| Summary: | Twenty 9<i>O</i>-substituted palmatine derivatives were prepared and tested for their biological effect against collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure−activity relationship (SAR) indicated that the introduction of a benzyl motif on the 9<i>O</i> atom was favorable for activity. Among them, compound <b>6c</b> provided the highest inhibitory effect against COL1A1 with an IC<sub>50</sub> value of 3.98 μM, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, α-soomth muscle actin (α-SMA), matrix metalloprotein 2 (MMP2) in both mRNA and protein levels, indicating extensive inhibitory activity against fibrogenesis. A further primary mechanism study indicated that it might repress the hepatic fibrogenesis via inhibiting both canonical transforming growth factor-beta 1 (TGF-β1)/Smads and non-canonical janus-activated kinase 1 (JAK1)/singal transducer and activator of transcription 3 (STAT3) signaling pathways. Additionally, <b>6c</b> owned a high safety profile with the LD<sub>50</sub> value of over 1000 mg·kg<sup>−1</sup> in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization.
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