Sesquiterpene endoperoxide

The isolation and structural determination of the naturally occurring potent antimalar-ial sesquiterpene endoperoxides, artemisinin (qinghaosu) (6)28-31.439 recogni-... 

Artemisinin (Fig. 10.1) is a highly phytotoxic sesquiterpene endoperoxide,12 found only in the glandular trichomes of Artemisia annua,11 Duke et a/.13 first tested it for phytotoxicity because of its high level of activity against malarial parasites (Plasmodium spp).23 Others later verified that it is strongly phytotoxic.3,4,30 These studies showed little more than that the compound is highly phytotoxic. Chen and... 

Artemisia annua is one of the most important Asteraceae species as antimalarial plant. There are many reports of microbial biotransformation of artemisinin (283), which is active antimalarial rearranged cadinane sesquiterpene endoperoxide, and its derivatives to give novel antimalarials with increased activities or differing pharmacological characteristics. 

Artemisinin affects root growth and chlorophyll content, and is accompanied with a reduction of mitosis [22]. Abnormal multipolar configurations indicate that this sesquiterpene disrupts the formation of microtubule-organizing centers. However, it is not likely that inhibition of mitosis is the sole mechanism of action of sesquiterpene endoperoxide lactones. 

A few examples of the intermolecular reductive process have been reported in natural product synthesis. A total synthesis of the antimalarial drug (+)-artemismin, a sesquiterpene endoperoxide, was achieved via an intermolecular reductive radical reaction (Scheme 25.20)." lodolactone 44 was treated with methyl vinyl ketone (MVK) using TTMSS as a chain carrier and reductive reagent to provide... 

Antimalarial drug artemisinine, sesquiterpenic 8-lactone with 1,2,5-trioxane (endoperoxide) fragment 98CSR273. 

Endoperoxides of carbocyclic 1,3-dienes are most often transformed into either 1,4-diols, 1,3-diepoxides or 1,4-hydroxyenones. The 1,4-diol formation is illustrated in the synthesis of the sesquiterpene ( )-cybullol (6.8)614). 

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]. 

Artemisinin ( qinghaosu ) (18), a sesquiterpene lactone antimalarial compound with an endoperoxide group, discovered in the Peoples Republic of China as a constituent of Artemisia annua L., has created great interest in the biomedical community, owing to its unique mechanism of action on the heme complex. Artemisinin serves as an option for the treatment of chloroquine (4l)-resistant malaria and is used in some Asian countries as an antimalarial. However, the use of artemisinin as a single agent anti-malarial is a potential risk since the malaria parasite may become resistant to this compound class. 

Artemisinin is a natural endoperoxide-containing sesquiterpene, isolated from a plant used in traditional Chinese medicine. Acetalic artemisinin derivatives (arte-mether, artesunate) are very active against chemo-resistant forms of Plasmodium falciparum, and are clinically used for the treatment. However, they suffer from an unfavourable pharmacological profile. They are quickly metabolised by fast oxidative metabolism, hydrolytic cleavage and glucuronidation. 

Artemisinins (artesunate, artemether,1 dihydroartemisinin1) Sesquiterpene lactone endoperoxides Treatment of P falciparum infections oral combination therapies for uncomplicated disease intravenous artesunate for severe disease... 

Artemisinins1 Sesquiterpene lactone endoperoxides Treatment of infection with multidrug-resistant P falciparum... 

Artemisinin (23), isolated from a Chinese medicinal plant, annual wormwood Artemisia annua L.), is a unique sesquiterpene lactone bearing an endoperoxide moiety. This compound displays a strong antimalarial activity and inhibits seed germination and plant growth.11... 

Figure 3.8 Artemisinin and related endoperoxide-containing sesquiterpenes structures of artemisinin and related congeners (dihydroartemisinin and arte-mether), the fluorescent artemisinin probe used to identify the targeting of SERCA, and two putative radical intermediates that are formed upon reaction with haem and a haem adduct.

Acton, N. Klayman, D. L. Artemisitene, a new sesquiterpene lactone endoperoxide from Artemisia annua. Planta Med., 1985, 5 441-442. 

Sy, L. K. Brown, G. D. Haynes, R. A novel endoperoxide and related sesquiterpenes from Artemisia annua which are possibly derived from aUylic hydroperoxides. Tetrahedron, 1998, 54(17) 4345 356. 

ABSTRACT Marine invertebrates such as ascidians, sponges and others are a prolific source of bioactive secondary metabolites. We have isolated a variety of marine natural products from the Okinawan marine invertebrates by using the sea urchin egg assay. Our recent work, the isolation, structure determination and activities of chlorinated macrolides, sesterterpenic acids, a bromotyrosine derivative, acetogenin derived endoperoxides, diterpene alkaloids, sesquiterpene quinones and spiro-sesquiterpenes, is presented in this article. The syntheses of these metabolites are also described. 

Artemisinin (Fig. 1), isolated in 1972 from Chinese medicinal plant Artemisia annua L, is a novel antimalarial drug with a sesquiterpene lactone structure containing an internal endoperoxide linkage which is essential for the drug s activity. Artemisinin and its derivatitives form a series of antimalarial compounds with activity against chloroquine-resistant malaria parasites. In contrast to chloroquine, artemisinin penetrates the blood brain barrier, which makes it especially valuable for the treatment of cerebral malaria. ... 

Two major breakthroughs of the past few decades have renewed the assault of scientists to this infective disease. The first is the complete sequencing of the genome of Plasmodium falciparum [4] that is expected to provide useful information for the identification of new drug targets. The second is the discovery by Chinese researchers of artemisinin (qinghaosu), an endoperoxide sesquiterpene lactone, as the active principle of the sweet wormwood, Artemisia annua, an herbal remedy used in folk Chinese medicine for 2000 years [5]. This molecule and its... 

Artemisinin (44) is a structurally complex cadinane sesquiterpene lactone bearing an endoperoxide group embedded in a 1,2,4-trioxane ring. With its unique juxtaposition of peracetal, acetal and lactone functionalities, it has very much to interest organic chemists. Totally synthetic routes to artemisinin have been developed [64], but their complexity suggests that they will very unlikely supplant the natural extract as drug source. 

The antiprotozoal potential of sesquiterpenes is well established since artemisinin (39) and a second endoperoxide sesquiterpene yinghaosu A, were identified as new drugs with high clinical relevance. In addition to artemisinin and other sequiterpene endoperoxides,... 

Malaria remains a parasitic scourge that is still extending in incidenoe. In 1972, the aotive principle from Artemisia annua, a plant used for centuries in Chinese traditional medioine to treat fevers and malaria, was established as a novel antimalarial ohemotype. This oompound, artemisinin ( qinghaosu in Chinese), is a sesquiterpene lactone with an endoperoxide group that is essential for activity, and it reacts with the iron in heme in the malarial parasite, Plasmodium falciparum (Fig. 1.3). Beoause this compound is poorly soluble in water, a number... 

---