Discovery of a bamboo sap-derived dihydroxyacetophenone analog as a potent anti-inflammatory agent against acute liver failure

Acute liver failure (ALF) remains a life-threatening condition with few effective therapeutic options. Bioassay-guided fractionation of bamboo sap (Succus Bambusae) enabled identification of 1-(2,3-dihydroxyphenyl)ethan-1-one (ZL-2, IC₅₀ = 17.25 μM) as an anti-inflammatory lead compound. Synthesis and structure-activity relationship (SAR) evaluation of 27 structural analogs revealed that both the hydroxyl substitution pattern and acyl chain length critically govern anti-inflammatory potency and cytotoxicity. Among the series evaluated, the 2,5-dihydroxy series with a C₇ acyl chain (compound 20) showed the highest potency (IC₅₀ = 2.70 μM); however, its narrow therapeutic window (SI = 1.6) necessitated further optimization. Diacetylation of the phenolic hydroxyls afforded compound 27, which achieved an optimal balance of potency (IC₅₀ = 2.84 μM) and selectivity (SI > 35). Mechanistically, compound 27 suppressed macrophage-mediated inflammation and oxidative stress by inhibiting NF-κB and STAT3 phosphorylation in both RAW 264.7 cells and bone marrow-derived macrophages. In the LPS/D-galactosamine murine ALF model, oral administration of compound 27 (40 mg/kg) significantly reduced serum ALT/AST, hepatic necrosis, and pro-inflammatory cytokines. Notably, these protective effects were abolished in Tlr4^-/- mice, demonstrating TLR4 pathway dependency. Compound 27 represents a novel, synthetically accessible anti-inflammatory agent with in vivo hepatoprotective efficacy, warranting further preclinical investigation.