Synthesis and in vivo evaluation of new steviol derivatives that protect against cardiomyopathy by inhibiting ferroptosis

Targeting ferroptosis as a promising therapeutic strategy to treat cardiomyopathy

“…Fer-1 can ameliorate TMEM43 knockdown-induced deteriorating effects in LPS-induced cardiac injury. Taken together, TMEM43 protects against SCM by inhibiting ferroptosis (Chen Z. et al, 2022). The islet cell autoantigen 69, which can regulate inflammation and immune response, induces ferroptosis to cause septic cardiac dysfunction through the stimulator of interferon gene trafficking (Kong et al, 2022).…”

“…25 attenuates DICM through inhibiting ferroptosis in vivo and in vitro by limiting iron accumulation, restoring GPX4, and preventing LPO (Chen L. et al, 2022). AMPK inhibitor compound C reversed protective function of 25 against DICM, suggesting that 25 markedly downregulated ferroptosis by activating AMPKdependent signaling pathways (Chen Z. et al, 2022). Dexazoxane(26) , melatonin(27) (Sun et al, 2022), and EGCG(28) (He et al, 2021) also works as a GPX4 activators to attenuates DICM through inhibiting ferroptosis.…”

“…Compounds that alleviate DICM through inhibiting ferroptosis include huaier polysaccharide (22) ( Ma X. et al, 2022 ), LCZ696 (23) ( Liu X. et al, 2022 ), fisetin (24) ( Li D. et al, 2021 ), salidroside (25) ( Chen H. et al, 2022 ), resveratrol (10) ( Yu P. et al, 2022 ), dexazoxane (26) ( Zhang H. et al, 2021 ), melatonin (27) ( Sun et al, 2022 ), EGCG (28) ( He et al, 2021 ), 16d and 16e (29) ( Xu et al, 2022 ), ethoxyquin (30) ( Tadokoro et al, 2022 ), and 7j (31) ( You et al, 2022 ) inhibit DICM through inhibiting ferroptosis ( Table 3 ). 22 is a naturally occurring bioactive macromolecule, found in Huaier fungus and has been shown to exert antitumor and antimetastasis activity ( Tian Y. et al, 2021 ; Gou et al, 2022 ).…”

“…While compounds 16d and 16e (29) ( Xu et al, 2022 ), ethoxyquin (30) ( Tadokoro et al, 2022 ), and resveratrol (10) ( Yu P. et al, 2022 ) functions as inhibitors of LPO to attenuates DICM through inhibiting ferroptosis. 29 is two derivatives of steviol, an ent-kaurene diterpenoid, possesses broad-spectrum bioactivity.…”

“…29 is two derivatives of steviol, an ent-kaurene diterpenoid, possesses broad-spectrum bioactivity. 29 attenuates DICM in zebrafish cardiomyopathy model through inhibiting ferroptosis via suppressing the GSH depletion, iron accumulation, and LPO, decreasing ROS overproduction, and restoring the mitochondrial membrane potential ( Xu et al, 2022 ). Ethoxyquin (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline, 30 is a competent radical-trapping antioxidant.…”