Wu_2026_Bioorg.Chem_174_109742

Therapeutic targeting of human carboxylesterase 1 A (hCES1A) represents a promising strategy for treating hyperlipidemia and related metabolic disorders. The first comprehensive phytochemical investigation of the ethnomedicinal plant Rhodoleia championii afforded four tocochromanol-type meroterpenoids (1-4) and twenty pentacyclic triterpenoids (5-24). Six of these compounds, designated as rhodolins A-F (1-3 and 5-7), were previously undescribed, with compound 1 representing a novel tetranor-tocochromanol scaffold. Their structures and absolute configurations were elucidated based on extensive spectroscopic analysis and quantum chemical calculations. While most lupane-type triterpenes exhibited remarkable hCES1A inhibition at 1 or 10 microM, rhodolin F (7) showed the most potent activity (IC(50) = 21 nM), functioning as a reversible, non-competitive mechanism inhibitor (K(i) = 18 nM). Molecular analysis revealed that 7 stabilized a closed conformation of hCES1A by reinforcing a hydrophobic allosteric network, underscoring its superior potential as an allosteric modulator. Notably, in Caki-1 cells, compound 7 significantly suppressed intracellular hCES1A activity (IC(50) = 0.24 microM) and dose-dependently reduced lipid droplet accumulation without cytotoxicity. These findings not only provided a molecular basis for the traditional use of R. championii but also highlighted lupane-type triterpenoids, particularly rhodolin F, as promising leads for the development of novel hyperlipidemia therapeutics.