α-Hederin

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Structural formula
Structural formula of alpha-hederin
General
Surname α-Hederin
other names

(3β, 4α) -3 - {[2- O - (6-Deoxy-α- L -mannopyranosyl) -α- L -arabinopyranosyl] oxy} -23-hydroxyolean-12-en-28-acid

Molecular formula C 41 H 66 O 12
Brief description

white solid

External identifiers / databases
CAS number 27013-91-8
EC number 248-166-5
ECHA InfoCard 100,043,773
PubChem 73296
ChemSpider 66036
Wikidata Q25105925
properties
Molar mass 750.96 g mol −1
Physical state

firmly

Melting point

265-268 ° C

safety instructions
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

α-Hederin ( alpha-hederin ) is a poorly water-soluble saponin and pentacyclic triterpenoid , which is found in plants such as Hedera helix (common ivy), Nigella sativa (real black cumin), Kalopanax septemlobus (tree aralia) or the genus Pulsatilla ( pasque flowers) ) can be found. In these plants it arises from the aglycon hederagenin and can be converted into the bisdesmosidic saponin hederacoside C by glycosylation .

Extraction

α-Hederin can be obtained by enzymatic or chemical hydrolysis of hederacoside C , which is the main saponin in ivy, and then purified. A partial synthesis based on the methyl ester of hederagenin is also described.

Medical importance

α-Hederin is a relatively well-studied active ingredient, which has been assigned numerous properties in preclinical studies. These properties include:

The pure substance hardly plays a role clinically, but is contained in extracts from ivy leaves mainly in the form of its precursor hederacoside C and is used in the treatment of acute bronchitis and cold-related respiratory diseases. In addition, α-Hederin is known in the Islamic world as an important component of black cumin in folk medicine.

Pharmacological effect

Spatial conformational representation of α-hederin to illustrate the relatively flat structure of the lipophilic triterpene structure

A selective interaction with the β2-adrenoceptors is known via α-hederin , which, among other things, can be found increasingly in the airways. Upon strong stimulation, β2-adrenoceptors are internalized by the respective cells (e.g. type II alveolar cells or cells of the smooth bronchial muscles), ie removed from the cell surface in order to reduce the responsiveness to the natural receptor agonist adrenaline .

After activation of a sufficient number of β2 adrenoceptors, the increased intracellular cAMP concentration leads to phosphorylation of the receptor by two different enzymes ( PKA and GRK2 ), which ultimately trigger the translocation of the phosphorylated receptors to so-called coated pits, where the internalization of the Receptors takes place. α-Hederin acts as an indirect GRK2 inhibitor, which means that α-Hederin is not to be understood as a GRK2 blocker, but rather makes access to the phosphorylation site of the β2 adrenoceptor for GRK2 so difficult that there is insufficient phosphorylation. This prevents internalization and β2-adrenoceptors remain largely present on the cell surface, where they can intensify the effects mediated by adrenaline (e.g. surfactant secretion and bronchodilation caused by increased cAMP concentrations ).

The mechanism of the anti-inflammatory effect is also assumed to be an influence on the β2-adrenergic signaling pathway . There is a positive relationship between the expression of interleukin-6 (IL-6) and the β2-adrenoceptor-mediated expression of β-arrestin 2 . β-arrestin 2 binds to the IκBα-NFκB complex, which inhibits phosphorylation by the IκB kinase. If there is no phosphorylation, this complex cannot be cleaved, NFκB cannot be translocated into the cell nucleus and the gene, e.g. That for IL-6, cannot be transcribed. As a result, less IL-6 is ultimately produced. Preventing the internalization of the toll-like receptor 4 is also discussed.

Its special interaction with the membrane, which is able to drastically lower its cholesterol content, is held responsible for the anticancer effect of α-hederin.

safety instructions

In higher concentrations, α-hederin has a hemolytic effect in cell experiments (HD 50 <30 µM).

Individual evidence

  1. ↑ a b c d e f g data sheet α-Hederin, analytical standard at Sigma-Aldrich , accessed on October 11, 2017 ( PDF ).
  2. ↑ Karen Plé, Martin Chwalek, Laurence Voutquenne-Nazabadioko: Synthesis of α-Hederin, δ-Hederin, and Related Triterpenoid Saponins. In: European Journal of Organic Chemistry. 2004, 2004, p. 1588, doi : 10.1002 / ejoc.200300723 .
  3. ↑ R. Keyhanmanesh, S. Saadat, M. Mohammadi, AA Shahbazfar, M. Fallahi: The Protective Effect of α-Hederin, the Active Constituent of Nigella sativa, on Lung Inflammation and Blood Cytokines in Ovalbumin Sensitized Guinea Pigs. In: Phytotherapy Research. Volume 29, number 11, November 2015, pp. 1761–1767, doi : 10.1002 / ptr.5429 , PMID 26292851 .
  4. ↑ M. Fallahi, R. Keyhanmanesh, AM Khamaneh, MA Ebrahimi Saadatlou, S. Saadat, H. Ebrahimi: Effect of Alpha-Hederin, the active constituent of Nigella sativa, on miRNA-126, IL-13 mRNA levels and inflammation of lungs in ovalbumin-sensitized male rats. In: Avicenna journal of phytomedicine. Volume 6, number 1, 2016 Jan-Feb, pp. 77-85, PMID 27247924 , PMC 4884220 (free full text).
  5. ↑ a b J. Schulte-Michels, F. Runkel, S. Gokorsch, H. Häberlein: Ivy leaves dry extract EA 575® Decreases LPS-induced IL-6 release from murine macrophages. In: The Pharmacy. Volume 71, Number 3, March 2016, pp. 158-161, PMID 27183712 .
  6. ↑ YK Kim, RG Kim, SJ Park, JH Ha, JW Choi, HJ Park, KT Lee: In vitro antiinflammatory activity of kalopanax saponin A isolated from Kalopanax pictus in murine macrophage RAW 264.7 cells. In: Biological & Pharmaceutical Bulletin. Volume 25, Number 4, April 2002, pp. 472-476, PMID 11995927 .
  7. ↑ S. Saadat, M. Mohammadi, M. Fallahi, R. Keyhanmanesh, MR Aslani: The protective effect of α-hederin, the active constituent of Nigella sativa, on tracheal responsiveness and lung inflammation in ovalbumin-sensitive guinea pigs. In: The Journal of Physiological Sciences. Volume 65, Number 3, May 2015, pp. 285-292, doi : 10.1007 / s12576-015-0367-6 , PMID 25752254 .
  8. ↑ M. Mendel, M. Chłopecka, N. Dziekan, W. Karlik, M. Wiechetek: Participation of extracellular calcium in α-hederin-induced contractions of rat isolated stomach strips. In: Journal of Ethnopharmacology. Volume 146, number 1, March 2013, pp. 423-426, doi : 10.1016 / j.jep.2012.12.023 , PMID 23274745 .
  9. ↑ a b c A. Sieben, L. Prenner, T. Sorkalla, A. Wolf, D. Jakobs, F. Runkel, H. Häberlein: Alpha-hederin, but not hederacoside C and hederagenin from Hedera helix, affects the binding behavior , dynamics, and regulation of beta 2-adrenergic receptors. In: Biochemistry. Volume 48, Number 15, April 2009, pp. 3477-3482, doi : 10.1021 / bi802036b , PMID 19278262 .
  10. ^ A. Trute, J. Gross, E. Mutschler, A. Nahrstedt: In vitro antispasmodic compounds of the dry extract obtained from Hedera helix. In: Planta medica. Volume 63, Number 2, April 1997, pp. 125-129, doi : 10.1055 / s-2006-957627 , PMID 9140224 .
  11. ↑ A. Wolf, R. Gosens, H. Meurs, H. Häberlein: Pre-treatment with α-hederin increases β-adrenoceptor mediated relaxation of airway smooth muscle. In: Phytomedicine: international journal of phytotherapy and phytopharmacology. Volume 18, number 2-3, January 2011, pp. 214-218, doi : 10.1016 / j.phymed.2010.05.010 , PMID 20637581 .
  12. ↑ I. Gülçin, V. Mshvildadze, A. Gepdiremen, R. Elias: Antioxidant activity of saponins isolated from ivy: alpha-hederin, hederasaponin-C, hederacolchiside-E and hederacolchiside-F. In: Planta medica. Volume 70, Number 6, June 2004, pp. 561-563, PMID 15241892 .
  13. ^ TA Prescott, LP Rigby, NC Veitch, MS Simmonds: The haploinsufficiency profile of α-hederin suggests a caspofungin-like antifungal mode of action. In: Phytochemistry. Volume 101, May 2014, pp. 116-120, doi : 10.1016 / j.phytochem.2014.01.022 , PMID 24569176 .
  14. ↑ MA Randhawa, MS Alghamdi: Anticancer activity of Nigella sativa (black seed) - a review. In: The American Journal of Chinese Medicine. Volume 39, number 6, 2011, pp. 1075-1091, doi : 10.1142 / S0192415X1100941X , PMID 22083982 .
  15. ↑ JH Lorent, C. Léonard, M. Abouzi, F. Akabi, J. Quetin-Leclercq, MP Mingeot-Leclercq: α-Hederin Induces Apoptosis, Membrane Permeabilization and Morphologic Changes in Two Cancer Cell Lines Through a Cholesterol-Dependent Mechanism. In: Planta medica. Volume 82, Number 18, December 2016, pp. 1532-1539, doi : 10.1055 / s-0042-114780 , PMID 27574896 .
  16. ↑ F. Delmas, C. Di Giorgio, R. Elias, M. Gasquet, N. Azas, V. Mshvildadze, G. Dekanosidze, E. Kemertelidze, P. Timon-David: Antileishmanial activity of three saponins isolated from ivy, alpha -hederin, beta-hederin and hederacolchiside A1, as compared to their action on mammalian cells cultured in vitro. In: Planta medica. Volume 66, Number 4, May 2000, pp. 343-347, doi : 10.1055 / s-2000-8541 , PMID 10865451 .
  17. ↑ J. Schulte-Michels, A. Wolf, S. Aatz, K. Engelhard, A. Sieben, M. Martinez-Osuna, F. Häberlein, H. Häberlein: α-Hederin inhibits G protein-coupled receptor kinase 2-mediated phosphorylation of β2-adrenergic receptors. In: Phytomedicine: international journal of phytotherapy and phytopharmacology. Volume 23, number 1, January 2016, pp. 52-57, doi : 10.1016 / j.phymed.2015.12.001 , PMID 26902407 .
  18. ^ A b K. Wojciechowski, M. Orczyk, T. Gutberlet, T. Geue: Complexation of phospholipids and cholesterol by triterpenic saponins in bulk and in monolayers. In: Biochimica et Biophysica Acta. Volume 1858, number 2, February 2016, pp. 363-373, doi : 10.1016 / j.bbamem.2015.12.001 , PMID 26654784 .