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

The ellagitannin corilagin and its analogue 1,3,6-tri--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 Fe-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 Fe-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.