Synthesis and anti-inflammatory activity of saponin derivatives of delta-oleanolic acid

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.

Automated summary

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.