HPLC-Based Activity Profiling for hERG Channel Inhibitors in the South African Medicinal Plant Galenia africana.
The human ether-a-go-go-related gene channel is a voltage-activated K(+) channel involved in cardiac action potential. Its inhibition can lead to QT prolongation, and eventually to potentially fatal arrhythmia. Therefore, it is considered a primary antitarget in safety pharmacology. To assess the risk of human ether-a-go-go-related gene channel inhibition by medicinal plants, 700 extracts from different parts of 142 medicinal plants collected in Southern Africa were screened on Xenopus laevis oocytes. A CH2Cl2 extract from the stems and leaves of Galenia africana (Aizoaceae) reduced the peak tail human ether-a-go-go-related gene current by 50.4 ± 5.5 % (n = 3) at a concentration of 100 µg/mL. By means of high-performance liquid chromatography-based activity profiling, nine flavonoids were identified in the active time windows. However, the human ether-a-go-go-related gene channel inhibition of isolated compounds was less pronounced than that of extract and active microfractions (human ether-a-go-go-related gene inhibition between 10.1 ± 5 and 14.1 ± 1.6 at 100 µM). The two major constituents, 7,8-methylenedioxyflavone (1) and 7,8-dimethoxyflavone (13), were quantified (4.3 % and 9.4 %, respectively, in the extract). Further human ether-a-go-go-related gene inhibition tests for compounds 1 and 13 at 300 µM showed a concentration-dependent inhibitory activity (33.2 ± 12.4 and 30.0 ± 7.4, respectively). In a detailed phytochemical profiling of the active extract, a total of 20 phenolic compounds, including six new natural products, were isolated and identified.
Department of Chemistry, University of the Free State, Bloemfontein, South Africa.
Kun
K
Du
Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland.
Maria
M
De Mieri
Institute of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.
Priyanka
P
Saxena
Department of Chemistry, University of the Free State, Bloemfontein, South Africa.
Khanya V
KV
Phungula
Department of Chemistry, University of the Free State, Bloemfontein, South Africa.
Anke
A
Wilhelm
Department of Chemistry, University of the Free State, Bloemfontein, South Africa.
Madalina Marina
MM
Hrubaru
National Museum, Bloemfontein, South Africa.
Elmarie
E
van Rensburg
National Museum, Bloemfontein, South Africa.
Pieter C
PC
Zietsman
Institute of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.
Steffen
S
Hering
Directorate Research Development, University of the Free State, Bloemfontein, South Africa.
Jan H
JH
van der Westhuizen
Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland.
Matthias
M
Hamburger
D000200:Action Potentials / Q000187:drug effects; D000353:Africa, Southern; D035722:Aizoaceae / Q000737:chemistry*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005260:Female; D005419:Flavonoids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects; D010636:Phenols / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D010936:Plant Extracts / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D018515:Plant Leaves / Q000737:chemistry; D018547:Plant Stems / Q000737:chemistry; D010946:Plants, Medicinal; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D014982:Xenopus laevis
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005419:Flavonoids; C000606913:KCNH2 protein, human; D010636:Phenols; D010936:Plant Extracts; D026902:Potassium Channel Blockers