ABSTRACT
Hepatic stellate cells (HSCs) activation is a key event in the development of liver fibrosis, and blockage of the activation of HSCs has been shown to alleviate liver fibrosis. Sophoridine, a bioactive alkaloid found in many Chinese herbs, exhibits a broad spectrum of pharmacological effects, but its activities are not strong. In this study, a series of structurally modified derivatives of sophoridine were designed and synthesized. Among them, sophoridine α-aryl propionamide derivative ZM600 displayed a significant inhibitory effect on the activation of HSCs. The in vivo experiment demonstrated that ZM600 markedly ameliorated carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced liver fibrosis with a significant improvement of extracellular matrix deposition. Mechanism investigations revealed that ZM600 specifically inhibited the activation of NF-κB, PI-3K/AKT, and TGF-ß/Smads signaling pathways. These results suggest that ZM600 has a protective effect on liver fibrosis, which provides a new candidate for the treatment of liver fibrosis.
Subject(s)
Alkaloids , Hepatic Stellate Cells , Liver Cirrhosis , Matrines , Quinolizines , Animals , Quinolizines/pharmacology , Quinolizines/chemical synthesis , Quinolizines/chemistry , Quinolizines/therapeutic use , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Alkaloids/pharmacology , Alkaloids/chemistry , Alkaloids/chemical synthesis , Alkaloids/therapeutic use , Male , NF-kappa B/metabolism , NF-kappa B/antagonists & inhibitors , Signal Transduction/drug effects , Carbon Tetrachloride , Mice , Structure-Activity Relationship , Rats , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Drug Discovery , Antifibrotic Agents/pharmacology , Antifibrotic Agents/therapeutic use , Antifibrotic Agents/chemistry , Antifibrotic Agents/chemical synthesis , Rats, Sprague-DawleyABSTRACT
The ecto-5'-nucleotidase (CD73) is an important enzyme in the adenosine pathway and catalyzes the extracellular hydrolysis of adenosine monophosphate (AMP) yielding adenosine which is involved in the inflammation and immunosuppression. Inhibitors of CD73 have potential as novel immunotherapy agents for the treatment of cancer and infection. In this study, we discovered a series of fluorinated betulinic acid derivatives as potent CD73 inhibitors by a fluorine scanning strategy. Among these, three compounds ZM522, ZM553 and ZM557 exhibited inhibitory activity with IC50 values of 0.56 uM, 0.74 uM and 0.47 uM, respectively. In addition, these compounds showed a 7-fold, 5-fold and 8-fold increase in activity compared to the positive control drug α, ß-methylene adenosine diphosphate (APCP) against the human CD73 enzyme. Two of these (ZM522 and ZM553) also exhibited effective interferon gamma (INF-γ) elevation and indicated the regulation of rescued T cell activation. Therefore, our study provides both a lead optimization strategy and potential compounds for further development of small molecule CD73 inhibitors.