(±)-Hypandrone A, a pair of polycyclic polyprenylated acylphloroglucinol enantiomers with a caged 7/6/5/6/6 pentacyclic skeleton from Hypericum androsaemum

Abstract

(±)-Hypandrone A (1), a pair of highly modified polycyclic polyprenylated acylphloroglucinol (PPAP) enantiomers, with an unprecedented caged 2,8,17-trioxapentacyclo-[11.4.2.0^1,9.0^4,9.0^10,15]-nonadecane core, were isolated from the fruits of Hypericum androsaemum. The racemate (±)-1 was successfully separated into the two optically pure enantiomers (ee ≥ 99%) using a preparative HPLC system. Their structures including absolute configurations were elucidated via spectroscopic analyses, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Biological studies revealed that (−)-1 is a potent inhibitor of the NLRP3 inflammasome pathway and could inhibit the protein expression of NLRP3, ASC, cleaved caspase-1 and the active form N-GSDMD fragment, thereby blocking NLRP3 inflammasome-induced pyroptosis.