Xeniaphyllane-Type Diterpenoids from the Soft Coral Sclerophytum humesi: Resolving Absolute Configurations and...

A combined bioassay- and ¹H NMR-guided isolation strategy led to the discovery of four new terpenoids, including three xeniaphyllane-type diterpenoids, sclerohumins P-R (1-3), and a norcaryophyllene-type, sclerophyllene A (4), from the soft coral Sclerophytum humesi. The structures and absolute configurations of these compounds were elucidated by comprehensive spectroscopic analysis, including NMR, HRESIMS, SOR, TDDFT-ECD, and DP4+ probability analysis. The stereogenic centers at C-15 in related xeniaphyllanes were proposed for the first time based on comparative SOR analysis. Compounds 1 and 2 possess a tricyclic 4/9-fused carbocyclic framework featuring an epoxide moiety, whereas compounds 3 and 4 exhibit related bicyclic scaffolds. A plausible biogenetic pathway originating from geranylgeranyl pyrophosphate (GGPP) was proposed to account for their structural diversity. Compounds 1 and 2 showed potent AChE inhibitory activity (IC₅₀ = 1.7 and 4.4 μM, respectively), while being inactive against BChE and noncytotoxic toward normal cell lines (HEK293 and Vero). Mechanistic studies combining enzyme kinetics and molecular docking revealed that 1 and 2 act as mixed-type AChE inhibitors, with K_i values of 1.02 and 1.87 μM, respectively. These findings represent the first report of xeniaphyllane-type diterpenoids with potential for neurotherapeutic development.