Planta Med 2013; 79 - WS8
DOI: 10.1055/s-0033-1351810

Anti-inflammatory depsides from Cetrelia monachorum potently targeting mPGES-1, 5-LO and NF-κB

SK Oettl 1, J Gerstmeier 2, K Wiechmann 2, J Bauer 3, AG Atanasov 4, EH Heiss 4, B Waltenberger 1, J Boustie 5, V Dirsch 4, H Stuppner 1, O Werz 2, JM Rollinger 1
  • 1Leopold Franzens University of Innsbruck, Institute of Pharmacy/Pharmacognosy, 6020 Innsbruck, Austria
  • 2Friedrich Schiller University of Jena, Chair of Pharmaceutical/Medicinal Chemistry, 07743 Jena, Germany
  • 3University Tuebingen, Department of Pharmaceutical Analytics, 72076 Tuebingen, Germany
  • 4University of Vienna, Department of Pharmacognosy, 1090 Vienna, Austria
  • 5University of Rennes 1, Institute of Chemical Sciences of Rennes, UMR 6226, Team PNSCM, 35043 Rennes, France

Lichens, often underestimated and still underexplored with respect to pharmaceutical lead discovery, provide a vast diversity of small chemical entities with a variety of reported bioactivities. Based on a previously performed pharmacophore-based virtual screening, we identified lichen constituents as potent microsomal prostaglandine E2 synthase 1 (mPGES-1) inhibitors [1]. Here, we focused on further in vitro anti-inflammatory activities of lichen compounds. An in vitro screening of 17 Alpine lichen species for inhibition of 5-LO, mPGES-1 and NF-κB revealed Cetrelia monachorum (Zahlbr.) W.L. Culb. & C.F. Culb. as promising source for novel anti-inflammatory leads. Phytochemical investigation of the ethanolic crude extract resulted in the isolation and identification of 11 constituents, belonging to depsides and derivatives of orsellinic acid, olivetolic acid and olivetol. The two depsides imbricaric acid and perlatolic acid exerted inhibitory activities on mPGES-1 (IC50 1.9 and 0.4µM, resp) and 5-LO as demonstrated in a cell-based assay (IC50 5.3 and 1.8µM, resp) and on the purified enzyme (IC50 3.5 and 0.4µM, resp). Dual inhibition of mPGES-1 and 5-LO provides safer and more effective anti-inflammatory properties [2]. Furthermore, the two main constituents, imbricaric acid and perlatolic acid, quantified in the extract with a content of 15.22% and 9.10%, resp, showed significant inhibition of TNF-α-induced NF-κB activation in luciferase reporter cells with IC50 values of 2.0 and 7.0µM, resp. These findings attest imbricaric acid and perlatolic acid a pronounced threefold anti-inflammatory profile [3], which warrants further investigation on their pharmacokinetics and in vivo efficacy.

Acknowledgements: Supported by the Austrian Science Fund (S10703, S10704).

References:

[1] Bauer J et al. ChemMedChem 2012 7: 2077 – 81.

[2] Radmark O, Samuelsson B J Intern Med 2010 268: 5 – 14.

[3] Oettl SK et al. 2013 submitted.