*2.4. Cynaropicrin*

Cynaropicrin (**4**) (Figure 5) is a guaianolide type sesquiterpene lactone with a chemical formula of C19H22O6 and a 5,7,5 fused tricyclic skeleton [112].

**Figure 5.** Structure of cynaropicrin (**4**).

The sesquiterpene lactone cynaropicrin was isolated from artichoke (*Cynara scolymus* L.) in 1960 for the first time [113] and later it was found in C*ynara cardunculus* L. [114,115] and *Cynara scolymus* L. species [116], being considered as a chemotaxonomic marker for artichoke plant species [112]. Cynaropicrin (**4**) was also found in many species of Asteraceae family such as *Centaurea drabifolia* subsp. *floccosa* (Boiss.) Wagenitz and Greuter [117], *Psephellus sibiricus* (L.) Wagenitz [118]*, Rhaponticum pulchrum* Fisch. and C.A.Mey. [119], *Moquinia kingii* (H.Rob.) Gamerro [120], *Saussurea calcicola* Nakai [121], *Saussurea costus* (Falc.) Lipsch. [122,123], *Tricholepis glaberrima* DC. [124], and many others [112]. Yields of cynaropicrin (**4**) extraction from *Cynara cardunculus* L. leaves using ethanol, ethyl acetate, dichloromethane and water were 56.9, 37.5, 40.3 and 13.6 mg/g dry weight, respectively [125].

The biological activities of cynaropicrin (**4**), as with other sesquiterpenic lactones, are related to its pharmacophore γ-butyrolactone ring [112]. There are many studies reporting on the important pharmacological activities of cynaropicrin (**4**), and plants rich in cynaropicrin (**4**), such as antitumor, anti-inflammatory, antitrypanosomal, and antihepatitis C virus, among many others. Due to these notable effects, cynaropicrin (**4**) will be suitable for the development of medicinal compounds [123].

Cynaropicrin (**4**) is the first natural product that in vivo potently inhibits the African trypanosome diseases [126]. Using the acute model of mice infected with *Trypanosoma brucei rhodesiense* STIB 900, when treated with two doses of 10 mg/kg (b.p.) per day, on the 7th day after infection, there was a 92% reduction in parasitemia when compared to the untreated group. Additionally, selectivity indices of 7.8 were obtained for cynaropicrin (**4**) against L6 cells of rat myoblasts [127]. The action mechanism is still under study to date, but is thought to be related to the interaction of compound **4** with the trypanothione redox system in *Trypanosoma brucei* [127]. However, Da Silva et al. [128] demonstrated that cynaropicrin (**4**) at a dose of up to 50 mg/kg (b.w.) per day has no effect in mice infected with *Trypanosoma cruzi*, in either Y or Colombiana strains. The synthesis and semi-synthesis of several cynaropicrin (**4**) derivatives allowed the structure/antitrypanosomal activity of these compounds to be evaluated. It was concluded that the α-methylene-γ-lactone structure is indispensable to maintain the biological effect, whereas 3-OH and 19-OH derivatization does not change the activity and some types of side-chain promote the selectivity of the compound [129,130]. The in vivo evaluation of some derivatives, using the *Trypanosoma brucei rhodesiense* acute mouse model, indicated that the dimethylamino derivative exhibits much less toxicity than cynaropicrin (**4**), but also less activity [129].

Cynaropicrin (**4**) also showed the ability in vivo to delay the effects of skin photoaging, promoting the proliferation of melanocytes and keratinocytes, by acting as inhibitor of NF-kB transcription activity [131].
