Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / isolation & purification
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Anti-Inflammatory Agents / pharmacology*
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Boswellia / chemistry*
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Characidae
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Cyclooxygenase 1 / drug effects
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Cyclooxygenase 2 / drug effects
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / isolation & purification
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Cyclooxygenase Inhibitors / pharmacology*
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Dinoprostone / antagonists & inhibitors
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Humans
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Inhibitory Concentration 50
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Intramolecular Oxidoreductases / antagonists & inhibitors*
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Intramolecular Oxidoreductases / metabolism*
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Lipoxygenase Inhibitors / pharmacology
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Molecular Structure
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Pentacyclic Triterpenes / chemistry
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Pentacyclic Triterpenes / isolation & purification
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Pentacyclic Triterpenes / pharmacology*
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Prostaglandin Antagonists / chemistry
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Prostaglandin Antagonists / isolation & purification
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Prostaglandin Antagonists / pharmacology
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Prostaglandin-E Synthases
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Resins, Plant / chemistry
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Structure-Activity Relationship
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Tetracycline / antagonists & inhibitors
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Triterpenes / chemistry
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Triterpenes / isolation & purification
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Triterpenes / pharmacology*
Substances
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Anti-Inflammatory Agents
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Cyclooxygenase Inhibitors
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Lipoxygenase Inhibitors
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Pentacyclic Triterpenes
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Prostaglandin Antagonists
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Resins, Plant
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Triterpenes
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lupeolic acid
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boswellic acid
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Cyclooxygenase 1
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Cyclooxygenase 2
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PTGS2 protein, human
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Intramolecular Oxidoreductases
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PTGES protein, human
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Prostaglandin-E Synthases
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Tetracycline
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Dinoprostone