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

Abstract

Ascynols A–C (1–3), three polycyclic polyprenylated acylphloroglucinol (PPAP) derivatives sharing an unusual cyclopentane core, were isolated from the aerial parts of Hypericum ascyron L. Compounds 1 and 3 were elucidated to possess two novel 6/6/5/5 and 5/5 architectures, respectively. Additionally, twenty-four analogues (4–27) 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 23 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.