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Four previously undescribed highly oxygenated diterpenoids (<b>1</b>–<b>4</b>), zeylleucapenoids A–D, characterized by halimane and labdane skeletons, were isolated from the aerial parts of <i>Leucas zeylanica</i>. Their structures were elucidated primarily via NMR experiments. The absolute configuration of <b>1</b> was established using theoretical ECD calculations and X-ray crystallographic analysis, whereas those for <b>2</b>–<b>4</b> were assigned using theoretical ORD calculations. Zeylleucapenoids A–D were tested for anti-inflammatory activity against nitric oxide (NO) production in RAW264.7 macrophages, of which only <b>4</b> showed significant efficacy with an IC₅₀ value of 38.45 μM. Further, active compound <b>4</b> was also evaluated for the inhibition of the release of pro-inflammatory cytokines TNF-<i>α</i> and IL-6 and was found to have a dose-dependent inhibitory effect, while it showed nontoxic activity for zebrafish embryos. A subsequent Western blotting experiment revealed that <b>4</b> inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, molecular docking analysis indicated that the possible mechanism of action for <b>4</b> may be bind to targets via hydrogen and hydrophobic bond interactions.