5-Methylated polyprenylated acylphloroglucinol derivatives as low-voltage-gated Ca2+ channel inhibitors†

Abstract

Ascynols A–C (), three polycyclic polyprenylated acylphloroglucinol (PPAP) derivatives sharing an unusual cyclopentane core, were isolated from the aerial parts of Hypericum ascyron L. Compounds and were elucidated to possess two novel 6/6/5/5 and 5/5 architectures, respectively. Additionally, twenty-four analogues () were also obtained, among which fourteen are new compounds. These compounds represent 11 different structural types and can be categorized into 6 groups based on their biosynthetic origin. Their structures were determined from spectroscopic analysis, quantum chemical calculation, and X-ray diffraction data. All the isolates are decorated with a methyl group at C-5 instead of a prenyl or geranyl group as in most other PPAPs. Biologically, sixteen compounds were identified as potent inhibitors of low-voltage-gated calcium channels (LVGCCs; Ca_v3.1–3.3), with IC₅₀ values ranging from 1.89 to 16.55 μmol L⁻¹. Moreover, compound exhibited strong and dose-dependent antinociception in an acetic acid-induced mouse model of visceral pain and its effect is comparable to that of Z944, a representative LVGCC inhibitor under clinical trial.