Triterpene Acids from Frankincense and Semi-Synthetic Derivatives That Inhibit 5-Lipoxygenase and Cathepsin G

Abstract

Age-related diseases, such as osteoarthritis, Alzheimer’s disease, diabetes, and cardiovascular disease, are often associated with chronic unresolved inflammation. Neutrophils play central roles in this process by releasing tissue-degenerative proteases, such as cathepsin G, as well as pro-inflammatory leukotrienes produced by the 5-lipoxygenase (5-LO) pathway. Boswellic acids (BAs) are pentacyclic triterpene acids contained in the gum resin of the anti-inflammatory remedy frankincense that target cathepsin G and 5-LO in neutrophils, and might thus represent suitable leads for intervention with age-associated diseases that have a chronic inflammatory component. Here, we investigated whether, in addition to BAs, other triterpene acids from frankincense interfere with 5-LO and cathepsin G. We provide a comprehensive analysis of 17 natural tetra- or pentacyclic triterpene acids for suppression of 5-LO product synthesis in human neutrophils. These triterpene acids were also investigated for their direct interference with 5-LO and cathepsin G in cell-free assays. Furthermore, our studies were expanded to 10 semi-synthetic BA derivatives. Our data reveal that besides BAs, several tetra- and pentacyclic triterpene acids are effective or even superior inhibitors of 5-LO product formation in human neutrophils, and in parallel, inhibit cathepsin G. Their beneficial target profile may qualify triterpene acids as anti-inflammatory natural products and pharmacological leads for intervention with diseases related to aging.

Pentacyclic triterpene acids: use, mode of action, Biological activity and synthesis

“…Oleanolic and ursolic acids have been identified in almond hulls. Frankincense [7] is a traditional Ayurvedic medicine that has experienced increasing popularity also in Western countries during the past decades, it is a natural and rich source for a variety of pentacyclic triterpene acids which reaching 14 to 25% (w/w). Many triterpene acids with pentacyclic ursane, oleanane, and lupine scaffolds or tetracyclic tirucallane scaffolds have been isolated and characterized from the genus Boswellia.…”

“…The functionalities at carbons C3 and C28 of the lupane skeleton seem to be important for this activity of the triterpenes. [7] Thus, the quantitative determination of PTAs is also very important in the scope of food analysis. [22] Oleanolic acid 2 and ursolic acid 3 are used for wound healing properties [19] and in the treatment of various gastrointestinal disorders such as gastric and intestinal ulcers, antinociceptive properties when administered orally to rats antiviral effect on certain herpes virus strains.…”

“…In addition to boswellic acids (BAs), Koeberle et al [7] demonstrated that other triterpene acids are effective or even superior inhibitors of 5-lipoxygenase (5-LO) product formation in human neutrophils, and in parallel, inhibit cathepsin G. Their beneficial target profile may qualify triterpene acids as antiinflammatory natural products and pharmacological leads for intervention with diseases related to aging. Indeed, PTAs proved to be bactericides [8] both against Gram-positive and Gram-negative bacterial strains, and what should be here underlined, in some cases they were also active against bacterial strains exhibiting multidrug resistance.…”

“…PTAs [7] have been demonstrated to possess potent, non-redox and specific inhibitory action on 5lipoxygenase (5-LO) activity and leukotriene B, (LTB,) formation from endogenous arachidonic acid (AA) in rat peritoneal neutrophils. In view of its potency and selectivity, betulinic acid (1) can be considered to be a non-steroidal anti-inflammatory drug (NSAID) of the 5-lipoxygenase pathways.…”

“…[6] A few compounds like corosolic acid (Scheme 1) (dietary supplement against diabetes) are already on the market and several others are under clinical trials or ready to be launched on the market. [5] In folk medicine, lipophilic frankincense extracts [7] in which the major content is PTAs are used as alternative to anti-inflammatory steroidal drugs (i.e., glucocorticoids) or NSAIDs for treatment of inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, asthma, atopic dermatitis, and inflammatory bowel diseases.…”