The Synthesis And Anti-Liver Fibrosis Activity Study Of 3-Furylindazole Derivatives

Indazole is one of the very important organic chemical intermediates. The indazole nucleus is effective pharmacophore in medicinal chemistry. For example, 1-benzyl-3-(5’-hydroxymethyl-2’-furyl) indazole (YC-1) has various pharmacological activities including the activation of soluble gualylate cyclase, in hibition of hypoxia-induced factor. The latest study suggested YC-1 had a positive activity on anti-fibrotic, but the antifibrotic mechanism of YC-1 acts have yet not to be well characterized. So in this paper, we take the anti-liver fibrosis activity of furyl-indazole derivatives and YC-1to further study.First, considering the structure-activity relationship of YC-1 and its existing derivatives, a proper modification at benzyl or hydroxymethyl position was carried out. So four compounds (FIAC, F IACA, FIPOC, F IPOCA) which had bulky substituents containing carbonyl group were synthesized; Amide or electron-deficient olefins structure was introduced to hydroxymethyl position to synthesized FIMPa and nine compounds containing different substituent group.Second, we detected the anti-fibrotic effect on activated human hepatic stellate cells (HSCs) LX-2 cell of all compounds by CCK-8 assay. The results indicated YC-1, FIMA, FIA, FIAC, FIPOC and FIMPa could effectively inhibited LX-2 cells proliferation, the IC50 were 78.5,73.8,75.0,48.7,49.0,115.3 uM respectively; The other nine compounds containing electron-deficient olefins promoted LX-2 cell proliferation. Next, we studied LX-2 cells apoptosis focus on YC-1, FIAC, FIPOC and FIMPa. Both PI simple staining and Annexin V FITC/PI double staining showed that YC-1 and its derivatives induced cell apoptosis, especially FIAC, the death rate of LX-2 cells was 59.3% at 48h.Then, we evaluated the effects of the four compounds on α-SMA and caspase-3 expression by western blot. The results indicated they all decreased the expression of α-SMA, and increased the expression of caspase-3, especially FIAC. These results suggested that they might be potential drugs for hepatic fibrosis therapy.