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 δ-oleanolic acid (10) as a potent AMPK activator. Based on these findings, 23 saponin derivatives of δ-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-α 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.

五环三萜（PTs）是许多草药和药物制剂的活性成分，并以其抗炎活性而闻名。另一方面，最近，AMP激活的蛋白激酶（AMPK）的抗炎作用引起了人们的广泛关注。在这项研究中，我们发现多种天然存在的PT皂苷元和皂苷可以刺激AMPK的磷酸化，并确定δ-油酸（10）是有效的AMPK激活剂。基于这些发现，合成了23种δ-油酸皂苷衍生物，以发现更有效的具有改善的药代动力学性质的抗炎药。细胞分析的结果表明，皂苷29能够显着抑制LPS诱导的THP1巨噬细胞分泌促炎因子TNF-α和IL-6。初步的机理研究表明29能刺激AMPK和乙酰辅酶A羧化酶（ACC）的磷酸化。与糖苷配基相比，29的生物利用度显着提高。更重要的是，在LPS / D-GalN诱导的暴发性肝衰竭小鼠中，有29种显示出显着的抗炎和肝保护作用。两者合计，PT皂苷有望作为炎症性疾病的治疗剂。