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

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posted on 23.08.2019, 20:15 by Lan-Lan Lou, Fu-Qiang Ni, Lin Chen, Sharpkate Shaker, Wei Li, Rong Wang, Gui-Hua Tang, Sheng Yin
A germacrane sesquiterpenoid library containing 30 compounds (231) 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.