Aromatic Norditerpenoids From Blachia pentzii With Anti-Pulmonary Fibrosis Activity

Eleven highly oxygenated aromatic norditerpenoids, blapenoids A-K were isolated from the roots of Blachia pentzii, and fully characterized using comprehensive spectroscopic analysis, electronic circular dichroism (ECD), and x-ray crystallography. Notably, blapenoids A-I feature a densely oxygenated 7,8-seco-norditerpenoid backbone of the cleistanthane family, branching into the first reported 7,16,17,19,20-pentanor scaffold (blapenoids A-D), and an unprecedented 16,17,19,20-tetranor skeleton (blapenoids E-I), for which a plausible biosynthetic pathway was proposed. Intriguingly, chiral-phase HPLC resolved blapenoids E-G into enantiopure forms, whereas the structurally analogous blapenoids H and I existed as scalemic mixtures (er 35:1, R/S). This stereochemical divergence was corroborated by methylation of (+)- and (-)-blapenoid G, followed by LC-MS analysis. Biological assays revealed that some compounds noncytotoxically inhibited transforming growth factor (TGF-β)-induced fibrogenesis in human lung fibroblasts. Notably, blapenoid K emerged as the most potent (IC₅₀ = 3.82 µM), dose-dependently suppressing α‑smooth muscle actin (α-SMA), fibronectin, and collagen I transcripts, alongside corresponding protein-level inhibition of α-SMA and fibronectin, supporting aromatic norditerpenoids as promising lead compounds for further anti-pulmonary fibrosis research.