Planta Med 2016; 82(11/12): 1009-1015
DOI: 10.1055/s-0042-105572
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

hERG Channel Blocking Ipecac Alkaloids Identified by Combined In SilicoIn Vitro Screening[*]

Jadel M. Kratz**
1  Department of Pharmacognosy, University of Vienna, Vienna, Austria
,
Christina E. Mair**
1  Department of Pharmacognosy, University of Vienna, Vienna, Austria
,
Sarah K. Oettl**
2  Institute of Pharmacy/Pharmacognosy, University of Innsbruck, Innsbruck, Austria
,
Priyanka Saxena
3  Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
,
Olaf Scheel
4  Cytocentrics Bioscience GmbH, Rostock, Germany
,
Daniela Schuster
5  Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria
,
Steffen Hering
3  Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
,
Judith M. Rollinger
1  Department of Pharmacognosy, University of Vienna, Vienna, Austria
› Author Affiliations
Further Information

Publication History

received 07 March 2016
revised 21 March 2016

accepted 21 March 2016

Publication Date:
04 May 2016 (eFirst)

Abstract

Human ether-a-go-go-related gene channel blocking is associated with QT interval prolongation and increased risk of potentially fatal arrhythmias. As natural products keep increasing in popularity, there is an urgent need for studies assessing human ether-a-go-go-related gene channel-related cardiotoxic risks. We selected 49 plant species based on the results of a pharmacophore-based virtual screening campaign, in parallel with a literature data survey concerning highly consumed herbal medicines with reported cardiac liabilities. Lead-like enhanced extracts were prepared, an initial in vitro screening was performed at 100 µg/mL by voltage clamp on Xenopus oocytes, and five human ether-a-go-go-related gene channel blocking extracts were identified. In accordance to the six virtually predicted alkaloids, the root extract of Carapichea ipecacuanha inhibited human ether-a-go-go-related gene channel currents by 32.5 %. A phytochemical workflow resulted in the isolation and identification of five out of the six virtually predicted alkaloids. All isolates blocked human ether-a-go-go-related gene channel currents to different extents. The major ipecac constituents emetine (1) and cephaeline (2) showed IC50 values of 21.4 and 5.3 µM, respectively, measured by whole-cell patch clamp in HEK293 cells. This is the first report on human ether-a-go-go-related gene channel blockers from C. ipecacuanha. Its roots and rhizomes are used to produce different pharmacopeial ipecac preparations that are mainly used as emetics for poisoning treatment. Our findings raise further questions regarding the safety and over-the-counter appropriateness of these herbal products.

* Dedicated to Professor Dr. Dr. h. c. mult. Kurt Hostettmann.


** These authors contributed equally to this work.


Supporting Information