Covalent Bridging of Corilagin Improves Antiferroptosis Activity: Comparison with 1,3,6-Tri‑O‑galloyl-β‑d‑glucopyranose

The ellagitannin corilagin and its analogue 1,3,6-tri-O-galloyl-β-d-glucopyranose (TGG) were found to protect bone marrow-derived mesenchymal stem cells (bmMSCs) against erastin-induced ferroptosis by cellular assays. However, the antiferroptosis bioactivity of corilagin was higher than that of TGG. Corilagin also exhibited higher antioxidant and Fe2+-chelation levels than TGG. Treated with 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, corilagin and TGG yielded a corilagin- and a TGG–DPPH adduct, respectively. The corilagin–DPPH adduct retained the covalent bridge throughout the ultrahigh-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS) analysis. The strength of the covalent bridge is attributable to enhancement of its partial π–π conjugation. Thus, the bridge has sufficient strength to twist the chair conformation of the glucopyranosyl ring and to assemble two large aromatic rings, thereby improving the antioxidant (including Fe2+-chelation) reactivities. The bridge can also stabilize the product intermediate via partial π–π conjugation. Hence, corilagin is a superior ferroptosis inhibitor and antioxidant compared to TGG.