Cynaropicrin is a sesquiterpene lactone of the guaianolide type found mainly in leaves of artichoke plants. It is one of the compounds that gives the artichoke its characteristic bitterness. It is found in artichoke leaves with an abundance of approximately 87 g/kg, but can hardly be found in other parts of the plant. Cynaropicrin makes up about 0.7% of leaf extracts of the artichoke. It exhibits a large diversity of bioactivities and shows properties such as anti-inflammatory, antifeedant and activation of bitter sensory receptors, but has not yet been used in medicine. Despite its pharmacologically beneficial properties, it can be toxic in higher doses. The compound has attracted attention in recent years as a potential anticancer drug.
History
The knowledge of the health benefits of the artichoke dates back to the 4th century B.C., but its use was not rediscovered until the 16th century. Research into the composition of the artichoke started in the first half of the 20th century. In the early 1950s, cynarin was isolated from the leaves and some years later cynaropicrin was discovered. Cynaropicrin was first isolated from the leaves of the Cynara scolymus L. (artichoke) in 1959 by a group of researchers of the Czechoslovak Academy of Sciences in Prague. It was found to be the main compound causing the bitter flavour of the artichoke. The researchers encountered difficulties in acquiring cynaropicrin in a crystalline form, which they later found to be caused by its ability to readily polymerize.
Structure and reactivity
Cynaropicrin has a 5-7-5 fused tricyclic skeleton and contains two hydroxyl groups on each side of the molecule, allowing it to form a homopolymer. Its γ-butyrolactone ring is involved in most of its biological functions. The unsaturated carbonyl group on the lactone ring allows for nucleophilic Michael addition. Cynaropicrin is soluble in water and has no violations of the rule of five.
Synthesis
Cynaropicrin is synthesized in the leaves of the artichoke plant and was found to accumulate in the trichomes. While the full mechanism of biosynthesis of cynaropicrin is unknown, it is proposed that biosynthesis starts with three isoprene C5-units, which are processed by the mevalonate pathway to form farnesyl pyrophosphate (FPP). With germacrene A and germacrene A acid as intermediates, FPP is converted into costunolide using two syntheses and a cytochrome P450 oxidase. Multiple yet unknown reactions occur to first form guaianolide and later cynaropicrin.
Mechanism of action
Cynaropicrin is shown to have various effects, and thus various mechanisms of action.
Anti-Hepatitis C virus
Cynaropicrin inhibits the entry of pan-genomic Hepatitis C virus into cells and inhibits cell-cell transmission.
Anti-hyperlipidemic
Cynaropicrin also shows anti-hyperlipidemic activity. The oxygen functional groups and the methylene of the GBL ring were found the help in anti-hyperlipidemic activity. Inhibition of gastric emptying also plays a minor role in this property.
Anti-tumor and cytotoxic activity
Cynaropicrin inhibits the activation of major adhesion molecules CD29 and CD98 involved in inflammation, but not CD43. This indicates that it might be a specific immunopharmacological effect. These adhesion molecules are essential factors in regulating the inflammatory process. It is linked to the inhibition of extracellular signal-related kinase (ERK).
Research shows that it had a pro-apoptotic activity on cancer cell lines U937, Eol-1 and Jurkat T cells. Its cytotoxic activity was inhibited by N-acetyl-L-cysteine and L-cysteine, reactive oxygen species and rottlerin (protein kinase Cδ inhibitor), indicating that PKCδ and ROS are important for its pro-apoptotic activity of cynaropicrin by proteolytic cleavage of PKCδ.
Transcription factor ‘Signal inducer and activator of transcription 3’ (STAT3) is continuously activated in cancer cells. It plays a critical role in the inhibition of apoptosis and induces chemoresistance. The α-β-unsaturated carbonyl moiety in cynaropicrin leads to a drop of intracellular GSH concentration via the Michael reaction. This inhibits the phosphorylation of STAT3 and increases the S-glutathionylation of STAT3 and therefore deactivating it. This leads to an increase in the expression of apoptotic genes.