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Artemisinin

Page history last edited by PBworks 14 years ago

 

Artemisinin is a natural product that can be isolated in the leaves of wormwood. Artemisinin is primarily used as a drug to fight against falciarum malaria but current research has tested its viability for cancer treatment. The drug can be extracted from Artemisia annua under certain conditions or can be synthesized from artemisinic acid. The structure of Artemisia contains a sesquiterpene endoperoxide lactone. 1

 

History

The first actual account of Artemisinin antimalaria potential was recorded around the fourth century in Zhouhou Beji Fang ("The Handbook of Prescriptions for Emergencies"). However, it was not fully appreciated until 1960 when the Chinese military screened hundreds of drugs to find one that would help their soldiers fight malaria. 1

 

 

Today, artemisinin is modified to combat against the ever evolving malaria parasite. This modification also includes ways to improve its poor bioavailability. The drug is used predominately in China, Vietnam and other Asian and African countries. 1

 

 

Structure and General Info

 

 

IUPAC (3R,5aS,6R,8aS,9R,12S,12aR)-octahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano(4,3-j)-1,2-benzodioxepin-10(3H)-one
Structure C15H22O5
CAS # 63968-64-9
Mol. Mass 282.33 g/mol
Density 1.24 ± 0.1 g/cm³
Melting Point 151-154 °C

 

Artemisinin can be seen above. The most prominent characteristic is the peroxide and the lactone function groups.

 

Mechanism of action

Current research is still being done to find the specific mechanism of action of artemisinin. One idea involves the parasite infecting red blood cells which causes the release of heme groups that contain iron complexes. The iron then reduces the peroxide in artemisinin, which produces oxygen radicals that can damage and kill the parasite.1

 

Although it is clear that radical oxygens are created, how and where the oxygen radicals attack the malaria parasite is still under debate. One theory suggests that the radical oxygens effect the electron transport chain, which causes the destruction of the mitochondrial membrane.2 Other observations have pointed at the inhibition of the parasite's digestive vacuole cysteine protease activity.3

 

Another theory suggests that artemisinins effects the calcium transporter PfATP6. Non mutated parasites are easily inhibited by artemether (a derivative to artemisinin) but a single point mutation in PfATP6 leads to resistance.4

 

Synthesis

The cost to extract artemisinin is costly which is not viable for underdeveloped countries. The average cost to extract artemisinin from wormwood trees and turn them into a drug costs $2.40 per dose.5

 

 

Biosynthesis from Microbes

However, in 2006 a team from Berkely has published an article claiming that they have engineered saccharomyces cerevisiae microbes 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. 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. 5

 

The synthesis of artemisinin is shown below in three parts: the formation of IPP and DMAPP, the formation of E,Z-FPP and finally the formation of Artemisinin.

 

 

 

 

Total Synthesis

In 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which is then converted to methoxymethyl ether (3). The ether is hydroborated and then undergoes oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which then is 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.6

 

 

Clinical Use

Numerous drug derivatives of Artemisinin are availabe to treat malaria. The uptake of these drugs can range from oral, rectal, intramuscular, or intravenous. Also, these derivatives can be made water soluble or lipid soluble.

 

A notable water soluble derivative is Artesunate. Since the drug is water soluble it can be injected intravenously in amounts of:

2.4 mg/kg loading dose over 5 minutes

1.2 mg/kg dose 12 hours later

1.2 mg/kg once daily after that

 

Artesunate is normally taken with another antimalaria drug to avoid the possibility of resistance. The drug works by destroying the egg production in Schistosoma haematobium infection.7

 

A notable lipid soluble derivative is Artemether. Since this form is lipid soluble it cannot be used intravenously but can be taken up orally, rectally and intramuscularly. A normal oral dosage of co-artemether consist of taking 4 tables at 0, 8, 24, 36,48 and 60 hours.8

 

References

 

 

1C J Woodrow, R K Haynes and S Krishna. "Artemisinins" Postgraduate Medical Journal 2005; 81:71-78

 

 

2C J Woodrow, R K Haynes and S Krishna. "Li et al.", PLOS Genetics, September 2005, Volume 1, Issue 3

 

 

3Pandey, Tekwani, Singh, Chauhan. "Malaria Research" International Centre for Genetic Engineering and Biotechnology

 

 

4C J Woodrow, R K Haynes and S Krishna. "Artemisinins" Postgraduate Medical Journal 2005; 81:71-78

 

 

5 Uhlemann C. et al. Nature Struct. Mol. Biol. 12, 628-629;2005

 

 

6 G. Schmid, W. Hofheinz. "Total Synthesis of qinghaosu" J. Am. Chem. Soc.; 1983; 105 (3); 624-625

 

 

7Boulangier D, Dieng Y, Cisse B, et al. (2007). "Antischistosomal efficacy of artesunate combination therapies administered as curative treatments for malaria attacks.". Trans R Soc Trop Med Hyg 101 (2): 113–16.

 

 

8Silamut K., Newton P., Teja-Isavadharm P., Suputtamongkol Y.,Siriyanonda D., Rasameesoraj M.,Pukrittayakamee S. and White N. "Artemether Bioavailability after Oral or Intramuscular Administration in Uncomplicated Falciparum Malaria" AAC 2003; v47: 3795–3798

 

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