Design and Synthesis of Hederagenin Derivatives for the Treatment of Sepsis by Targeting TAK1 and Regulating the TAK1-NF-κB/MAPK Signaling

Sepsis is a systemic inflammatory response caused by infection and is a leading cause of death worldwide. We designed and synthesized a series of hederagenin analogues with anti-inflammatory activity. The most effective compound, 14, reduced the release of TNF-α and IL-6 in RAW264.7 cells induced by lipopolysaccharide by affecting NF-κB/MAPK signaling. It demonstrated significant protection against sepsis in vivo and ameliorated histopathological changes in the liver, lungs, and kidneys. It exhibited good safety in subacute toxicity assays. Western blotting results indicated that it reduced the generation of p-p65, p-IκB, p-p38, p-JNK, and p-ERK. Immunofluorescence assay results suggested that the compound inhibited nuclear translocation of p65 and c-Fos. It was found to target TAK1 with a novel molecular backbone, distinct from the few TAK1 inhibitors previously reported. This work provides a new lead structure for the study of TAK1 inhibitors and a potential target for TAK1 in sepsis therapy.脓毒症（Sepsis）是由感染引发的全身性炎症反应，亦是全球范围内的主要致死病因之一。我们设计并合成了一系列具有抗炎活性的常春藤皂苷元（hederagenin）类似物。其中活性最优的化合物14可通过影响核因子-κB（NF-κB）/丝裂原活化蛋白激酶（MAPK）信号通路，抑制脂多糖（lipopolysaccharide）诱导的RAW264.7细胞中肿瘤坏死因子-α（TNF-α）与白细胞介素-6（IL-6）的释放。该化合物在体内展现出显著的脓毒症保护作用，并可改善肝脏、肺脏与肾脏的组织病理学损伤。在亚急性毒性试验中，其表现出良好的安全性。蛋白质免疫印迹（Western blotting）结果显示，该化合物可降低磷酸化p65（p-p65）、磷酸化IκB（p-IκB）、磷酸化p38（p-p38）、磷酸化JNK（p-JNK）以及磷酸化ERK（p-ERK）的生成量。免疫荧光试验结果表明，该化合物可抑制p65与c-Fos的核转位。研究发现，该化合物以全新的分子骨架靶向转化生长因子β激活激酶1（TAK1），与此前报道的少数TAK1抑制剂存在显著差异。本研究为TAK1抑制剂的研发提供了全新的先导化合物结构，同时为脓毒症治疗中TAK1靶点的应用提供了潜在可能。