Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor, and activation of the Keap1-Nrf2 signaling is expected to rescue cells from a variety of stimuli such as reactive toxicants and pro-inflammatory factors. Several triterpenoids react with cysteine residues of Keap1 as Michael acceptors and thereby activate the Keap1-Nrf2 signaling. One of well-known Nrf2 activators, bardoxolone methyl, was evaluated for chronic kidney disease, although Phase 3 was terminated due to adverse events. Many bardoxolone methyl derivatives are already reported, which are mostly derivatized by chemical modification. We alternatively adopted a biotransformation technique, and succeeded in obtaining a more potent novel Nrf2 activator, RS9 (methyl (1α,2α,21β)-2-cyano-21-hydroxy-3,12-dioxo-1,2-epoxyolean-9(11)-en-28-oate), from microbial transformation products (WO-2014/148455). Nrf2 activity was evaluated by NADPH:quinone oxidoreductase-1 induction activity in Hepa1c1c7 cells (a mouse hepatic epithelial cell line). Though bardoxolone methyl doubled the specific activity with a concentration of 0.9 nM, the value of RS9 was 0.2 nM. Moreover, the induction of Nrf2-targeted genes was observed at one-tenth lower concentration in RS9. Interestingly, the cytotoxicity of RS9 was substantially reduced compared to bardoxolone methyl. A comparison of RS compounds suggests that epoxidation in the A-ring contributes to a reduction in cytotoxicity and hydroxylation in the E-ring is involved in the improvement of activity. Bardoxolone methyl did not inhibit oxidant stress-induced cellular damage in ARPE-19 cells (a human retinal pigment epithelial cell line); however RS9 significantly suppressed the damage. RS9 also showed efficacy in several kinds of ocular disease models <i>in vivo</i>. These results imply that Nrf2 activators are promising for ocular diseases and our novel Nrf2 activators will shed new light on the treatment of retinovascular diseases.

Novel Nrf2 activators from microbial transformation products suppress oxidant stress-induced cellular damage in ARPE-19 cells

249th National Meeting (2015)

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