jm9b00708_si_001.pdf (13.39 MB)
Germacrane Sesquiterpenoids as a New Type of Anticardiac Fibrosis Agent Targeting Transforming Growth Factor β Type I Receptor
journal contribution
posted on 2019-08-23, 20:15 authored by Lan-Lan Lou, Fu-Qiang Ni, Lin Chen, Sharpkate Shaker, Wei Li, Rong Wang, Gui-Hua Tang, Sheng YinA 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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Compound 11Anticardiac Fibrosis Agent Targeting Transforming Growth Factor β Typecomponent aristolactoneChinese medicine Aristolochia yunnanensisIC 50germacrane sesquiterpenoid library30 compoundsSMAGermacrane SesquiterpenoidsTGF β typeγ- lactone ringaortic constrictionFNNew TypeSARmicromolar levelheart functionAACanticardiac fibrosis agentgrowth factor β 1Mechanistic studyfuture anticardiac fibrosis drug development
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