Biatractylonoids A-E, Five Eudesmane-Type Sesquiterpenoid Dimers from the Rhizomes of Atractylodes macrocephala with Anti-inflammatory Activity

Natural products, particularly dimeric sesquiterpenoids, have garnered significant interest among organic chemists due to their intriguing biological properties. In this study, we isolated five novel dimeric eudesmane-type sesquiterpenoids, biatractylonoids A-E (1-5), from the rhizomes of Atractylodes macrocephala. The structures and absolute configurations of these compounds were elucidated by comprehensive spectroscopic analysis, chemical calculations, and single-crystal X-ray diffraction. Compounds 1-4 exhibit a previously unreported dimerization pattern, featuring an unique 2-oxaspiro[4.4]nonane moiety. Notably, 4 possesses an unprecedented heptacyclic ring system with a unique 6/6/5/5/5/5/6 arrangement, fused to two monomers via a novel dimerization pattern that includes a five-membered O-heterocyclic ring. 5 results from the linkage of an eudesmane-type sesquiterpenoid to atractylone through furfuryl alcohol. Biologically, 1-3 exhibited inhibitory activities against NO release with IC₅₀ values ranging from 16.1 to 21.0 μM, as compared with the positive control (l-NAME, IC₅₀ value: 18.8 μM). Furthermore, compound 1 markedly decreased the secretion of TNF-α, IL-6, and IL-1β in LPS-induced RAW 264.7 cells in a dose-dependent manner. Mechanistic studies revealed that 1 potentially targeted PLD1 through hydrogen bonding interactions with Val792 and Arg923, thereby regulating its biological function. These compounds exhibited unique structures and significant anti-inflammatory activity, and PLD1 was identified as a potential target of compound 1.