Design and Synthesis of Betulinic Acid Derivatives as Antifibrotic Agents for Liver Fibrosis

Hepatic fibrosis is a major contributor to liver-related mortality and overall mortality. Currently, there is no established treatment for hepatic fibrosis. Research indicates that the transforming growth factor (TGF-β) signaling pathway is one of the key pathways involved in hepatic stellate cell (HSC) activation and fibrosis progression. Consequently, inhibiting the TGF-β signaling pathway represents a potential therapeutic strategy to combat hepatic fibrosis progression. Betulinic acid (BA) was widely extractable from natural plants, exhibits significant antifibrotic therapeutic effects. Three series of BA derivatives were synthesized and evaluated their antihepatic fibrosis activities. Most compounds showed no significant cytotoxicity in vitro. At nontoxic concentrations, these compounds effectively suppressed the TGF-β-induced upregulation of the liver fibrosis markers type I collagen and α-SMA. Notably, compound 3d dose-dependently inhibited extracellular matrix (ECM) deposition in TGF-treated HSCs and suppressed HSC activation. These findings indicate that compound 3d, acting as an antihepatic fibrosis agent, attenuates hepatic fibrosis by inhibiting the TGF-β signaling pathway.