Key result
Compound 11 ameliorated myocardial fibrosis and heart function in rats at 5 mg/kg by inhibiting the TGFβ/Smad signaling pathway via targeting the TGFβ type I receptor (IC50 = 14.9 nM).
Effect estimate: IC50 14.9 nM
Compound 11, a novel germacrane sesquiterpenoid, demonstrates potential as an anticardiac fibrosis agent by inhibiting the TGFβ/Smad signaling pathway via TGFβ type I receptor targeting.
Should not yet inform clinical practice; leaves open translation of TGFβRI inhibition to human cardiac fibrosis.
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.
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Lou et al. (2019) studied Cardiac fibrosis. Compound 11 (germacrane sesquiterpenoid) was evaluated on Inhibition of TGFβ type I receptor (IC50 14.9 nM). Compound 11 ameliorated myocardial fibrosis and heart function in rats at 5 mg/kg by inhibiting the TGFβ/Smad signaling pathway via targeting the TGFβ type I receptor (IC50 = 14.9 nM).
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