Discovery of ent-labdane derivatives from Andrographis paniculata and their anti-inflammatory activity

The plant Andrographis paniculata has a long history of cultivation in Southeast Asia, especially its extensive antiinflammatory activity, and the famous natural antibiotic andrographolide comes from this plant. In China, A. paniculata, as the main crop, has become a major source of traditional Chinese medicine (TCM) for the clinical treatment of inflammation. To further explore the diverse diterpene lactones with better anti-inflammatory activity from A. paniculata, twenty-one ent-labdanes, including six undescribed compounds (andropanilides DI), were isolated. Their structures with absolute configurations were thoroughly determined by comprehensive NMR spectroscopic data, HRESIMS analysis and quantum chemical calculations. All isolated compounds were evaluated for anti-inflammatory activities based on the Griess method. Meanwhile, after structure-activity relationships analysis, the anti-inflammatory activity of andropanilide D (1) (IC50 = 2.31 DM) was found to be better than that of the positive control drug (dexamethasone, IC50 = 6.52 DM) and andrographolide (IC50 = 5.89 DM). Further mechanisms of activity indicated that andropanilide D significantly reduced the secretion of TNF-alpha, IL -6 and IL-1 beta and downregulated the protein expression of COX-2 and iNOS in LPS-induced RAW264.7 macrophages in a concentration-dependent manner based on Western blot and ELISA experiments. In conclusion, andropanilide D possesses potential medicinal value for the treatment of inflammation and further expands the material basis of the anti-inflammatory effect of A. paniculata.