Tetra- and pentacyclic triterpene acids from the ancient anti-inflammatory remedy frankincense as inhibitors of microsomal prostaglandin E(2) synthase-1.
The microsomal prostaglandin E2 synthase (mPGES)-1 is the terminal enzyme in the biosynthesis of prostaglandin (PG)E2 from cyclooxygenase (COX)-derived PGH2. We previously found that mPGES-1 is inhibited by boswellic acids (IC50 = 3-30 μM), which are bioactive triterpene acids present in the anti-inflammatory remedy frankincense. Here we show that besides boswellic acids, additional known triterpene acids (i.e., tircuallic, lupeolic, and roburic acids) isolated from frankincense suppress mPGES-1 with increased potencies. In particular, 3α-acetoxy-8,24-dienetirucallic acid (6) and 3α-acetoxy-7,24-dienetirucallic acid (10) inhibited mPGES-1 activity in a cell-free assay with IC50 = 0.4 μM, each. Structure-activity relationship studies and docking simulations revealed concrete structure-related interactions with mPGES-1 and its cosubstrate glutathione. COX-1 and -2 were hardly affected by the triterpene acids (IC50 > 10 μM). Given the crucial role of mPGES-1 in inflammation and the abundance of highly active triterpene acids in frankincence extracts, our findings provide further evidence of the anti-inflammatory potential of frankincense preparations and reveal novel, potent bioactivities of tirucallic acids, roburic acids, and lupeolic acids.
Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen , Auf der Morgenstelle 8, D-72076 Tuebingen, Germany.
Moritz
M
Verhoff
Stefanie
S
Seitz
Michael
M
Paul
Stefan M
SM
Noha
Johann
J
Jauch
Daniela
D
Schuster
Oliver
O
Werz
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D029743:Boswellia / Q000737:chemistry*; D060126:Characidae; D051545:Cyclooxygenase 1 / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D015394:Molecular Structure; D053978:Pentacyclic Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011448:Prostaglandin Antagonists / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases; D012116:Resins, Plant / Q000737:chemistry; D013329:Structure-Activity Relationship; D013752:Tetracycline / Q000037:antagonists & inhibitors; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000094042:Lupanes
D000893:Anti-Inflammatory Agents; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D019746:Intramolecular Oxidoreductases; D016859:Lipoxygenase Inhibitors; D053978:Pentacyclic Triterpenes; D011448:Prostaglandin Antagonists; D000071876:Prostaglandin-E Synthases; D012116:Resins, Plant; D013752:Tetracycline; D014315:Triterpenes; C482140:lupeolic acid; D000094042:Lupanes; C054625:boswellic acid; C496540:PTGS2 protein, human; C000605862:PTGES protein, human