期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 209, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112932
关键词
Pentacyclic triterpenes; delta-oleanolic acid; saponins; AMPK activator; anti-inflammation
资金
- National Natural Science Foundation of China [81730094, 91853125]
Pentacyclic triterpenes (PTs) have been found to activate AMPK, with synthesized delta-oleanolic acid saponin 29 showing significant anti-inflammatory effects and liver protection in mice with acute hepatic failure.
Pentacyclic triterpenes (PTs) are the active ingredients of many medicinal herbs and pharmaceutical formulations, and are well-known for their anti-inflammatory activity. On the other hand, anti-inflammatory effects of AMP-activated protein kinase (AMPK) have recently drawn much attention. In this study, we found that a variety of naturally occurring PTs sapogenins and saponins could stimulate the phosphorylation of AMPK, and identified delta-oleanolic acid (10) as a potent AMPK activator. Based on these findings, 23 saponin derivatives of delta-oleanolic acid were synthesized in order to find more potent anti-inflammatory agents with improved pharmacokinetic properties. The results of cellular assays showed that saponin 29 significantly inhibited LPS-induced secretion of pro-inflammatory factors TNF-alpha and IL-6 in THP1-derived macrophages. Preliminary mechanistic studies showed that 29 stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). The bioavailability of 29 was significantly improved in comparison with its aglycon. More importantly, 29 showed significant anti-inflammatory and liver-protective effects in LPS/D-GalN-induced fulminant hepatic failure mice. Taken together, PTs saponins hold promise as therapeutic agents for inflammatory diseases. (C) 2020 Elsevier Masson SAS. All rights reserved.
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