Parthenolide structure

In 1959-61, a Czech group [8,9] reported the isolation of a new sesquiterpene lactone from Chrysanthemum (Tanacetum) parthenium as part of a study of the sesquiterpene lactones of the Compositae family. They named it parthenolide. The initial structure for parthenolide was later revised [10,11] and the accepted structure for parthenolide today is represented by structure (1). Parthenolide is a germacranolide-type sesquiterpene lactone. The crystal structure for parthenolide has also been reported [12]. Extractions of C. (T.) parthenium grown in Mexico, known locally as santamaria, did not yield parthenolide [13], but a closely related compound was isolated and named santamarine (3). This suggests that regional variations in the chemical constituents may occur. 

Parthenolide was only the first of many sesquiterpene lactones to be isolated from feverfew. Two further compounds were isolated and named chrysartemin A (4) and B (5) [14]. The structure of chrysartemin B was later revised [15], Recently, several studies have shown that chrysartemin A and B are not present in feverfew as the structures shown in (4) and (5) but are in fact the isomeric canin (19) and artecanin (20), respectively (see... 

Indeed, TCA (42) at a concentration of 10 Xg/mL, has been shown to elevate levels of ROS, as measured by flow cytometry. Consistent with earlier observations regarding structure-activity relationships, Me-TCA (44) showed 3-fold induction of ROS while dihydro-TCA (43) had no effect on the cellular levels of ROS.It is noteworthy that parthenolide (45), a sesquiterpene natural product structurally related to TCA, has previously been shown to increase the levels of ROS by glutathione depletion in hepatocellular carcinoma cell lines. In a separate study, parthenolide was able to inhibit DNA synthesis, cause cell cycle arrest, and induce apoptosis which are important mechanisms for controlling tumor growth. 

Michael-type addition of a suitable nucleophile, e.g. thiols, on to the a,f)-unsaturated lactone. Such alkylation reactions are believed to explain biological activity, and, indeed, activity is typically lost if either the double bond or the carbonyl group is chemically reduced. In some structures, additional electrophilic centres offer further scope for alkylation reactions. In parthenolide (Figure 5.31), an electrophilic epoxide group is also present, allowing transannular cyclization and generation of a... 

In addition to its importance for inflammatory responses, NF-kB also plays a role in the regulation of cell homeostasis and apoptosis [62-64] and it was thus straightforward to assume a link between the known cytotoxic activity of STLs and their NF-kB inhibitory activity [3], It was demonstrated that helenalin indeed induces apoptosis and that it does so via a CD95 death receptor independent pathway and requires the activation of caspases [43], Further STLs for which quite detailed studies on pro-apoptotic activity and mechanism exist are the germacronolides parthenolide and costunolide (structures 32 and 52 in Fig. (9)) [44, 45]. 

Perhaps the most prominent example with respect to anti-secretive effects of STLs is related to the well-known anti migraine activity of feverfew (Tanacetum parthenium, Asteraceae). The main STL from this plant is parthenolide (PAR), structure 1 in Fig. (15), and it has been shown that PAR is a potent inhibitor of serotonin (5HT)-release from thrombocytes. Although it is not finally clarified to which extent this effect is involved along with the numerous other reported activities of PAR in the clinically proven efficacy of feverfew [71, 72], it should at least contribute to the overall effect. 

Govindachari TR, Joshi BS, Kamat VN 1965 Structure of parthenolide. Tetrahedron 21 1509- 1519... 

---