Germacrane Sesquiterpenoids as a New Type of Anticardiac Fibrosis Agent Targeting Transforming Growth Factor β Type I Receptor

A germacrane sesquiterpenoid library
containing 30 compounds (2–31) was
constructed by structural modification
of a major component aristolactone (1) from the traditional
Chinese medicine Aristolochia yunnanensis. Compound 11 was identified as a promising anticardiac
fibrosis agent by systematic screening of this library. 11 could inhibit the expression of fibronectin (FN), α-smooth
muscle actin (α-SMA), and collagens in transforming growth factor
β 1 (TGFβ1)-stimulated cardiac fibroblasts at a micromolar
level and ameliorate myocardial fibrosis and heart function in abdominal
aortic constriction (AAC) rats at 5 mg/kg dose. Mechanistic study
revealed that 11 inhibited the TGFβ/small mother
against decapentaplegic (Smad) signaling pathway by targeting TGFβ
type I receptor (IC50 = 14.9 ± 1.6 nM). The structure–activity
relationships (SARs) study indicated that the unsaturated γ-lactone
ring and oxidation of C-1 were important to the activity. These findings
may provide a new type of structural motif for future anticardiac
fibrosis drug development.