Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185Rome, Italy.
Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, 200031Shanghai, China.
J Med Chem. 2022 Dec 8;65(23):15805-15818. doi: 10.1021/acs.jmedchem.2c01457. Epub 2022 Nov 17.
We synthesized new aroyl diheterocyclic pyrrole (ARDHEP) that exhibited the hallmarks of ferroptosis. Compound 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 went through stimulation of oxidative stress injury and Fe accumulation. Quantitative polymerase chain reaction analysis of the mRNA expression in U-87 MG and SKOV-3 tumor tissues from -treated mice showed the presence of //// 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 was found to be metabolically stable when incubated with human liver microsomes.
我们合成了新型芳基二杂环吡咯（ARDHEP），其表现出铁死亡的特征。化合物强烈抑制 U-87 MG、OVCAR-3 和 MCF-7 癌细胞，诱导裂解的 PARP 增加，但在 0.1 μM 时对正常人原代 T 淋巴细胞没有毒性。乳过氧化物酶、丙二醛、乳酸、总谷胱甘肽和 ATP 水平分析表明，通过刺激氧化应激损伤和铁积累，在体内抑制癌细胞增殖。用处理的小鼠的 U-87 MG 和 SKOV-3 肿瘤组织的定量聚合酶链反应分析显示，两组中均存在与铁死亡相关的 //// 基因的存在。免疫荧光染色显示 Ki67、CD31 和铁死亡负调控蛋白谷胱甘肽过氧化物酶 4（GPX4）和 FTH1 的蛋白表达显著降低。当与人肝微粒体孵育时，化合物被发现具有代谢稳定性。
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