Unusual diterpenoids featuring a 4/9-fused ring system from Sclerophytum humesi trigger intrinsic apoptosis via caspase-dependent PARP cleavage in pancreatic cancer.

Marine soft corals are prolific sources of structurally diverse secondary metabolites with notable pharmacological potential. From the soft coral Sclerophytum humesi, seven xeniaphyllane-derived diterpenoids were isolated through cytotoxicity-guided fractionation, including a novel dimeric metabolite, bisclerohumin A (1), five new diterpenoids, sclerohumins B-F (2-6), and one known compound (7). Notably, compound 1 represents a rare dimer, the first example of a metabolite formed from two xeniaphyllane diterpenoids through a unique 16-peroxyl bridge. Moreover, compounds 2-5 possess a 20-exomethylene moiety, which is unusual among xeniaphyllane-type diterpenoids. Structural elucidation was achieved through comprehensive spectroscopic analyses, including NMR, HRESIMS, ESIMS, ECD, and DP4+ probability assessments. Compounds 1, 3, and 4 exhibited pronounced cytotoxicity against six cancer cell lines, with IC50 values ranging from 1.35 to 41.70 μM, and induced G2-M phase cycle arrest in MIA PaCa-2 cells. Mechanistic studies revealed that 4 suppresses the expression of Bcl-2 and Bcl-xL proteins, triggers the activation of caspase-3, and leads to the cleavage of PARP1 in pancreatic cancer. Furthermore, a plausible biosynthetic pathway for 1-6 was proposed, highlighting Sclerophytum humesi as a promising source of structurally unique and biologically active natural products.