Bicyclic polyprenylated acylphloroglucinol-related meroterpenoids as potent DRAK2 inhibitors from Hypericum patulum

As a both edible and medicinal plant, Hypericum patulum (Hypericaceae) is used as a natural herbal tea, scented tea, and folk medicine. In this study, eight undescribed bicyclic polyprenylated acylphloroglucinol-related meroterpenoids named hyperpatins A-H, along with eight known ones, were isolated from this plant. Their structures were elucidated on the basis of spectroscopic techniques, chemical method, X-ray crystallographic experiments, and electronic circular dichroism analyses. Hyperpatins A-H possess a characteristic pyran ring system diversely fused with the bicyclo[3.3.1]nonane-2,4,9-trione core, and hyperpatins C and D incorporate a unique alpha,beta-unsaturated aldehyde moiety. Some of the isolates exhibited potent inhibitory effects on death-associated protein kinase-related apoptosis-inducing kinase 2 with IC50 values ranging from 2.60 +/- 0.29 to 17.93 +/- 3.08 mu M. This is the first report of DRAK2 inhibitory activity for acylphloroglucinol-related meroterpenoids. The most active molecule hyperpatins C showed binding affinity with DRAK2 by hydrogen-bond and hydrophobic interactions in molecular docking and promoted the glucose-stimulated insulin secretion ability of primary islets.