PDF herunterladen
Planta Med 2015; 81(12/13): 1154-1162
DOI: 10.1055/s-0035-1545929
Natural Product Chemistry
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

HPLC-Based Activity Profiling for hERG Channel Inhibitors in the South African Medicinal Plant Galenia africana [*]

Kun Du   #
1   Department of Chemistry, University of the Free State, Bloemfontein, South Africa
,
Maria De Mieri   #
2   Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland
,
Priyanka Saxena
3   Institute of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
,
Khanya V. Phungula
1   Department of Chemistry, University of the Free State, Bloemfontein, South Africa
,
Anke Wilhelm
1   Department of Chemistry, University of the Free State, Bloemfontein, South Africa
,
Madalina Marina Hrubaru
1   Department of Chemistry, University of the Free State, Bloemfontein, South Africa
,
Elmarie van Rensburg
4   National Museum, Bloemfontein, South Africa
,
Pieter C. Zietsman
4   National Museum, Bloemfontein, South Africa
5   Centre for Environmental Management, University of the Free State, Bloemfontein, South Africa
,
Steffen Hering
3   Institute of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
,
Jan H. van der Westhuizen
6   Directorate Research Development, University of the Free State, Bloemfontein, South Africa
,
Matthias Hamburger
2   Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 19. Dezember 2014
revised 09. März 2015

accepted 14. März 2015

Publikationsdatum:
29. April 2015 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

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.

Key words

hERG channel inhibition - herbal extract - Galenia africana - Aizoaceae - HPLC-based activity profiling - flavonoids

* Dedicated to Professor Dr. Dr. h. c. mult. Adolf Nahrstedt on the occasion of his 75th birthday.


# These authors contributed equally to this work.


Supporting Information

 

  • References

  • 1 Vasina V, De Ponti F. The hERG K+ channel: target and antitarget strategies in drug development. Pharmacol Res 2008; 57: 181-195
    CrossrefPubMedGoogle Scholar
  • 2 Deisemann H, Ahrens N, Schlobohm I, Kirchhoff C, Netzer R, Möller C. Effects of common antitussive drugs on the hERG potassium channel current. J Cardiovasc Pharmacol 2008; 52: 494-499
    CrossrefPubMedGoogle Scholar
  • 3 Polak S, Wiśniowska B, Brandys J. Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugsʼ cardiotoxic properties. J Appl Toxicol 2009; 29: 183-206
    CrossrefPubMedGoogle Scholar
  • 4 Scholz EP, Zitron E, Kiesecker C, Lück S, Thomas D, Kathöfer S, Kreye VAW, Katus HA, Kiehn J, Schoels W, Karle CA. Inhibition of cardiac HERG channels by grapefruit flavonoid naringenin: implications for the influence of dietary compounds on cardiac repolarisation. Naunyn Schmiedebergs Arch Pharmacol 2005; 371: 516-525
    CrossrefPubMedGoogle Scholar
  • 5 Lin CR, Ke XG, Ranade V, Somberg J. The additive effects of the active component of grapefruit juice (naringenin) and antiarrhythmic drugs on HERG inhibition. Cardiology 2008; 110: 145-152
    CrossrefPubMedGoogle Scholar
  • 6 Zitron E, Scholz E, Owen RW, Lück S, Kiesecker C, Thomas D, Kathöfer S, Niroomand F, Kiehn J, Kreye VAW, Katus HA, Schoels W, Karle CA. QTc prolongation by grapefruit juice and its potential pharmacological basis – HERG channel blockade by flavonoids. Circulation 2005; 111: 835-838
    CrossrefPubMedGoogle Scholar
  • 7 Schramm A, Jähne EA, Barburin I, Hering S, Hamburger M. Natural products as potential hERG channel inhibitors – outcomes from a screening of widely used herbal medicines and edible plants. Planta Med 2014; 80: 1045-1050
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 8 Schramm A, Baburin I, Hering S, Hamburger M. hERG channel inhibitors in extracts of Coptidis rhizoma. Planta Med 2011; 77: 692-697
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 9 Vries FA, Bitar HEL, Green IR, Klassen JA, Mabusela WT, Bodo B, Johnson Q. An antifungal active extract from the aerial parts of Galenia africana. 11th Napreca Symposium Book of Proceedings. Antananarivo: Napreca; 2005: 123-131
    Google Scholar
  • 10 Watt C, Breyer-Brandwijk MG. The medicinal and poisonous plants of southern and eastern Africa. Edinburg: E & S Livingstone Ltd.; 1962: 449
    Google Scholar
  • 11 Mativandlela SPN, Muthivhi T, Kikuchi H, Oshima Y, Hamilton C, Hussein AA, van der Walt ML, Houghton PJ, Lall N. Antimycobacterial flavonoids from the leaf extract of Galenia africana . J Nat Prod 2009; 72: 2169-2171
    CrossrefPubMedGoogle Scholar
  • 12 Potterat O, Hamburger M. Concepts and technologies for tracking bioactive compounds in natural product extracts: generation of libraries, and hyphenation of analytical processes with bioassays. Nat Prod Rep 2013; 30: 546-564
    CrossrefPubMedGoogle Scholar
  • 13 Potterat O, Hamburger M. Combined use of extract libraries and HPLC-based activity-profiling for lead discovery. Planta Med 2014; 80: 1171-1181
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 14 Kuroyanagi M, Yamamoto Y, Fukushima S, Ueno A, Noro T, Miyase T. Chemical studies on the constituents of Polygonum nodosum . Chem Pharm Bull 1982; 30: 1602-1608
    CrossrefPubMedGoogle Scholar
  • 15 Huan Y, Dong W, Li T, Baochang C. Flavonoid aglycones of Oxytropis falcata . Chem Nat Comp 2009; 45: 239-241
    CrossrefPubMedGoogle Scholar
  • 16 Tran VH, Druke RK, Abu-Mellal A, Duke CC. Propolis with high flavonoid content collected by honey bees from Acacia paradoxa . Phytochemistry 2012; 81: 126-132
    CrossrefPubMedGoogle Scholar
  • 17 Al-Taweel AM, Perveen S, El-Shafae AM, Fawzy GA, Malik A, Afza N, Iqbal L, Latif M. Bioactive phenolic amides from Celtis africana . Molecules 2012; 17: 2675-2682
    CrossrefPubMedGoogle Scholar
  • 18 Herath W, Mikell JR, Khan IA. Microbial metabolism. Part 10: Metabolites of 7,8-dimethoxyflavone and 5-methoxyflavone. Nat Prod Res 2009; 23: 1231-1239
    CrossrefPubMedGoogle Scholar
  • 19 Bernard-Gautier V, Boudjemeline M, Rosa-Neto P, Thiel A, Shirrmacher R. Towards tropomyosin-related kinase B (trKB) receptors ligands for brain imaging with PET: radiosynthesis and evaluation of 2-(4-[18F]fluorophenyl)-7,8-dihydroxy-4H-chromen-4-one and 2-(4-([N-methyl-11C]-dimethylamino)phenyl)-7,8-dihydroxy-4H-chromene-4-one. Bioorg Med Chem 2013; 21: 7816-7829
    CrossrefPubMedGoogle Scholar
  • 20 Yoon H, Eom S, Hyun J, Jo G, Hwang D, Lee S, Yong Y, Park JC, Lee YH, Lim Y. 1H and 13C NMR data on hydroxy/methoxy flavonoids and the effects of substituents on chemical shifts. Bull Korean Chem Soc 2011; 32: 2101-2104
    CrossrefPubMedGoogle Scholar
  • 21 Zhang Q, Guo WJ, Fu CL, Ma S, Zhu MQ. Chemical constituents from an endophyte Cercosporella sp . Chem Nat Comp 2013; 49: 117-118
    CrossrefPubMedGoogle Scholar
  • 22 Visweswara Rao K, Viswanadham N. A note on 7, 8-dimethoxy flavones. Proc Indian Acad Sci 1949; 29: 218-220
    PubMedGoogle Scholar
  • 23 Wang QA, Liao TG, Tang JG, Fan HF. [Improved synthesis and structure modification of 7-hydroxyflavone and 7,8-dihydroxyflavone.]. Hunan Daxue Xuebao (Ziran Kexueban) 2004; 31: 1-4
    PubMedGoogle Scholar
  • 24 Anjaneyulu ASR, Sudha Rani G, Mallavadhani UV, Murthy YLN. Synthesis and characterization of some new chalcones and flavanones. Indian J Heterocycl Chem 1994; 4: 9-14
    PubMedGoogle Scholar
  • 25 Bhattacharya RK, Pyrozi PR. Effect of plant flavonoids on microsome catalyzed reactions of aflatonine B1 leading to activation and DNA adduct formation. Cancer Lett 1988; 39: 85-91
    CrossrefPubMedGoogle Scholar
  • 26 Dlade D, Ferreira D, Marajs LPJ. Circular dichroism, a powerful tool for the assessment of absolute configuration of flavonoids. Phytochemistry 2005; 66: 2167-2215
    PubMedGoogle Scholar
  • 27 Brandt EV, Ferreira D, Roux DG. Ring expansion of crombeone, a natural 5-hydroxypeltogynone. J Chem Soc Chem Commun 1971; 116-117
    PubMedGoogle Scholar
  • 28 Clare JJ, Trezise DJ. Expression and analysis of recombinant ion channels: from structural studies to pharmacological screening. Weinheim: Wiley-VCH Verlag; 2006: 1-25
    CrossrefGoogle Scholar
  • 29 Witchel HJ, Milnes JT, Milcheson JS, Anchox JC. Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes. J Pharmacol Toxicol Methods 2002; 48: 45-80
    CrossrefPubMedGoogle Scholar
  • 30 Windisch A, Timin EN, Schwarz T, Stork-Riedler D, Erker T, Ecker GF, Hering S. Trapping and dissociation of propafenone derivatives in HERG channels. Br J Pharmacol 2011; 162: 1542-1552
    CrossrefPubMedGoogle Scholar
  • 31 Stork D, Timin EN, Berjukow S, Huber C, Hohaus A, Auer M, Hering S. State dependent dissociation of HERG channel inhibitors. Br J Pharmacol 2007; 151: 1368-1376
    PubMedGoogle Scholar
  • 32 Baburin I, Beyl S, Hering S. Automated fast perfusion of Xenopus oocytes for drug screening. Pflugers Arch 2006; 453: 117-123
    CrossrefPubMedGoogle Scholar