Preutremutin A: An Unprecedented Tetracyclic Tremulane Sesquiterpenoid from Endophytic Strain of Rhododendron capitatum with Neuroprotective Activity.

Four new seco-tremulane sesquiterpenoids, preutremutins A-D (1-4), were isolated from an endophytic Preussia fungus associated with Rhododendron capitatum for the first time. Preutremutin A (1) possesses an unprecedented 5/5/5/5 tetracyclic skeleton, representing a novel ring-rearrangement pattern in tremulane-type natural products. Preutremutin D (4) is the first reported dimeric tremulane sesquiterpenoid, formed via an ether linkage between two monomeric units. Their full structures were elucidated by spectroscopic analysis, ECD calculations, and single-crystal X-ray diffraction. Furthermore, this study presents the first evaluation of these sesquiterpenoids for neuroprotective effects in H2O2- and 6-OHDA-induced PC-12 oxidative injury models as well as LPS-stimulated BV-2 microglia. Notably, compound 4 exerts neuroprotective effects by significantly upregulating the antioxidant proteins Catalase and HO-1, thereby activating the cellular endogenous antioxidant defense system. Collectively, these findings not only expand the structural diversity of tremulane sesquiterpenoids but also provide the first pharmacological and mechanistic evidence supporting their neuroprotective potential.