Abstract
Mint species are widely used in traditional and conventional medicine as topical analgesics for osteoarthritic pain and for disorders of the gastrointestinal and respiratory tracts which are all associated with chronic inflammation. To identify the structural determinants of anti-inflammatory activity and potency which are required for chemical optimization towards development of new anti-inflammatory drugs, a selected group of monoterpenes especially abundant in mint species was screened by measuring bacterial lipopolysacharide (LPS)-induced nitric oxide (NO) production in murine macrophages. Nine compounds significantly decreased LPS-induced NO production by more than 30%. IC50 values were calculated showing that the order of potency is: (S)-(+)-carvone > (R)-(−)-carvone > (+)-dihydrocarveol > (S)-8-hydroxycarvotanacetone > (R)-8-hydroxycarvotanacetone > (+)-dihydrocarvone > (−)-carveol > (−)-dihydrocarveol > (S)-(-)-pulegone. Considering the carbon numbering relative to the common precursor, limonene, the presence of an oxygenated group at C6 conjugated to a double bond at C1 and an isopropenyl group and S configuration at C4 are the major chemical features relevant for activity and potency. The most potent compound, (S)-(+)-carvone, significantly decreased the expression of NOS2 and IL-1β in macrophages and in a cell model of osteoarthritis using primary human chondrocytes. (S)-(+)-carvone may be efficient in halting inflammation-related diseases, like osteoarthritis.
Highlights
Mint species are widely used in traditional and conventional medicine as topical analgesics for osteoarthritic pain and for disorders of the gastrointestinal and respiratory tracts which are all associated with chronic inflammation
The purpose of this study was to assess, under standardized conditions, the anti-inflammatory activity of a selected group of monoterpenes belonging to the limonene synthase pathway that are abundant in mint species (Fig. 1a) and to compare the potency of the active ones by determining their half-maximal inhibitory www.nature.com/scientificreports concentrations (IC50)
To the best of our knowledge and among the nine active compounds, (S)-(+)-carvone (4), (+)-dihydrocarvone (7), (+)- (8) and (−)-dihydrocarveol (9), (S)-(−)-pulegone (13) and the carvone derivatives (20 and 21), were never reported to have anti-inflammatory effects, while carvone, either as the racemic mixture[31] or the (R)(−) enantiomer (5)[3,32,33] and (−)-carveol (6)[33], were recently reported to inhibit some effects correlated with inflammation
Summary
Mint species are widely used in traditional and conventional medicine as topical analgesics for osteoarthritic pain and for disorders of the gastrointestinal and respiratory tracts which are all associated with chronic inflammation. Among several chemical classes identified in mint essential oils, monoterpenes belonging to the limonene synthase pathway, such as menthol, menthone, pulegone and carvone, are especially abundant[8] Some components of this group of monoterpenes have been reported to possess anti-inflammatory activity[9] that may justify, at least in part, the beneficial effects attributed to mint species by traditional and conventional medicine[10,11]. Elucidating the SAR is essential to guide the chemical modification of these compounds, namely to lower their vapour pressure at room temperature, without compromising pharmacological activity and/or increasing toxicity, and to enable their progression towards new therapeutic agents[13] Such knowledge is essential to explain the different anti-inflammatory properties and potency of distinct mint chemotypes and their essential oils and can be used to predict the therapeutic potential of a given product based on its chemical composition. These data were correlated with structural features to identify chemical determinants of activity and potency useful to enable chemical optimization of the active compounds
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