Imbricaric Acid and Perlatolic Acid: Multi-Targeting Anti-Inflammatory Depsides from Cetrelia monachorum

Sarah K. Oettl (1) , Jana Gerstmeier (2) , Shafaa Y. Khan (3) , Katja Wiechmann (2) , Julia Bauer (4) , Atanas G. Atanasov (5) , Clemens Malainer (5) , Ezzat M. Awad (3) , Pavel Uhrin (3) , Helke H. Heiss (5) , Birgit Waltenberger (1) , Daniel Remias (1) , Johannes M. Breuss (3) , Joël Boustie (6) , Verena M. Dirsch (5) , Hermann Stuppner (1) , Oliver Werz (2) , Judith M. Rollinger (1)

1 Leopold Franzens Universität Innsbruck - University of Innsbruck
2 Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany]
3 Medizinische Universität Wien = Medical University of Vienna
4 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
5 Department of Pharmacognosy
6 ISCR - Institut des Sciences Chimiques de Rennes

In vitro screening of 17 Alpine lichen species for their inhibitory activity against 5-lipoxygenase, microsomal prostaglandin E2 synthase-1 and nuclear factor kappa B revealed Cetrelia monachorum (Zahlbr.) W.L. Culb. & C.F. Culb. As conceivable source for novel anti-inflammatory compounds. 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 (4) and perlatolic acid (5) approved dual inhibitory activities on microsomal prostaglandin E2 synthase-1 (IC50 = 1.9 and 0.4 µM, resp.) and on 5-lipoxygenase tested in a cell-based assay (IC50 = 5.3 and 1.8 µM, resp.) and on purified enzyme (IC50 = 3.5 and 0.4 µM, resp.). Additionally, these two main constituents quantified in the extract with 15.22% (4) and 9.10% (5) showed significant inhibition of tumor necrosis factor alpha-induced nuclear factor kappa B activation in luciferase reporter cells with IC50 values of 2.0 and 7.0 µM, respectively. In a murine in vivo model of inflammation, 5 impaired the inflammatory, thioglycollate-induced recruitment of leukocytes to the peritoneum. The potent inhibitory effects on the three identified targets attest 4 and 5 a pronounced multi-target anti-inflammatory profile which warrants further investigation on their pharmacokinetics and in vivo efficacy.

Domaines: Chimie thérapeutique

Sarah K. Oettl, Jana Gerstmeier, Shafaa Y. Khan, Katja Wiechmann, Julia Bauer, et al.. Imbricaric Acid and Perlatolic Acid: Multi-Targeting Anti-Inflammatory Depsides from Cetrelia monachorum. PLoS ONE, 2013, 8 (10), pp.e76929. ⟨10.1371/journal.pone.0076929⟩. ⟨hal-00872763⟩