Eugenilones A-N: sesquiterpenoids from the fruits of Eugenia uniflora

(+) and (-)-Eugenilones A-K, 11 pairs of undescribed enantiomeric sesquiterpenoids, together with three undescribed biogenetically related members eugenilones L-N, were discovered from the fruits of Eugenia uniflora Linn. (Myrtaceae). Structurally, eugenilones A-D were four caged sesquiterpenoids featuring 9,10-dioxatricyclo [6.2.2.0^2,7]dodecane, 11-oxatricyclo [5.3.1.0^3,8]undecane, and tricyclo [4.4.0.0^2,8]decane cores, respectively. Eugenilones E-K were eudesmane-type sesquiterpenoids, while eugenilones L-N were epoxy germacrane-type sesquiterpenoids. Notably, eugenilones A-K were efficiently resolved by chiral HPLC to give 11 pairs of optically pure enantiomers. The structures and absolute configurations of eugenilones A-N were determined through spectroscopic analyses, X-ray crystallography, and ECD calculations. The putative biosynthetic pathways for these undescribed isolates were proposed. Moreover, eugenilones A and E exhibited significant anti-inflammatory effects by inhibiting LPS-stimulated NO overproduction in RAW264.7 cells (IC₅₀ values of 4.89 ± 0.37 μM and 20.89 ± 1.49 μM, respectively) and TNF-α-induced NF-κB activation in HEK293 cells (IC₅₀ values of 10.97 ± 1.03 μM and 28.63 ± 1.59 μM, respectively).