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Diterpenoids from Euphorbia dulcis with Potassium Ion Channel Inhibitory Activity with Selective G Protein-Activated Inwardly Rectifying Ion Channel (GIRK) Blocking Effect

Author:
Kúsz, Norbert, Orvos, Péter, Bereczki, Laura, Fertey, Pierre, Bombicz, Petra, Csorba, Attila, Tálosi, László, Jakab, Gusztáv, Hohmann, Judit, Rédei, Dóra
Source:
Journal of natural products 2018 v.81 no.11 pp. 2483-2492
ISSN:
1520-6025
Subject:
Euphorbia dulcis, X-ray diffraction, atrial fibrillation, cell lines, diterpenoids, electrophysiology, equipment, methanol, nuclear magnetic resonance spectroscopy, potassium, potassium channels, spectral analysis, therapeutics
Abstract:
Nine new (1–9) and two known (10, 11) jatrophane diterpenoids were isolated from the methanol extract of Euphorbia dulcis. The structure elucidation of the compounds was performed by means of extensive spectroscopic analysis, including HRESIMS, 1D (¹H, JMOD), and 2D (HSQC, HMBC, ¹H–¹H-COSY, NOESY) NMR experiments. The absolute configuration of compound 1 was determined by single-crystal X-ray diffraction. The electrophysiological effects of compounds 1–11 and the five diterpenoids (12–16) previously isolated from Euphorbia taurinensis were investigated on stable transfected HEK-GIRK1/4 (Kir3.1/3.4) and HEK-hERG (Kv11.1) cell lines using automated patch-clamp equipment. The majority of the diterpenoids showed significant blocking activity on GIRK channels (60.8–88.7% at 10 μM), while compounds 1, 2, 9–11, 13, and 14 exerted notable inhibitory effects even at 1 μM concentration. None of the jatrophane diterpenoids interfered with the function of hERG proteins; however, compound 14 remarkably hampered K⁺ flow through hERG channels. These selective activities suggest that jatrophane diterpenoids may represent a group of potential lead compounds for the development of novel therapeutic agents against atrial fibrillation.
Agid:
6225222