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.