(±)-Rutacycoumarins A and B: two pairs of unprecedented coumarin enantiomers from the aerial part of Ruta graveolens L. and chemically synthesized.

CONTEXT: Benzofuran derivatives are important structural motifs found in natural products, often exhibiting significant biological activities. Ruta graveolens L. is a plant source known for containing diverse bioactive compounds. OBJECTIVE: This study aimed to isolate and characterize compounds from the aerial parts of R. graveolens, confirm their structures through synthesis, develop a novel synthetic methodology, and evaluate their potential anti-inflammatory effects and monoamine oxidase inhibitory activity. MATERIALS AND METHODS: The structures of benzofuran enantiomers were elucidated using integrated NMR, HRMS, and ECD analyses. (±)-Rutacycoumarins A and B were synthesized via a novel direct C3 alkylation of coumarin bearing phenolic hydroxyl groups. Biological evaluation assessed the anti-inflammatory effects of (±)-Rutacycoumarins A and B in LPS-stimulated HepG2 cells by measuring liver biomarkers and pro-inflammatory cytokines, and their inhibitory activity against monoamine oxidase B (MAO-B). RESULTS: Two novel Z/E pairs of benzofuran enantiomers, (±)-Rutacycoumarins A and B, featuring fused cyclopropane motifs, were isolated and structurally confirmed. Their synthesis employed a novel catalytic EDA complex (DIPEA/potassium ethyl xanthate donor, NHPI ester acceptor). (±)-Rutacycoumarins A and B reduced liver biomarkers and pro-inflammatory cytokines in LPS-treated HepG2 cells, and all four enantiomers inhibited MAO-B. CONCLUSIONS: This study isolated two novel benzofuran enantiomer pairs with fused cyclopropane motifs from R. graveolens Their structures were confirmed via a new catalytic EDA complex synthesis. Racemic mixtures reduced LPS-induced liver/cellular damage and cytokines in HepG2 cells, while all enantiomers inhibited MAO-B.