Discovery of PXR agonists from Hypericum japonicum: A class of novel nonaromatic acylphloroglucinol-terpenoid adducts.

Eight nonaromatic acylphloroglucinol-terpenoid adducts including 7 new compounds were isolated from H. japonicum. Among them, compounds 1 – 4 showed significant PXR agonistic activity. [Display omitted] • Seven novel nonaromatic acylphloroglucinol-terpenoid adducts were isolated. • Compounds 1 − 4 showed significant PXR agonistic activity in dual-luciferase reporter gene model. • Compounds 1 − 4 can upregulate the expression of PXR-targeted gene in mice primary hepatocyte model. • Compounds 1 − 4 efficiently promoted PXR nuclear translocation at 10 μM. • The binding models of active compounds and PXR were elucidated. Pregnane X receptor (PXR) has been considered as a promising therapeutic target for cholestasis due to its crucial regulation in bile acid biosynthesis and metabolism. To search promising natural PXR agonists, the PXR agonistic activities of five traditional Chinese medicines (TCMs) with hepatoprotective efficacy were assayed, and Hypericum japonicum as the most active one was selected for subsequent phytochemical investigation, which led to the isolation of eight nonaromatic acylphloroglucinol-terpenoid adducts including seven new compounds (1 − 4 , 5a , 5b and 6). Their structures including absolute configurations were determined by comprehensive spectroscopic, computational and X-ray diffraction analysis. Meanwhile, the PXR agonistic activities of aplenty compounds were evaluated via dual-luciferase reporter assay, RT-qPCR and immunofluorescence. Among them, compounds 1 − 4 showed more potent activity than the positive drug rifampicin. Furthermore, the molecular docking revealed that 1 − 4 were docked well on the PXR ligand binding domain and formed hydrogen bonds with amino acid residues Gln285, Ser247 and His409. This investigation revealed that H. japonicum may serve as a rich source of natural PXR agonists. [ABSTRACT FROM AUTHOR]