Planta Med 2015; 81 - PM_117
DOI: 10.1055/s-0035-1565494

Isolation and structure determination of novel jatrophane diterpenes from Euphorbia dulcis and their GIRK-channel-inhibitory activity

N Kúsz 1, D Rédei 1, P Orvos 2, 3, L Tálosi 2, G Jakab 4, J Hohmann 1
  • 1Department of Pharmacognosy, University of Szeged, Szeged, Hungary
  • 2Rytmion Ltd., Szeged, Hungary
  • 3Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
  • 4Institute of Environmental Sciences, Faculty of Water and Environmental Management, Szent István University, Szarvas, Hungary

GIRK channels (G protein-activated inwardly-rectifying potassium channels) play an important role in the regulation of action potentials in the heart. These membrane proteines are selectively expressed in the atria. Under physiological circumstances GIRK channels facilitate the hyperpolarization and prolong the refractory phase in the myocytes, thus decrease the heart rate. The malfunctions of GIRK channels are considered to be involved in the development of atrial fibrillation (AF). Selective blockade of GIRK channels may offer an alternative way in the treatment of AF [1].

The methanol extract of aerial parts of Euphorbia dulcis L. was subjected to liquid-liquid partition. Multistep chromatographic purification (CC, VLC, PLC, RP-HPLC) yielded five pure compounds. The structure determination was carried out by means of HRMS, together with 1D (1H, JMOD) and 2D NMR-methods (HSQC, HMBC, 1H-1H COSY, NOESY). Electrophysiological effects of diterpenes were investigated on stable transfected HEK-GIRK 1/4 cell lines using automated patch clamp equipment.

As a result, four novel and one known [2] jatrophane diterpenes were obtained from the plant. All of the compounds contain a rare olefin bond between C5-C6 and are acylated with acetic, benzoic and angelic acids. The isolated diterpenes were tested on HEK-GIRK 1/4 cell lines and exerted substantial inhibition. IC50 values of the three most active compounds are 1.33 ± 0.16 µM, 1.63 ± 0.19 µM and2.65 ± 0.48 µM, respectively. Moreover the GIRK-inhibitory effect of jatrophane diterpenes is reported here for the first time.

References:

[1] Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, Knaut M, Ravens U. The G protein-gated potassium current I K,ACh is constitutively active in patients with chronic atrial fibrillation. Circulation 2005; 112: 3697 – 706.

[2] Yamamura S, Shizuri Y, Kosemura S, Ohtsuka J, Tayama T, Ohba S, Ito M, Saito Y, Terada Y. Diterpenes from Euphorbia helioscopia. Phytochemistry 1989; 28: 3421 – 3436.