of proteins Ki67, CD31, and ferroptosis negative regulation proteins glutathione peroxidase 4 (GPX4) and FTH1. Compound 15 was found to be metabolically stable when incubated with human liver microsomes.

中文翻译：

---

新型吡咯微管蛋白组装抑制剂诱导胶质母细胞瘤和卵巢癌发生铁死亡

我们合成了具有铁死亡特征的新型芳酰基二杂环吡咯 (ARDHEP) 15。化合物15强烈抑制 U-87 MG、OVCAR-3 和 MCF-7 癌细胞，诱导裂解 PARP 的增加，但在 0.1 μM 时对正常人原代 T 淋巴细胞没有毒性。对乳过氧化物酶、丙二醛、乳酸、总谷胱甘肽和ATP水平的分析表明，15对癌细胞增殖的体内抑制作用是通过刺激氧化应激损伤和Fe ²⁺积累来实现的。来自15只治疗小鼠的 U-87 MG 和 SKOV-3 肿瘤组织中 mRNA 表达的定量聚合酶链反应分析表明存在Ptgs2 /Nfe2l2 / Sat1 / Akr1c1 / Gpx4基因与两组的铁死亡相关。免疫荧光染色显示蛋白 Ki67、CD31 和铁死亡负调节蛋白谷胱甘肽过氧化物酶 4 (GPX4) 和 FTH1 的表达显着降低。当与人肝微粒体孵育时，发现化合物15在代谢上是稳定的。