Parthenolide

DA = Damsinic acid HAD = hydrodamsinic acid PAR = parthenolide DAM = damsin. Values... 

Some studies have evaluated the quantity of a specific constituent in various herbal products by a thin-layer chromatography spectrophotometric method. Of 44 feverfew products that were evaluated, 14 (32%) did not contain the minimum of 0.2% parthenolide content (active ingredient) and 10 (22%) did not contain any detectable levels of parthenolide [30]. 

Heptinstall S, Awang DVS, Dawson BA, Kindack D, Knight DW, May J. Parthenolide content and bioactivity of feverfew (Tanacetum parthenium (1.) Schultz-Bip.). Estimation of commercial and authenticated feverfew products. J Pharm Pharmacol 44 391-395, 1992. 

The primary active chemical constituent in feverfew is parthenolide, a sesquiterpenoid lactone (figure 8.8) (Robbers et al. 1996). Levels of sesquiterpene lactones vary across different types of extracts ethanol extracts contain about 0.5%, whereas aqueous ones contain 0.3% (Gromek et al. 1991). The sesquiterpene lactones in feverfew inhibit the... 

Groenewegen WA, Heptinstall S. (1990). A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in-vitro. J Pharm Pharmacol. 

Weber JT, O Connor MF, Flayataka K, Colson N, Medora R, Russo EB, Parker KK. (1997b). Activity of Parthenolide at 5FIT2A receptors. J Nat Prod. 60(6) 651-53. 

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... 

An extract of T. parthenium is described in a patent [20] which, besides the known sesquiterpene lactones parthenolide (1) and chrysartemin A (4, see above), also contained previously unreported partholide (26) and chry-santhemolide (27), both of unknown stereochemistry. Further, dimers and trimers of the sesquiterpene nucleus such as chrysanthemonin (28) were said to be present in this extract which had not been reported before. 

There is little information on the stability of the sesquiterpene lactones. However, one report [21] states that a chloroform solution of parthenolide stored at room temperature was found to contain costunolide diepoxide (29) after a few days, probably formed by aerial oxidation. The literature also suggests that parthenolide can polymerize on prolonged storage [22]. 

There have been no reports on the chemical synthesis of parthenolide or indeed on the modification of the biological activity (see below) of parthenolide or the sesquiterpene lactones in general. However, routes for the synthesis of constunolide have been reported [23-25]. 

Sesquiterpene lactones are not exclusive to feverfew and most of the compounds extracted from the plant, including parthenolide [26], have also been... 

Parthenolide was found to be located in the glands on the surface of the leaves and seeds and was shown to have antimicrobial properties [33]. It was able to inhibit the growth of Gram-positive bacteria, yeast and filamentous... 

The ability of feverfew extract to inhibit 5HT-secretion in platelets was used to identify compounds responsible for the inhibitory effects on platelets [44], A crude feverfew extract was separated by chromatography and fractions were screened for antisecretory activity induced by adrenaline. In five active fractions compounds were identified as the sesquiterpene lactones parthenolide (1), canin (19), artecanin (20), secotanapartholide A (24) and 3 8-hydroxyparthenolide (2). The ability of parthenolide to affect platelet activity induced by other agents was confirmed in a study of direct comparison of crude feverfew extract with parthenolide [43], Parthenolide in the micromolar concentration range inhibited platelet 5HT-secretion. 

Agents that contain SH-groups such as cysteine or 2-mercaptopropionyl glycine were able to neutralize feverfew inhibitory activity on platelets [52]. Further, the same study demonstrated a dramatic reduction in the number of acid-soluble SH-groups, both by feverfew and parthenolide. These effects... 

There are only a few reports on the efficacy of feverfew in an in vivo situation. Inhibition of collagen-induced bronchoconstriction in an in vivo guinea-pig model was demonstrated [56] and it was concluded that this was consistent with in vivo phospholipase A2 inhibition. In a rat model of experimentally induced nephrocalcinosis, parthenolide was shown to protect the rats against this condition. Inhibition of prostaglandin biosynthesis may have been the mechanism of action of parthenolide in this case, as prostaglandins are thought to be involved in nephrocalcinosis [57]. 

As early as 1950, feverfew was reported to cause contact dermatitis in at least one patient [62] and parthenolide was found to cause an allergic reaction in patients with the same condition [63]. Since then there have been many reports [64-68] of feverfew-induced allergic reactions, the condition being worst in the summer months coinciding with the flowering season of the plant. The a-methylene butyrolactone group was found to be a partial requirement for activity in contact dermatitis [69]. 

The amount of parthenolide in capsules of the dried leaves given in two studies [5,60] measured as anti-secretory activity in platelets was estimated at 2-3 //mol by comparison with a known concentration of parthenolide. 

The capsules contained a mean of 82 mg feverfew and thus the level of activity calculated as parthenolide can be estimated as 0.67%. Other studies quote 0.87% sesquiterpene lactones calculated as parthenolide [27] and 0.25-0.30% of active (antimicrobial) material [33]. Bohlmann s extraction of individual components from the dried plant yielded 116 mg sesquiterpene lactones/kg dried feverfew which amounts to less than 0.01 % [17]. Another extraction yielded 330 mg endoperoxides/kg and 56 mg canin/kg alone [19] which would amount to a level of sesquiterpene lactones of at least 0.04%. Thus, the level of sesquiterpene lactones appears to vary with different sources of the plant and this could have been due to a number of factors including the conditions in which feverfew was grown, the season in which it was picked and the way in which it was stored. Another important determinant of the parthenolide content of feverfew appears to be the geographical location. A recent survey of commercial preparations found that all the North American commercial products tested contained less that 0.1% parthenolide, wheras much higher values were obtained for British products. A minimum level of 0.2% parthenolide in commercial products has been proposed by the Health Protection Branch of Health and Welfare Canada [71]. 

Quantitative analysis of feverfew with regards to sesquiterpene lactone content has been carried out by TLC [72,73] and HPLC [71,74,75] and H-NMR spectroscopy [75]. Measurements of parthenolide by HPLC correlated well with measurements by bioassays based on 5HT-secretion from platelets [75]. The availability of several techniques for quantitation of parthenolide levels in feverfew, makes some standardization of commercial preparations possible. 

The importance of NF-kB to inflammation, apoptosis resistance and tumour progression has resulted in the development of unique NF-kB inhibitors as part of cancer therapeutic regimens for GI and other cancers. Efforts are also being made to understand the efficacy of using natural substances obtained from plants, such as feverfew (e.g. parthenolide), bee glue (e.g. caffeic acid phenylethyl ester), tea (e.g. EGCG), spices (e.g. curcumin from turmeric) and mulberry figs (e.g. morin, a flavone) for the prevention both of persistent NF-kB activation and of the development of inflammatory pre-neoplastic lesions. 

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. 

Parthenolide inhibits serotonin release, an action that is thought to be a likely source of its effectiveness in migraine. Extracts have also been shown to reduce the production of prostaglandins (another possible mechanism) and leukotrienes. Interestingly, melatonin has been identified in feverfew, a possibly significant observation, since chronic migraines have been associated with low melatonin levels. 

Eupatorium formosanum L. Taiwan Pai Lan (whole plant) Sesquiterpine lactones, eupatolide, eupaformonin, eupaformosanin, michelenolide, costunolide, parthenolide, santamarine.33-501 Anticancer. 

Parthenolide Patchoulenone Patrinoside Patuletin Patulitrin Pectic acid Pectic compound Pectins... 

Tyrethrosin (X), an active component of extract from Chnfxtin Ihtmvm species, -was recently discussed by Barton and oo-workers, 0-as was the related substance parthenolide (XI) in another laboratory. 11... 

Khan, S.I., et al. 2003. Transport of parthenolide across human intestinal cells (Caco-2). Planta Med 69 1009. 

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... 

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