Diversity-oriented synthesis of a hyperacmotone A-based compound library as anti-liver fibrosis agent.

In this study, the natural product hyperacmotone A (HA) was subjected to preliminary structural diversification through a diversity-oriented synthesis strategy; and seven novel HA-derived pseudo-natural products (1-7) were successfully synthesized. Their structures, including absolute configurations, were established by HRESIMS, NMR spectroscopic analysis, in conjunction with quantum calculations of NMR chemical shifts and electronic circular dichroism (ECD). The anti-fibrotic activity and cytotoxicity of these compounds were systematically evaluated in a TGF-β1-induced human hepatic stellate cell (LX-2) fibrosis model. Among them, compound 6 exhibited over 80% inhibition of activated LX-2 cells at 20 μM, with low cytotoxicity against normal LX-2 cells. Further studies on compound 6 demonstrated that it dose-dependently suppressed the mRNA expression of key fibrotic markers (α-SMA, COL1A1, TGF-β1, TIMP1) and the protein expression of α-SMA and COL1A1 in LX-2 cells.