Abstract
Twenty 9O-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 9O atom was favorable for activity. Among them, compound 6c provided the highest inhibitory effect against COL1A1 with an IC50 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, 6c owned a high safety profile with the LD50 value of over 1000 mg·kg−1 in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization.
Highlights
The wound-healing response, as well as the accumulation of extracellular matrix (ECM) proteins, followed by a process of hepatocyte regeneration to replace dead hepatocytes and restore the physiological liver mass, which explains the generation of hepatic fibrosis (HF) [1,2]
Nonalcoholic steatohepatitis (NASH), alcoholic liver disease, and viral hepatitis represent the major etiologies leading to HF [4]
The structure−activity relationship (SAR) indicated that the introduction of 9O-benzyl motif was beneficial for activity, and the electron density on the benzene ring might affect the potency
Summary
The wound-healing response, as well as the accumulation of extracellular matrix (ECM) proteins, followed by a process of hepatocyte regeneration to replace dead hepatocytes and restore the physiological liver mass, which explains the generation of hepatic fibrosis (HF) [1,2]. HF typically reverts after the elimination of the causative injury. HF can progress to irreversible and even fatal cirrhosis if the damage persists and a chronic response is established [3]. Nonalcoholic steatohepatitis (NASH), alcoholic liver disease, and viral hepatitis represent the major etiologies leading to HF [4]. HF and, cirrhosis impose a considerable economic burden on society [4]. An immense effort has been undertaken to elucidate the mechanisms of HF and develop therapeutic approaches. Novel anti-fibrotic treatment is still in great need
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