Artemisinin: Wikis

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Artemisinin
Systematic (IUPAC) name
(3R,5aS,6R,8aS,9 R,12S,12aR)-
octahydro-3,6,9-trimethyl-3,12-
epoxy-12H-pyrano[4,3-j]-
1,2-benzodioxepin-10(3H)-one
Identifiers
CAS number 63968-64-9
ATC code P01BE01
PubChem 68827
ChemSpider 62060
Chemical data
Formula C 15H22O5  
Mol. mass 282.332 g/mol
SMILES eMolecules & PubChem
Synonyms Artemisinine, Qinghaosu
Physical data
Density 1.24 ± 0.1 g/cm³
Melt. point 152–157 °C (306–315 °F)
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes Oral

Artemisinin (pronounced /ɑːtə'misinən/) is a drug used to treat multi-drug resistant strains of falciparum malaria. The compound (a sesquiterpene lactone) is isolated from the plant Artemisia annua. Not all plants of this species contain artemisinin. Apparently it is only produced when the plant is subjected to certain conditions, most likely biotic or abiotic stress. It can be synthesized from artemisinic acid.[1] The drug is derived from a herb used in Chinese traditional medicine, though it is usually chemically modified and combined with other medications.

Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health Organization as there have been signs that malarial parasites are developing resistance to the drug. Combination therapies that include artemisinin are the preferred treatment for malaria and are both effective and well tolerated in patients. The drug is also being studied as a treatment for cancer.

Contents

History

Artemisia has been used by Chinese herbalists for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest record dates back to 200 BC, in the "Fifty-two Prescriptions" unearthed from the Mawangdui Han Dynasty Tombs. Its antimalarial application was first described in Zhouhou Beji Fang ("The Handbook of Prescriptions for Emergencies"), edited in the middle of the fourth century by Ge Hong. In the 1960s a research program was set up by the Chinese army to find an adequate treatment for malaria. In 1972, in the course of this research, Tu Youyou (Chinese: 屠呦呦)[2] discovered artemisinin in the leaves of Artemisia annua (annual wormwood). The drug is named Qinghaosu (Chinese: ) in Chinese. It was one of many candidates then tested by Chinese scientists from a list of nearly 200 traditional Chinese medicines for treating malaria. It was the only one that was effective, but it was found that it cleared malaria parasites from their bodies faster than any other drug in history. Artemisia annua is a common herb and has been found in many parts of the world, including along the Potomac River, in Washington, D.C.

Images of the original scientific papers are available online[3] and a book, Zhang Jianfang, "Late Report – Record of Project 523 and the Research and Development of Qinghaosu", Yangcheng Evening News Publisher 2007(張劍方. 遲到的報告五二三項目與青蒿素研發紀實. 羊城晚報出版社, 2007),[4] was published in 2006, which records the history of the discovery.

It remained largely unknown to the rest of the world for about ten years, until results were published in a Chinese medical journal. The report was met with skepticism at first, because the Chinese had made unsubstantiated claims about having found treatments for malaria before. In addition, the chemical structure of artemisinin, particularly the peroxide, appeared to be too unstable to be a viable drug.

Artemisinin derivatives

Because artemisinin itself has physical properties such as poor bioavailability that limit its effectiveness, semi-synthetic derivatives of artemisinin, including artemether and artesunate, have been developed.

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Chemically modified analogues

There are a number of derivatives and analogues within the artemisinin family:

There are also simplified analogs in preclinical research.[5]

Purely synthetic analogues

To counter the present shortage in leaves of Artemisia annua, researchers have been searching for a way to develop artemisinin artificially in the laboratory. A 2006 paper in Nature[6] presented a genetically engineered yeast that can synthesize a precursor called artemisinic acid which can be chemically converted to artemisinin. The compound called OZ-277 (also known as RBx11160), developed by Jonathan Vennerstrom at the University of Nebraska, has proved to be even more effective than the natural product in test-tube trials. A six month trial of the drug on human subjects in Thailand was started in January 2005. Jay Keasling, a professor of biochemical engineering at the University of California at Berkeley published in 2003 a paper in Nature Biotechnology that described how the scientists had discovered a pathway to create artemisinin in bacteria, by inserting genes from three organisms into E. coli, one of the world’s most common bacteria. That research helped Keasling secure a $42.6-million grant from the Bill and Melinda Gates Foundation. Keasling helped start a new company, Amyris Biotechnologies, to refine the raw organism, then figure out how to produce it more efficiently. Within a decade, Amyris had increased the amount of artemisinic acid that each cell could produce by a factor of one million, bringing down the cost of the drug from as much as ten dollars for a course of treatment to less than a dollar There are also plans to have the plant grow in other areas of the world outside Vietnam and China (Kenya, Tanzania, Madagascar).

Indications

Malaria

Artemisinins can be used alone, but this leads to a high rate of recrudescence (return of parasites) and other drugs are required to clear the body of all parasites and prevent recurrence. The World Health Organization is pressuring manufacturers to stop making the uncompounded drug available to the medical community at large, saying it would be a significant loss if the malaria parasite developed resistance to Artemisinin.[7]

The World Health Organisation has recommended that a switch to artemisinin combination therapies (ACT) be made in all countries where the malaria parasite has developed resistance to chloroquine. Artemisinin and its derivatives are now standard components of malaria treatment in China, Vietnam, and some other countries in Asia and Africa, where it has been proven to be a safe and effective anti-malarial treatment. Fixed-dose combinations are preferred as this guarantees that the partner drug is present to eradicate the last parasites while the artemisinin component removes the majority at the start of the treatment[8].

A large number of fixed-dose ACTs are now available containing an artemisinin component and a partner drug which has a long half-life, such as mefloquine (ASMQ), lumefantrine (Coartem), amodiaquine (ASAQ), piperaquine (Duo-Cotecxin) and antifolates (Ariplus). Most are made to GMP standard. A separate issue concerns the quality of some artemisinin-containing products being sold in Africa and South-East Asia[9][10].

Artemisinins are not used for malaria prophylaxis (prevention) because of the extremely short activity of the drug. To be effective, it would have to be administered multiple times each day.

Cancer treatment

Artemisinin is undergoing early research and testing for the treatment of cancer, primarily by researchers at the University of Washington.[11][12] Artemisinin has a peroxide lactone group in its structure. It is thought that when the peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species. It has been shown to reduce angiogenesis and the expression of vascular endothelial growth factor in some tissue cultures.

Resistance

A study published in 2008 by Noedl and colleagues in the New England Journal of Medicine suggests a consensus among researchers that artemisinin is losing its potency in Cambodia and increased efforts are required to prevent drug-resistant malaria from spreading across the globe.[13]. These findings were subsequently supported by a detailed study from Western Cambodia[14].

Adverse effects

Artemisinins are generally well tolerated at the doses used to treat malaria.[15] The side effects from the artemisinin class of medications are similar to the symptoms of malaria: nausea, vomiting, anorexia, and dizziness. Mild blood abnormalities have also been noted. One serious adverse effect is an allergic reaction.[16] One case of liver inflammation has been reported.[17] The drugs that are used in combination therapies can contribute to the adverse effects that are experienced by those undergoing treatment. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives tend to be higher.[18]

Mechanism of action

There is no consensus regarding the mechanism through which artemisinin derivatives kill the parasites. Their site of action within the parasite also remains controversial.

At the chemical level, one theory states that when the parasite that causes malaria infects a red blood cell, it consumes hemoglobin within its digestive vacuole, liberating free heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite leading to its death[19].

Numerous studies have investigated the type of damage that oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin.[20] These observations were supported by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin and inhibition of hemozoin formation by malaria parasites. Electron microscopic evidence linking artemisinin action to the parasite's digestive vacuole has been obtained showing that the digestive vacuole membrane suffers damage soon after parasites are exposed to artemisinin.[21]

Artemisinins have been reported to inhibit PfATP6, the parasite's SERCA-type enzyme (calcium transporter), expressed in Xenopus oocytes. In this isolated system, resistance to artemisinin is reported to be conferred by a single mutation in PfATP6[22]. A study from French Guiana in field isolates of malaria parasites identified an unrelated mutation in PfATP6 that was associated with resistance to artemether[23]. However this series of studies does not constitute convincing evidence that PfATP6 is a site of action of artemisinins, or that mutations in PfATP6 cause reduced artemisinin susceptibility. Robust evidence in this context can be obtained by a transfection study, and it is notable that data from such a study were presented at the Molecular Approaches to Malaria Conference (Lorne, Australia) in February, 2008 [24] yet remain unpublished. There is no evidence to suggest a role for PfATP6 in mediating the artemisinin resistance that appears to be emerging in Cambodia[13][14].

A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane.[25]

Dosing

The WHO approved adult dose of co-artemether (artemether-lumefantrine) for malaria is 4 tablets at 0, 8, 24, 36, 48 and 60 hours (six doses).[26][27] This has been proven to be superior to regimens based on amodiaquine.[28] Artemesinin is not soluble in water and therefore Artemisia annua tea was postulated not to contain pharmacologically significant amounts of artemesinin.[29] However, this conclusion was rebuked by several experts who stated that hot water (85 oC), and not boiling water, should be used to prepare the tea. Although Artemisia tea is not recommended as a substitute for the ACT (artemisinin combination therapies) more clinical studies on artemisia tea preparation have been suggested.[30]

Synthesis

In 2006 a team from Berkeley published an article claiming that they had engineered Saccharomyces cerevisiae yeast that can produce the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and turned into a drug that they claim will cost roughly 0.25 cents per dose. Details of the formation of artemisinic acid involves a mevalonate pathway, expression of amorphadiene synthase, a novel cytochrome P450 monooxygenase (CYP71AV1) and its redox partner from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.[31] Amyris Biotechnologies is collaborating with UC Berkeley and the Institute for One World Health to further develop this technology.[32]

Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 m and which produces 20 times more artemisinin than wild varieties. In northwestern Mozambique, ICRAF is working together with a medical organisation, Médecins sans frontières (MSF), ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea. Cultivation of this crop may well prove a valuable niche market for Africa, given the strong demand for the plant from pharmaceutical laboratories.

The biosynthesis of artemisinin is expected to involve the mevalonate pathway (MVA) and the cyclization of FDP (farnesyl diphosphate). Although it is not clear whether the DXP (deoxyxylulose phosphate)pathway can also contribute 5-carbon precursors (IPP or/and DMAPP), as occurs in other sesquiterpene biosynthetic system. 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 as the final precursor to artemisinin. Dihydroartemisinic acid then undergoes photoxidation to produce dihydroartemisinic acid hydroperoxide. Ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation furnish the biosynthesis of artemisinin.

Rxn2 1.png

Figure 1. Biosynthesis of Artemisinin.

The total synthesis of artemisinin can also be performed using basic organic reagents. In 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which as converted to methoxymethyl ether (3). The ether was hydroborated and then underwent oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which would be oxidized to (6). Next, the compound was protonated and treated with (E)-(3-iodo-1-methyl-1-propenyl)-trimethylsilane to give (7). This resulting ketone was reacted with lithium methoxy(trimethylsily)methylide to obtain two diastereomeric alcohols, (8a) and (8b). 8a was then debenzylated using (Li, NH3) to give lactone (9). The vinylsilane was then oxidized to ketone (10). The ketone was then reacted with fluoride ion that caused it to undergo desilylation, enol ether formation and carboxylic acid formation to give (11). An introduction of a hydroperoxide function at C(3) of 11 gives rise to (12). Finally, this underwent photooxygenation and then treated with acid to produce artemisinin.[33]

The Artemisinin Project

The Artemisinin Project is an program by Sanofi-Aventis, Amyris Biotechnologies, the Institute for OneWorld Health, and Jay Keasling, a researcher from the University of California, to combat malaria by producing artemisinin at low cost.[34] Naturally derived artemisinin is expensive and Keasling's proposal for its production by biotechnology is expected to reduce its price. With the help of the Gates Foundation, Keasling, OneWorld Health and Amyris developed a lab process for the production of artemisinin. Sanofi-Aventis was chosen to put the process into mass-production.

Legal Status

For many years, access to the purified drug and the plant it was extracted from were restricted by the Chinese government. It was not until the late 1970s and early 80s that news of the discovery reached scientists outside China. The World Health Organisation (WHO) tried to contact Chinese scientists and officials to find out more, but drew a blank. Dr Ying Lee, one of the scientists involved in the research into artemisinin, said the Chinese distrusted the West. The Chinese suspected the West just wanted to exploit the drug and sell it around the world slightly altered and repatented. The fact that there were several Americans on the WHO's steering board on malaria and that some were from the military did not help clear the distrust. It can be noted Americans had just invested a lot into mefloquine, an analogue of chloroquine.

References

  1. ^ Acton, N. & Roth, R.J. On the conversion of dihydroartemisinic acid into artemisinin. J. Org. Chem. 57, 3610-3614 (1992)
  2. ^ ChinaVitae: Tu Youyou
  3. ^ Qinghaosu Project
  4. ^ ycwb.com
  5. ^ Gary H. Posner; Michael H. Parker; Northrop, John; Elias, Jeffrey S.; Ploypradith, Poonsakdi; Xie, Suji; Shapiro, Theresa A. (1999). "Orally Active, Hydrolytically Stable, Semisynthetic, Antimalarial Trioxanes in the Artemisinin Family". J. Med. Chem. 42 (2): 300–304. doi:10.1021/jm980529v. PMID 9925735.  
  6. ^ Ro DK, Paradise EM et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature. (2006) 440: 940-943.
  7. ^ "WHO ultimatum on artemisinin monotherapy is showing results". British Medical Journal. http://www.bmj.com/cgi/content/full/332/7551/1176-b. Retrieved 2008-11-14.  
  8. ^ White NJ. Antimalarial drug resistance (2004) J Clin Invest 113: 1084-92
  9. ^ BBC news
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  11. ^ University of Washington: News
  12. ^ University of Washington: Artemisinin
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  16. ^ 1.Taylor WR, White NJ. Antimalarial drug toxicity: a review (2004) Drug Saf 27: 25-61. 2. Leonardi E, Gilvary G, White NJ, et al. Severe allergic reactions to oral artesunate: a report of two cases (2001) Trans R Soc Trop Med Hyg 95: 182-3
  17. ^ "Hepatitis Temporally Associated with an Herbal Supplement Containing Artemisinin --- Washington, 2008". CDC. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5831a3.htm.  
  18. ^ R. Price et al. (1999). "Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives". American Journal of Tropical Medicine and Hygiene 60 (4): 547–555. PMID 10348227. http://www.ajtmh.org/cgi/content/abstract/60/4/547.  
  19. ^ Cumming, Jared N.; Ploypradith, Poonsakdi; Gary H. Posner Antimalarial activity of artemisinin (qinghaosu) and related trioxanes: mechanism(s) of action. Advances in Pharmacology (San Diego) (1997), 37 253-297
  20. ^ Pandey et al.
  21. ^ del Pilar Crespo M, et al., Artemisinin and a series of novel endoperoxide antimalarials exert early effects on digestive vacuole morphology. Antimicrob Agents Chemother. 2008 Jan;52(1):98-109.
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  23. ^ Jambou R, Legrand E, Niang M, Khim N, Lim P, Volney B, et al. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6 (Dec 2005) Lancet 366(9501):1960-3
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  25. ^ Li et al., PLOS Genetics, September 2005, Volume 1, Issue 3
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  30. ^ Bioline
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  32. ^ Amyris Biotechnologies
  33. ^ G. Schmid, W. Hofheinz. "Total Synthesis of qinghaosu" J. Am. Chem. Soc.; 1983; 105 (3); 624-625
  34. ^ Steve Hamm (January 26, 2009). "'Crative Capitalism' versus Malaria". Business Week: 083.  

External links


The stereochemistry of the carbon bearing the peroxide and a methyl in the headline structure differs from that in the biosynthetic scheme. The stereochemistry in the biosynthetic scheme is the same as that for artemisinin in the Merck index (12th ed) and in a review by Ganesan (Curr Opinion in Chemical Biol 2008, 12, 306).


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