School of Basic Medical Science, Guangzhou University of Chinese Medicine, Waihuan East Road No. 232, Guangzhou 510006, China.
The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Waihuan East Road No. 232, Guangzhou 510006, China.
Molecules. 2021 Jul 15;26(14):4300. doi: 10.3390/molecules26144300.
The search for a safe and effective inhibitor of ferroptosis, a recently described cell death pathway, has attracted increasing interest from scientists. Two hydrolyzable tannins, chebulagic acid and chebulinic acid, were selected for the study. Their optimized conformations were calculated using computational chemistry at the B3LYP-D3(BJ)/6-31G and B3LYP-D3(BJ)/6-311 + G(d,p) levels. The results suggested that (1) chebulagic acid presented a chair conformation, while chebulinic acid presented a skew-boat conformation; (2) the formation of chebulagic acid requires 762.1729 kcal/mol more molecular energy than chebulinic acid; and (3) the 3,6-HHDP (hexahydroxydiphenoyl) moiety was shown to be in an ()- absolute stereoconfiguration. Subsequently, the ferroptosis inhibition of both tannins was determined using a erastin-treated bone marrow-derived mesenchymal stem cells (bmMSCs) model and compared to that of ferrostatin-1 (Fer-1). The relative inhibitory levels decreased in the following order: Fer-1 > chebulagic acid > chebulinic acid, as also revealed by the in vitro antioxidant assays. The UHPLC-ESI-Q-TOF-MS analysis suggested that, when treated with 16-(2-(14-carboxytetradecyl)-2-ethyl-4,4-dimethyl-3-oxazolidinyloxy free radicals, Fer-1 generated dimeric products, whereas the two acids did not. In conclusion, two hydrolyzable tannins, chebulagic acid and chebulinic acid, can act as natural ferroptosis inhibitors. Their ferroptosis inhibition is mediated by regular antioxidant pathways (ROS scavenging and iron chelation), rather than the redox-based catalytic recycling pathway exhibited by Fer-1. Through antioxidant pathways, the HHDP moiety in chebulagic acid enables ferroptosis-inhibitory action of hydrolyzable tannins.
寻找一种安全有效的铁死亡途径抑制剂，最近描述的细胞死亡途径，引起了科学家们越来越多的兴趣。两种可水解单宁酸，诃子酸和柯子酸，被选为研究对象。使用计算化学在 B3LYP-D3（BJ）/6-31G 和 B3LYP-D3（BJ）/6-311 + G（d，p）水平上计算了它们的优化构象。结果表明：（1）诃子酸呈椅式构象，而诃子酸呈偏舟式构象；（2）形成诃子酸需要比诃子酸多 762.1729 kcal/mol 的分子能量；（3）3,6-HHDP（六羟基二苯酰基）部分显示为（）-绝对立体构型。随后，使用 erastin 处理的骨髓间充质干细胞（bmMSCs）模型测定了两种单宁酸的铁死亡抑制作用，并与 Fer-1 进行了比较。体外抗氧化试验结果显示，相对抑制水平依次降低：Fer-1>诃子酸>诃子酸。UHPLC-ESI-Q-TOF-MS 分析表明，当用 16-（2-（十四烷酰基）-2-乙基-4,4-二甲基-3-恶唑啉氧基自由基处理时，Fer-1 生成二聚体产物，而两种酸则没有。总之，两种可水解单宁酸，诃子酸和诃子酸，可以作为天然的铁死亡抑制剂。它们的铁死亡抑制是通过常规的抗氧化途径（ROS 清除和铁螯合）介导的，而不是 Fer-1 表现出的基于氧化还原的催化循环途径。通过抗氧化途径，诃子酸中的 HHDP 部分使可水解单宁酸具有铁死亡抑制作用。
