Abstract
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 (R)- 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.
Highlights
Ferroptosis is a recently discovered cell death pathway, which has been demonstrated to be driven by iron-dependent lipid peroxidation (LPD) [1,2,3]
Earlier studies typically ignored the stereochemistry of HHDP [28,29]
HHDP-containing tannins exist as two atropisomers [31]
Summary
Introduction iationsFerroptosis is a recently discovered cell death pathway, which has been demonstrated to be driven by iron-dependent lipid peroxidation (LPD) [1,2,3]. The promotion of ferroptosis can kill cancer cells. It may offer a novel therapeutic option for cancer, and it has become a key topic in the cell biology field [4,5,6,7,8]. In addition to the promotion of ferroptosis, its inhibition represents a key topic because of its potential for rescuing pathologic cells. Ferroptosis inhibitors, offer promise in the treatment of various noncancerous diseases, such as Parkinson’s disease, Alzheimer’s disease, atherosclerosis, and liver disease [9,10,11,12,13,14]. Some academic institutions have synthesized quite a few ferroptosis inhibitors, such as ferrostatin-1 (Fer-1)
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