Synthesis, Anti-Inflammatory Activities, and Molecular Docking Study of Novel Pyxinol Derivatives as Inhibitors of NF-κB Activation.

Pyxinol, an active metabolite of ginsenosides in human hepatocytes, exhibits various pharmacological activities. Here, a series of C-3 modified pyxinol derivatives was designed and virtually screened by molecular docking with the key inflammation-related proteins of the nuclear factor kappa B (NF-κB) pathway. Some of the novel derivatives were synthesized to assess their effects in inhibiting the production of nitric oxide (NO) and mitochondrial reactive oxygen species (MtROS) in lipopolysaccharide-triggered RAW264.7 cells. Derivative 2c exhibited the highest NO and MtROS inhibitory activities with low cytotoxicity. Furthermore, 2c decreased the protein levels of interleukin 1β, tumor necrosis factor α, inducible nitric oxide synthase, and cyclooxygenase 2 and suppressed the activation of NF-κB signaling. Cellular thermal shift assays indicated that 2c could directly bind with p65 and p50 in situ. Molecular docking revealed that 2c 's binding to the p65-p50 heterodimer and p50 homodimer was close to their DNA binding sites. In summary, pyxinol derivatives possess potential for development as NF-κB inhibitors.