Triadenosides A-F, benzophenone rhamnosides from Triadenum japonicum and their anti-ferroptosis activity

Previously undescribed benzophenone rhamnosides, triadenosides A-F (1-6), were isolated from the aerial parts of Triadenum japonicum (Blume) Makino (Hypericaceae), where known compounds including benzophenone rhamnosides (7 and 8), benzophenone C-glucoside (9), flavonols and their glycosides (10-17), and biflavone (18) were also isolated and identified. Detailed spectroscopic analysis revealed that triadenoside A (1) was 2,3',5'-trihydroxy-4,6-dimethoxybenzophenone 2-O-α-L-rhamnopyranoside, while the absolute configuration of the rhamnosyl moiety was confirmed by HPLC analysis. Triadenosides B-E (2-5) were assigned as acetyl derivatives of 1 in their rhamnosyl moieties. In contrast, triadenoside F (6) was elucidated to be 2,3',5',6-tetrahydroxy-4-methoxybenzophenone 2-O-α-L-(4″-O-acetyl)rhamnopyranoside. Compounds 1-18 isolated from T. japonicum as well as some benzophenone derivatives (5a-5e, 6a, and 8a) prepared from 5, 6, and 8 were evaluated for their inhibitory activity against RSL3-induced ferroptosis on human hepatoma Hep3B cells, showing significant inhibitory effects of triadenosides A-E (1-5) and their derivatives (5c, 5d, and 5e) with EC₅₀ values ranging from 18.0 to 41.4 nM comparable to that of a ferroptosis inhibitor, ferrostatin-1, whereas triadenoside F (6) did not exhibit such activity.