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

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.