Hypertums A-J, bioactive polycyclic polyprenylated acylphloroglucinols with diverse skeletons from Hypericum perforatum L. (St. John's wort)

Ten previously undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs), hypertums A-J (1-10), together with eighteen known analogues (11-28), belonging to five subclasses of PPAPs, were isolated from the aerial parts of Hypericum perforatum L. (St. John's wort). The chemical structures and the absolute configurations of these compounds were elucidated by comprehensive analysis of NMR spectra, HR-ESI-MS data, quantum chemical calculations, chemical transformation, and X-ray crystallography. The carbon skeletons of compounds 1-5 were first characterized from H. perforatum. Compounds 6 and 7 were rare congeners assembled with two different polyprenylated acylphloroglucinol moieties through an ester bond. The plausible biosynthetic pathways for 1-10 were postulated. Compound 3, yezo'otogirin A (27) and yezo'otogirin B (28) exhibited weak acetyl- cholinesterase inhibitory activities at 50 mu M. The isolated PPAPs were also evaluated for their antineuroinflammatory activity. Compound 3 inhibited nitric oxide (NO) production in LPS-stimulated BV-2 microglial cells with IC50 value of 34.34 mu M and also suppressed the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, anti-neuroinflammatory effect of 3 was also supported in zebrafish model.