IUPAC Name
3,12-Epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one, octahydro-3,6,9-trimethyl-, (3R,5aS,6R,8aS,9R,12S,12aR)-
Other Names
(+)-Arteannuin; (+)-Artemisinin; (+)-Qinghaosu; Arteannuin; Artemef; Artemisine; Artemisinin; Artemisinine; Huanghuahaosu; NSC 369397; QHS; Qing Hau Sau; Qing Hau Su; Qinghaosu; Qinghosu
CAS Number 693968-64-9
Physical Data
Density: 1.24 g/ml
Melt. point: 152 - 157°C
Introduction
Artemisinin is a sequiterpene lactone endoperoxide isolated from the glandular secretory trichomes (GSTs) of Artenisia annua. Besides being a well-unkown anti-malarial drug, it has also been shown to be effective against other infections diseases including schistosomiasis and hepatitis B. Most recently, it has also been shown to be effective against numerous types of tumors.[1] Artemisinin is known as "qinghao" in Chinese traditional medicine. As early as 168 BC, ancient Chinese scrpts reported the use of Artenisia annua, for treatment of diseases. In the early 1970's, artemisinin was isolated in pure form from the shoots of A. annua (annual or sweet wormwood) plants and its structure was determined in 1979.[2]
Artemisinin is currently the best therapeutic against both drug-resistant and cerebral malaria causing by protozoa of the genus Plasmodium, especially P. falciparum, entering the blood system from the salivary glands of mosquitoes. Malaria is responsible for 2 - 3 million deaths each year. Artemisinin was shown to be an effective blood schizotocide in humans infected with malaria, and showing virtually no toxicity, even for pregnant women.[3]
Artemisinin is in short supply, as its complex structure requires that it to be extracted from plants. Artemisinin has been reported to accumulate in the shoots and seeds with highest levels in leaves and flowers. Neither artemisinin nor its precursors were detected in roots. Its content in flowers is 4-5 times higher than in leaves. Artemisinin concentration in A. annua is low, in the range of 0.01 - 0.8%.[4] Although chemical synthesis is possible, it is complicated and economically not viable due to low yields. The most abundant sequiterpenes in the plat are artemisinic acid (0.2 - 0.8%) and lesser amounts (0.1%) of arteannuin B. Fortunately, artemisinin acid may be converted chemically into artemisinin by a relatively simple and efficient process.[4]
Figure 1. The most natural abundant sesquiterpenes in the plant
Mechanism of Action
The mode of action of artemisinin is still under investigation. Iron-dependent active oxygen-mediated effects and mitochondrial membrane depolarization have been suggested. The evidence is emerging for PfATP6, a sarco-endoplasmic reticulum Ca2+ - ATPase of the P. falciparum parasite.[ef] It has also been suggested the heme-mediated decomposition of the endoperoxide bridge to produce carbon-centered free radicals. The resulting carbon-centered free radicals alkylate heme and proteins, which controlls tumor protein.
Biosythesis
The biosynthesis of artemisinin is expected to involve the mevalonate pathway (MVA) and the cyclization of FDP (farnesyl diphosphate). Althought it is not clear whether the DXP (deoxyxylulose phosphate)pathway can also contribut 5-carbon precurosrs (IPP or/and DMAPP), as occurs in other sesquiterpene biosynthetic system. It is believed that in plants the mevalonate pathway is located in the cytosol, while DXP (mevalonate independent pathway) is localized to plastides. Adam and Zapp also suggested the crosstalk between cytosol and plastides and a possible exchange of IPP between the two pathways.
Figure 2. Simplified biosythentic pathway of artemisinin
Figure 3. Biosynthesis of artemisinin
The formation of amorpha-4,11-diene 3 is catalyzed by amorpha 4,11-diene synthase (ADS) from the sequiterpene skeleton farnesy diphosphate (FPP), which followed by oxidation reaction to form artemisinic alcohol 4 in the presence of NADPH. The routes from artemisinic alcohol to artemisinin remain controversial and they differ mainly in when the reduction step takes place. Both routes suggested dihydroartemisinic acid 9 as the precusor to artemisinin. Dihydroartemisinic acid then undergoes photoxidation to produce dihydroartemisinic acid hydroperoxide. Ring expansion by the cleavage of hydroeroxide and a second oxygen-mediated hydroperoxidation furnish the biosynthesis of artemisinin.
References:
1. Wobbe, K. K., Elkholy, S., Weathers, P.J., Artemisinin: the biosynthetic pathway and its regulation in A. Annua, a terpenoid-rich speicies, Plant, 2006, 42, 309-317
2. Covello, P.S. et al., Funtional genomics and the biosynthesis of artemisinin, Phytochemistry, 2007, 68, 1864-1871
3. Dewick, Paul M, Medicinal Natural Products, 2nd Ed, John Wiley & Son, 2001, 198-200
4. Kim, Soo-Un et al., Cyclization Mechanism of Amorpha-4,11-diene synthase, a key enzyme in artemisinin biosynthesis, J. Nat. Prod. 2006, 69, 758-762
5. Jain, S.K. et al, Enzymatic synthesis of artemisinin from natural and synthetic precusors, J. Nat. Prod., 1998, 61, 633-636
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