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Artemisinin

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on May 13, 2007 at 9:46:30 pm
 

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.

 

 


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 till 1960 when the Chinese military screen hundreds of drugs to find one that would help there soldiers fight malaria.

 

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.

 

Structure and General Info

 

 

StructureC15H22O5
Mol. Mass282.33 g/mol
Density1.24 ± 0.1 g/cm³
Melting Point151-154 °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 than reduces the peroxide in artemisinin, which produces free radicals that can damage and kill the parasite.3

 

Biosynthesis

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

 

Synthesis from Microbes

However, in 2006 a team from Berkely have 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. The reaction pathway is shown below:1

 

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 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 (13). Finally, this underwent photooxygenation and then treated with acid to produce artemisinin.2

 

 

Clinical Use

 

References

1 Richmond Sarpong, Jay D. Keasling. "Production of the antimalarial drug precursor artemisinic acid in engineered yeast" Nature 440, 940-943 (13 April 2006)

 

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

 

3C J Woodrow, R K Haynes and S Krishna. "Artemisinins" Postgraduate Medical Journal 2005; 81:71-78

 

 

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John Le

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