Tetra- and Pentacyclic Triterpene Acids from the Ancient Anti-inflammatory Remedy Frankincense as Inhibitors of Microsomal Prostaglandin E₂Synthase-1

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.

α-Pinene, linalool, and 1-octanol contribute to the topical anti-inflammatory and analgesic activities of frankincense by inhibiting COX-2

“…Boswellic acids are inhibitors of 5-lipoxygenase, but had little effect on COX-2 (Verhoff et al, 2014). As an important role in the inflammatory responses of inflammatory cells and tissues, COX-2 inhibition exerts potent anti-inflammatory and analgesic effects.…”

“…Boswellic acids in the resinous part are inhibitors of 5-lipoxygenase and thought to be responsible for anti-inflammatory activity (Verhoff et al, 2014); the gum portion may contribute to anti-oxidative effects (Batista et al, 2010); and the essential oil, a mixture of terpenes and sesquiterpenes or their derivatives, has anti-tumor (Singh et al, 2008) and antibacterial activities (Batista et al, 2010). More than three hundred volatiles have been identified in the essential oil, common compounds were α-pinene, 1-octanol, linalool, limonene, octyl acetate, α-thujene, and (E)-β-ocimene et al (Pan et al, 2015).…”

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

“…mPGES-1 as target of these NPs may provide a basis for their antiinflammatory properties and rationalize their use in folk medicine as remedy for treatment of inflammatory disorders. Among these plant-derived mPGES-1 inhibitors are prominent antiinflammatory and anti-tumoral compounds like the polyphenol curcumin from turmeric [86], epigallocatechin-3-gallate (EGCG) from green tea [87], the acylphloroglucinol hyperforin from St. John´s wort [66] and garcinol from Garcinia indica [88], triterpene acids from frankincense (e.g., tirucallic acids, lupeolic acids, boswellic acids,) [89,90], the diterpenoids carnosol and carnosic acid from Salvia officinalis [91], and the quinone embelin from Embelia ribes [92]. All of them inhibit mPGES-1 in cell-free assays in the submicromolar range (Table 1).…”

11-Keto-boswellic acid derived amides and monodesmosidic saponins induce apoptosis in breast and cervical cancers cells

“…One of these traditional remedies is olibanum. Olibanum (frankincense) is a resin obtained from trees of the genus Boswellia in the family Burseraceae and has been used in traditional remedies for decades [2]. This precious material has been traded on the Arabian peninsula for more than 5000 years, and it has been used in the traditional medicines of India, Africa, China but also in Western countries [3].…”

“…The resin contains different types of secondary metabolites, such as di-, sesqui-and triterpenes but also essential oils [2,15]. Among all of these, triterpenoids [16] are the most abundant, and many studies have shown among other effects the cytotoxic and antitumor properties of triterpenoids from frankincense.…”