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

In vitro screening of 17 Alpine lichen species for their inhibitory activity against 5-lipoxygenase, microsomal prostaglandin E 2 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 E 2 synthase-1 (IC 50 = 1.9 and 0.4 µM, resp.) and on 5-lipoxygenase tested in a cell-based assay (IC 50 = 5.3 and 1.8 µM, resp.) and on purified enzyme (IC 50 = 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 IC 50 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

IC₅₀ values of positive controls in mPGES-1, 5-LO and NF-κB assays (n=3).

<p>* n.d., not determined.</p

Perlatolic acid (<b>5</b>) inhibits leukocyte recruitment in thioglycollate-induced peritonitis mouse model.

<p>Box and whisker plots represent median, lowest and highest detected values (n=3; **p<0.001, *p<0.05; ANOVA/Tukey).</p

Schematic flow-chart of extraction and isolation (pure compounds encircled).

<p>Schematic flow-chart of extraction and isolation (pure compounds encircled).</p

IC₅₀ values of the isolated lichen compounds (1 - 11) in mPGES-1, 5-LO and NF-κB assays (n=3).

<p>* n.d., not determined; ** >10, significant inhibition at 10 µM; *** >>10, no significant inhibition at 10 µM.</p

Effect of lichen crude extracts on mPGES-1 (A), purified 5-LO enzyme (B), 5-LO in PMNL (C) and NF-κB (D); n=3-5.

<p>Effect of lichen crude extracts on mPGES-1 (A), purified 5-LO enzyme (B), 5-LO in PMNL (C) and NF-κB (D); n=3-5.</p