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, <b>14</b>, 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.
Authors
- L Zhang
- Yu Tao (ORCID: https://orcid.org/0000-0001-5087-7474)
- Xiaojin Gao (ORCID: https://orcid.org/0000-0002-8158-484X)
- Hui Qiao (ORCID: https://orcid.org/0000-0002-2476-4342)
- Yi Bi (ORCID: https://orcid.org/0000-0003-0879-0572)
- Xin Zhang (ORCID: https://orcid.org/0000-0002-3833-2938)
- Lei Zhang (ORCID: https://orcid.org/0000-0002-8830-1048)
- Haixia Li (ORCID: https://orcid.org/0000-0003-1336-2548)
- Jing Gao (ORCID: https://orcid.org/0000-0002-5940-1461)
- Xiao-Li Yang (ORCID: https://orcid.org/0009-0001-6695-7636)
- Yatong Zhu
- Wenbin Xie (ORCID: https://orcid.org/0000-0002-2396-1483)
- Xianhe Fang
- Haoran Cheng
Institutions
- Binzhou Medical University (CN)
- Shandong University of Aeronautics (CN)
- Yantai University (CN)
- Systèmes avancés de délivrance de principes actifs
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-01-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02032
- Citations
- 7
- Primary Topic
- Pharmacological Effects of Natural Compounds
- Type
- article
- Field-Weighted Citation Impact
- 10.90
Funders
- Yantai University
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province
- Taishan Scholar Project of Shandong Province
- National College Students Innovation and Entrepreneurship Training Program
- Science and Technology Support Plan for Youth Innovation of Colleges and Universities of Shandong Province of China