Myrsinane and related diterpenes from Euphorbia falcata with selective potassium ion channel activity

Plants belong to the genus Euphorbia are promising sources of biologically active compounds. Over 650 diterpenoids have been isolated from the members of this genus and a wide range of therapeutically relevant activities (e.g. antitumor, cytotoxic, multidrug resistance-reversing, antiviral and anti-inflammatory activity) have been reported.

Previously twenty diterpenes were isolated from E. falcata by our group. The isolated compounds contain myrsinane, premyrsinane and cyclomyrsinane skeletons, and are esterified with acetic, propanoic, isobutanoic, methylbutanoic, benzoic and nicotinic acids. All but one are new natural products.

In the present study, the effects of these compounds on the G protein-activated inwardly rectifying K⁺ (GIRK) channel and on the human Ether-à-go-go-Related Gene (hERG) channel were investigated. The GIRK channels regulate the electrical activity of cardiac atrial myocytes among others. Compounds that inhibit GIRK channel are promising tools in the treatment of atrial fibrillation. Compounds with hERG blocking activity may modify the action potential of the heart muscle which can lead to prolongation of the action potential and an increase risk of severe ventricular arrhythmias. The aim of our work was to find compounds which inhibit GIRK channel but do not influence the functions of hERG channel.

Thirteen of the tested compounds possessed significant blocking activity on GIRK channel and 5 of these exerted low activity on hERG channel. Compounds with a myrsinane skeleton with a keto function at C-7 were proved to be highly active. In addition, esters of 2-deoxy-cyclomyrsinane with aliphatic ester group at C-8 were also found to have remarkable selective ion channel activity.

Acknowledgement: This work was supported by the Hungarian Scientific Research Fund (OTKA K109846) and a János Bolyai Research Scholarship of the Hungarian Academy of Sciences.