Antiferroptotic Activities of Oxindole GIF-0726-r Derivatives: Involvement of Ferrous Iron Coordination and Free-Radical Scavenging Capacities
Antiferroptotic Activities of Oxindole GIF-0726-r Derivatives: Involvement of Ferrous Iron Coordination and Free-Radical Scavenging Capacities
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Oxindole GIF-0726-r 衍生物的抗铁死亡活性：亚铁配位和自由基清除能力的参与
DOI：
10.1021/acschemneuro.3c00042
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Hirata Y.
中科院分区：
文献类型：
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作者：
Takahashi M;Hamamoto A;Oh-Hashi K;Takemori H;Furuta K;Hirata Y.
铁凋亡和氧化是铁和氧化应激依赖性细胞死亡途径，与神经退行性疾病、癌症和代谢紊乱密切相关。因此，特异性抑制剂可能具有广泛的临床应用。我们先前报道了3-[4-（dimethylamino）benzyl]-2-oxindole（GIF-0726-r）及其衍生物通过抑制活性氧（ROS）积累来保护小鼠海马细胞系HT 22免受氧化/铁凋亡。在这项研究中，我们评估了GIF-0726-r衍生物的生物活性，在羟吲哚骨架和其他位置的修饰。在羟吲哚骨架的C-5中加入甲基、硝基或溴基，在膜胱氨酸-谷氨酸反向转运蛋白抑制过程中增强了对HT 22细胞的抗铁毒性功效，并随之导致细胞内谷胱甘肽耗竭。与此相反，侧链苯环上的二甲基氨基取代甲基，硝基，或胺基团显着抑制antiferroptotic活性，无论其他修改。具有抗铁活性的化合物也直接清除ROS，并减少自由亚铁离子在HT 22细胞和无细胞反应，而那些化合物没有抗铁活性的ROS或亚铁离子浓度的影响不大。与我们以前报道的羟吲哚化合物不同，抗铁蛋白化合物对核因子红细胞2相关因子2-抗氧化反应元件途径的影响很小。在C-3处具有4-（二甲氨基）苄基部分和在C-5处具有某些类型的庞大基团（无论是供电子的还是吸电子的）的羟吲哚GIF-0726-r衍生物可以抑制铁凋亡，从而在疾病的动物模型中进行安全性和有效性评价。
Ferroptosis and oxytosis are iron- and oxidative stress-dependent cell death pathways strongly implicated in neurodegenerative diseases, cancers, and metabolic disorders. Therefore, specific inhibitors may have broad clinical applications. We previously reported that 3-[4-(dimethylamino)benzyl]-2-oxindole (GIF-0726-r) and derivatives protected the mouse hippocampal cell line HT22 against oxytosis/ferroptosis by suppressing reactive oxygen species (ROS) accumulation. In this study, we evaluated the biological activities of GIF-0726-r derivatives with modifications at the oxindole skeleton and other positions. The addition of a methyl, nitro, or bromo group to C-5 of the oxindole skeleton enhanced antiferroptotic efficacy on HT22 cells during membrane cystine–glutamate antiporter inhibition and ensued intracellular glutathione depletion. In contrast, the substitution of the dimethylamino group on the side chain phenyl ring with a methyl, nitro, or amine group dramatically suppressed antiferroptotic activity regardless of other modifications. Compounds with antiferroptotic activity also directly scavenged ROS and decreased free ferrous ions in both HT22 cells and cell-free reactions while those compounds without antiferroptotic activity had little effect on either ROS or ferrous-ion concentration. Unlike oxindole compounds, which we have previously reported, the antiferroptotic compounds had little effect on the nuclear factor erythroid-2-related factor 2-antioxidant response element pathway. Oxindole GIF-0726-r derivatives with a 4-(dimethylamino)benzyl moiety at C-3 and some types of bulky group at C-5 (whether electron-donating or electron-withdrawing) can suppress ferroptosis, warranting safety and efficacy evaluations in animal models of disease.