期刊
MOLECULES
卷 24, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/molecules24061108
关键词
idiopathic pulmonary fibrosis; matrine; indole; structure activity relationship; fibroblast-to-myofibroblast transition; TGF-; Smad pathway
资金
- National Natural Science Foundation of China [81502929]
- Drug Innovation Major Project [2018ZX09711-001-005-008]
- CAMS Innovation Fund for Medical Sciences [2016-I2M-3-015]
- PUMC Youth Fund [2017350025]
A total of 18 matrine derivatives were designed, synthesized, and evaluated for their inhibitory effect against TGF-1-induced total collagen accumulation in human fetal lung fibroblast MRC-5 cell lines. Among them, compound 3f displayed the most potent anti-fibrotic activity (IC50 = 3.3 +/- 0.3 M) which was 266-fold more potent than matrine. 3f significantly inhibited the fibroblast-to-myofibroblast transition and extracellular matrix production of MRC-5 cells. The TGF-/small mothers against decapentaplegic homologs (Smad) signaling was also inhibited by 3f, as evidenced by inhibition of cytoplasm-to-nuclear translocation of Smad2/3 and suppression of TGF-1-induced upregulation of TGF- receptor type I (TGFRI). Additionally, 3f exhibited potent inhibitory effects against TGF-1-induced fibroblasts migration. These data suggested that 3f might be a potential agent for the treatment of idiopathic pulmonary fibrosis via repression of the TGF/Smad signaling pathway.
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