Feverfew is a traditional herbal remedy for the relief of arthritis, migraine, toothache, and menstrual difficulties. The plant is a perennial, strongly aromatic herb of the Compositae/Asteraceae family, and has been classified variously as Tanacetum parthenium, Chrysanthemum parthenium, Leucanthemum parthenium, or Pyrethrum parthenium, the former name being currently favoured. Studies have confirmed that feverfew is an effective prophylactic treatment in about 70% of migraine sufferers. It reduces the frequency of attacks, the vomiting associated with attacks, and the severity of attacks. The herb has been shown to inhibit blood platelet aggregation, the release of 5-hydroxytryptamine (serotonin) from platelets, the release of histamine from mast cells, and the production of prostaglandins, thromboxanes and leukotrienes. Of a range of sesquiterpene lactones of the germacrane and guianane groups characterized in the leaf material, the principal constituent and major active component is parthenolide (Figure 5.30) (up to about 1% in dried leaves). The powerful pungent odour of the plant arises from the volatile oil constituents, of which the monoterpene camphor (Figure 5.14) is a major constituent. Feverfew may be taken as the fresh leaf, often eaten with bread in the form of a sandwich to minimize the bitter taste, or it can be obtained
in dosage forms as tablets or capsules of the dried powdered leaf. The parthenolide content of dried leaf deteriorates on storage, and many commercial preparations of feverfew have been shown to contain little parthenolide, or to be well below the stated content. This may be a consequence of complexation with plant thiols via Michael addition. Consumers of fresh leaf can be troubled by sore mouth or mouth ulcers, caused by the sesquiterpenes. Parthenolide is also known to be capable of causing some allergic effects, e.g. contact dermatitis. The proposed mechanism of action of parthenolide via alkylation of thiol groups in proteins is shown in Figure 5.31.
various Artemisia species, e.g. wormseed (A. cinia; Compositae/Asteraceae), and has found considerable use for removal of roundworms, although potential toxicity limits its application. Structurally, a-santonin bears much similarity to parthenolide, and the most marked difference lies in the presence of the bicyclic decalin ring system. This basic skeleton, the eudesmane system, is formed from the germacryl cation by protonation and cyclization via the eudesmyl cation (Figure 5.27, route ii), whereas protonation at the more substituted end of a double bond (anti-Markovnikov addition, route i), could generate the guaiyl cation and guaiane skeleton. This latter skeleton is found in matricin (Figure 5.32), again from matricaria* flowers. This compound degrades on heating, presumably by elimination of acetic acid and water, and then decarboxylation to the azulene derivative chamazulene, responsible for the blue coloration of oil distilled from the flowers. Thapsigargin (Figure 5.29) from Thapsia garganica (Umbelliferae/Apiaceae) provides a further example of a guaianolide, esterified with a variety of acid groups. This compound is of considerable pharmacological interest as a tumour promoter, and as a potent activator of cells involved in the inflammatory response.
Another type of decalin-containing sesquiter-pene is seen in the structures of a-cadinene and amorpha-4,11-diene. a-Cadinene (Figure 5.33) is elimination of acetic acid and two molecules H2O; consider lactone as hydrolysed to hydroxyacid
chamazulene carboxylic acid chamazulene chamazulene
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