Artemisia annua and Artemisinin

Artemisia annua (Compositae/Asteraceae) is known as qinghao in Chinese traditional medicine, where it has been used for centuries in the treatment of fevers and malaria. The plant is sometimes called annual or sweet wormwood, and is quite widespread, being found in Europe, North and South America, as well as China. Artemisinin (qinghaosu) (Figure 5.34) was subsequently extracted and shown to be responsible for the antimalarial properties, being an effective blood schizontocide in humans infected with malaria, and showing virtually no toxicity. Malaria is caused by protozoa of the genus Plasmodium, especially P. falciparum, entering the blood system from the salivary glands of mosquitoes, and world-wide is responsible for 2-3 million deaths each year. Established antimalarial drugs such as chloroquine (see page 363) are proving less effective in the treatment of malaria due to the appearance of drug-resistant strains of P. falciparum. Artemisinin is currently effective against these drug-resistant strains.

" (Continued)

Artemisinin is a sesquiterpene lactone containing a rare peroxide linkage which appears essential for activity. Some plants of Artemisia annua have been found to produce as much as 1% artemisinin, but the yield is normally very much less, typically 0.05-0.2%. Apart from one or two low-yielding species, the compound has not been found in any other species of the genus Artemisia (about 400 species). Small amounts (about 0.01%) of the related peroxide structure artemisitene (Figure 5.35) are also present in A. annua, though this has a lower antimalarial activity. The most abundant sesquiterpenes in the plant are artemisinic acid (arteannuic acid, qinghao acid) (typically 0.2-0.8%) (Figure 5.34), and lesser amounts (0.1%) of arteannuin B (qinghaosu-II) (Figure 5.35). Fortunately, arteannuic acid may be converted chemically into artemisinin by a relatively simple and efficient process. Artemisinin may be reduced to the lactol (hemiacetal) dihydroartemisinin (Figure 5.35), and this has been used for the semi-synthesis of a range of analogues, of which the acetals artemether and arteether (Figure 5.35), and the water-soluble sodium salts of artelinic acid and artesunic acid (Figure 5.35), appear very promising antimalarial agents. These materials have increased activity compared with artemisinin and the chances of infection recurring are also reduced. Artemether has rapid action against chloroquinine-resistant P. falciparum malaria, and is currently being used as injection formulations. Arteether has similar activity. Being acetals, artemether and arteether are both extensively decomposed in acidic conditions, but are stable in alkali. The ester artesunic acid is also used in injection form, but is rather unstable in alkaline solution, hydrolysing to dihydroartemisinin. The ether artelinic acid is considerably more stable. These two compounds have a rapid action and particular application in the treatment of potentially fatal cerebral malaria. Dihydroartemisinin is a more active antimalarial than artemisinin and appears to be the main metabolite of these drugs in the body. They rapidly clear the blood of parasites, but do not have a prophylactic effect. Chemically, these agents are quite unlike any other class of current antimalarial agent, and when thoroughly evaluated, they may well become an important group of drugs in the fight against this life-threatening disease.

artemisinin

artemisitene

artemisinin

H OR

arteannuin B

artemisitene

arteannuin B

H OR

R = Me, artemether HO2C R = Et, arteether artelinic acid

artesunic acid yingzhaosu C

H OH dihydroartemisinin

H OH dihydroartemisinin

artesunic acid yingzhaosu C

yingzhaosu A

yingzhaosu A

" (Continued)

The relationship between a peroxide linkage and antimalarial activity is strengthened by the isolation of other sesquiterpene peroxides which have similar levels of activity as artemisinin. Thus, roots of the vine yingzhao (Artabotrys uncinatus; Annonaceae), which is also used as a traditional remedy for malaria, contain the bisabolyl derivatives yingzhaosu A and yingzhaosu C (Figure 5.35), the latter containing an aromatic ring of isoprenoid origin (compare the monoterpenes thymol and carvacrol, page 186). Artemisinin, and other peroxide-containing antimalarial agents, appear to complex with haemin, which is a soluble iron-porphyrin material released from haemoglobin as a result of proteolytic digestion by the malarial parasite. This material is toxic to Plasmodium, so is normally converted into an insoluble non-toxic form haemozoin (malarial pigment) by enzymic polymerization. Agents like chloroquine (see page 363) interfere with the polymerization process. Complexation of haemin with artemisinin by coordination of the peroxide bridge with the iron atom interrupts the detoxification process and leads to the generation of free radical species through homolytic cleavage of the peroxide. The resulting radicals ultimately damage proteins in Plasmodium.

in hops (Humulus lupulus; Cannabaceae), and P-caryophyllene is found in a number of plants, e.g. in the oils from cloves (Syzygium aromaticum; Myrtaceae) and cinnamon (Cinnamomum zeylan-icum; Lauraceae).

Gossypol* (Figure 5.37) is an interesting and unusual example of a dimeric sesquiterpene in which loss of hydrogen has led to an aromatic system (compare the phenolic monoterpenes thymol and carvacrol, page 186). This material is found in immature flower buds and seeds of the cotton plant (Gossypium species; Malvaceae), though originally isolated in small amounts from cottonseed oil. It can function as a male infertility agent, and is used in China as a male contraceptive. The cadinyl carbocation via 8-cadinene is involved in generating the basic aromatic sesquiterpene unit hemigossypol, and then dimerization is simply an example of phenolic oxidative coupling ortho to the phenol groups (Figure 5.37).

The formation of sesquiterpenes by a carboca-tion mechanism means that there is considerable scope for rearrangements of the Wagner -Meerwein type. So far, only occasional hydride migrations have been invoked in rationalizing the examples considered. Obviously, fundamental skeletal rearrangements will broaden the range of natural sesquiterpenes even further. That such processes do occur has been proven beyond doubt by appropriate labelling experiments, and humulyl cation humulyl cation

M<Th a caryophyllyl cation

M<Th a caryophyllyl cation

humulene humulene

ß-caryophyllene

ß-caryophyllene

cadinyl cation various oxidative

OH CHO

various oxidative

OH CHO

The Bonds Artimis
OH

cadinyl cation gossypol

Figure 5.37

gossypol

Figure 5.37

one-electron oxidation

radical coupling x 2

O CHO

O CHO

radical coupling x 2

OH

resonance forms of free radical

resonance forms of free radical

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