PDF(Pubmed)
Abstract：
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.
摘要：
Pyxinol,人参皂苷在人肝细胞中的活性代谢产物，表现出各种药理活性。这里,设计了一系列C-3修饰的pyxinol衍生物，并通过与核因子κB（NF-κB）途径的关键炎症相关蛋白的分子对接进行了虚拟筛选。合成了一些新型衍生物，以评估其在脂多糖触发的RAW264.7细胞中抑制一氧化氮（NO）和线粒体活性氧（MtROS）产生的作用。衍生物2c表现出最高的NO和MtROS抑制活性，细胞毒性低。此外，2c降低了白细胞介素1β的蛋白质水平，肿瘤坏死因子α,诱导型一氧化氮合酶，和环氧合酶2，并抑制NF-κB信号的激活。细胞热转移实验表明2c可以直接与p65和p50原位结合。分子对接显示2c与p65-p50异二聚体和p50同二聚体的结合接近其DNA结合位点。总之,pyxinol衍生物具有开发NF-κB抑制剂的潜力。
