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

A total of 18 matrine derivatives were designed, synthesized, and evaluated for their inhibitory effect against TGF-&beta
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 &mu
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-&beta
/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-&beta
1-induced upregulation of TGF-&beta
receptor type I (TGF&beta
RI). Additionally, 3f exhibited potent inhibitory effects against TGF-&beta
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&beta
/Smad signaling pathway.