Structurally diverse spirocyclic polycyclic polyprenylated acylphloroglucinols from Hypericum ascyron Linn. and their anti-tumor activity

Ten spirocyclic polycyclic polyprenylated acylphloroglucinols (PPAP), hunascynols A–J (1–10), and 12 known analogs were isolated from the aerial parts of Hypericum ascyron Linn. Compounds 1 and 2, which share a 1,2-seco-spirocyclic PPAP skeleton, could be derived from spirocyclic PPAP, with a common octahydrospiro[cyclohexan-1,5′-indene]-2,4,6-trione core, through a cascade of Retro-Claisen, keto-enol tautomerism, and esterification reactions. Aldolization of normal spirocyclic PPAP yielded 3, which has a caged framework with a 6/5/6/5/6 ring system. The structures of these compounds were determined using spectroscopy and X-ray diffraction. The inhibitory activities of all isolates were tested in three human cancer cell lines and a zebrafish model. Compounds 1 and 2 displayed moderate cytotoxicity against HCT116 cells (IC50 6.87 and 9.86 μM, respectively). The mechanisms of these compounds were evaluated using Western blot assays. Compounds 3 and 5 inhibited the growth of sub-intestinal vessels in zebrafish embryos. Further, the target genes were screened using real-time PCR. Ten undescribed spirocyclic polycyclic polyprenylated acylphloroglucinols, including two 1,2-seco and one with a cage-like framework, were isolated from Hypericum ascyron Linn. Some of these compounds exhibit anti-tumor activity. [Display omitted] •10 undescribed and 12 known spirocyclic PPAP were isolated from Hypericum ascyron.•1 and 2 are 1,2-seco-spirocyclic PPAP and 3 has a cage-like framework.•1 and 2 affected the growth of HCT116 in vitro.•3 and 5 reduced the length of sub-intestinal vessels in zebrafish embryos.