Wikstdaphnoids A–I, Daphnane Diterpenoid Orthoesters from Wikstroemia chamaedaphne with Anti-Liver Fibrosis Activity

Bioassay─combined with molecular networking─guided chemical investigation of Wikstroemia chamaedaphne (Thymelaeaceae) led to the isolation of 15 daphnane diterpenoid orthoesters (DDOs), of which 1-9 were new. Compounds 1-5 and 8-9 are a rare group of 1-alkyl macrocyclic DDOs. These structures were determined by extensive spectroscopic and computational methods as well as single-crystal X-ray diffraction. All of DDOs were evaluated for anti-liver fibrosis activity in TGF-β1-stimulated LX-2 cells by high-throughput screening assays, and the results showed that six of isolates significantly inhibited the expression of fibronectin (FN) at 10 μM, among which 1 and 11 exhibited the most potent activity that could dose-dependently inhibit protein levels of FN, α-smooth muscle actin (α-SMA), and collagen I in LX-2 and JS-1 cells. Our study indicated that macrocyclic DDOs could serve as a new type of structural motif in anti-liver fibrosis drug development.