Design and Synthesis of Matrine Derivatives as Novel Anti-Pulmonary Fibrotic Agents via Repression of the TGFβ/Smad Pathway.

ABSTRACT: A total of 18 matrine derivatives were designed, synthesized, and evaluated for their inhibitory effect against TGF-β1-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 μM) 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-β/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-β1-induced upregulation of TGF-β receptor type I (TGFβRI). Additionally, 3f exhibited potent inhibitory effects against TGF-β1-induced fibroblasts migration. These data suggested that 3f might be a potential agent for the treatment of idiopathic pulmonary fibrosis via repression of the TGFβ/Smad signaling pathway.

SUBMITTER: Li L 

PROVIDER: S-EPMC6470603 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature