artemisinin - wiki
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Systematic (IUPAC) name
(3 R,5aS ,6 R,8aS ,9 R,12S ,12a R)-Octahydro-3,6,9-trimethyl-
3,12-epoxy-12 H -pyrano[4,3- j]-1,2-benzodioxepin-10(3 H )-one
Clinical data
Legal status ?
Routes Oral
Identifiers
CAS number 63968-64-9
ATC code P01BE01
PubChem CID 68827
ChemSpider 62060
UNII 9RMU91N5K2
KEGG D02481
ChEBI CHEBI:223316
Artemisinin
ArtemisininFrom Wikipedia, the free encyclopedia
Artemisinin / ɑ rtɨˈmɪsɨnɨn/, also known as Qinghaosu (Chinese:青蒿素), and its derivatives are a group of
drugs that possess the most rapid action of all current drugs against Plasmodium falciparum malaria.[1]
Treatments containing an artemisinin derivative (artemisinin-combination therapies, ACTs) are now standard
treatment worldwide for P. falciparum malaria. Artemisinin is isolated from the plant Artemisia annua, sweet
wormwood, a herb employed in Chinese traditional medicine. It can now also be produced using genetically
engineered yeast.
Chemically, artemisinin is a sesquiterpene lactone containing an unusual peroxide bridge. This peroxide is
believed to be responsible for the drug's mechanism of action. Few other natural compounds with such a
peroxide bridge are known.[2]
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. Therapies that combine
artemisinin with some other antimalarial drug are the preferred treatment for malaria and are both effective
and well tolerated in patients. The drug is also increasingly being used in Plasmodium vivax malaria,[3] as well
as being a topic of research in cancer treatment.
Contents
1 History
1.1 Etymology
1.2 Discovery
2 Artemisinin derivatives
3 Indications
3.1 Uncomplicated malaria
3.2 Severe malaria
3.3 Cancer treatment
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ChEMBL CHEMBL77
Synonyms Artemisinine, Qinghaosu
Chemical data
Formula C15H22O5
Mol. mass 282.332 g/mol
Physical data
Density 1.24 ± 0.1 g/cm³Melt. point 152–157 °C (306–315 °F)
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3.4 Helminth parasites
4 Resistance
5 Adverse effects
6 Mechanism of action
7 Dosing
8 Production and price
9 Synthesis
9.1 Biosynthesis in A. annua
9.2 Chemical synthesis9.3 Synthesis in engineered organisms
10 References
11 External links
History
Etymology
Artemisinin is an antimalarial lactone derived from qing hao青蒿 (Artemisia annua or sweet wormwood). The medicinal value of this plant has been known to
the Chinese for at least 2,000 years. In 1596, Li Shizhen recommended tea made from qing hao specifically to treat malaria symptoms in his "Compendium of
Materia Medica". The genus name is derived from the Greek goddess Artemis and, more specifically, may have been named after Queen Artemisia II of Caria, a
botanist and medical researcher in the fourth century bce.[4]
Discovery
Artemisia annua ( A. annua) is a common herb found in many parts of the world, and has been used by Chinese herbalists for more than two thousand years in
the treatment of malaria. The earliest record dates back to 200 BC, in the "Fifty-two Prescriptions" unearthed from the Mawangdui Han Dynasty tombs. [5] Its
antimalarial application was first described, in Zhouhou Beiji Fang ("The Handbook of Prescriptions for Emergencies", Chinese:肘后备急方), edited in the
middle of the fourth century by Ge Hong; in that book, 43 malaria treatment methods were recorded. [6] Images of the original scientific papers that record the
history of the discovery, have been available online since 2006.[7]
SMILES
InChI
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A t i i i Wiki di th f l di htt // iki di / iki/A t i i i
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Artemether (lipid-soluble: for oral, rectal or intramuscular use)
Dihydroartemisinin
Artelinic acid
Artemotil
There are also simplified analogs in preclinical research.[18]
A synthetic compound with a similar trioxolane structure (ring containing three oxygen atoms) named arterolane[19] showed promise in in vitro testing. Phase II
testing in patients with malaria was not as successful as hoped, but the manufacturer decided to start Phase III testing anyway. [20] A combination with
piperaquine is also in development.
Indications
Uncomplicated 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 (WHO) is pressuring manufacturers to stop making the uncompounded drug available to the medical
community at large, aware of the catastrophe that would result if the malaria parasite developed resistance to artemisinins.[21]
The WHO has recommended artemisinin combination therapies (ACT) be the first-line therapy for P. falciparum malaria worldwide.[22] Combinations are
effective because the artemisinin component kills the majority of parasites at the start of the treatment, while the more slowly eliminated partner drug clears the
remaining parasites.[23]
Several fixed-dose ACTs are now available containing an artemisinin component and a partner drug which has a long half-life, such as mefloquine (ASMQ[24]),
lumefantrine (Coartem), amodiaquine (ASAQ), piperaquine (Duo-Cotecxin), and pyronaridine (Pyramax). Increasingly, these combinations are being made to
GMP standard. A separate issue concerns the quality of some artemisinin-containing products being sold in Africa and Southeast Asia.[25][26]
Artemisinins are not used for malaria prophylaxis (prevention) because of the extremely short activity (half-life) of the drug. To be effective, it would have to be
administered multiple times each day.
Severe malaria
Artesunate administered by intravenous or intramuscular injection has proven superior to quinine in large, randomised controlled trials in both adults [27] and
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availability for ACTs treatment. In August 2014, Sanofi announced the release of the first batch of semisynthetic artemisinin. 1.7 million doses of Sanofi's
ArteSunate AmodiaQuine Winthrop (ASAQ Winthrop), a fixed-dose artemisinin-based combination therapy will be shipped to half a dozen African countries
over the next few months.[72]
Synthesis
Biosynthesis in A. annua
The biosynthesis of artemisinin is believed to involve the mevalonate pathway (MVA) and the cyclization of farnesyl diphosphate (FDP). It is not clear whether
the non-mevalonate pathway pathway can also contribute 5-carbon precursors (IPP or/and DMAPP), as occurs in other sesquiterpene biosynthetic systems. 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 photo-oxidation to produce dihydroartemisinic acidhydroperoxide. Ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation finish the biosynthesis of artemisinin.
p , y p p w p g w
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Chemical synthesis
The total synthesis of the sesquiterpene lactone, artemisinin (quinghaosu) has been performed from available organic starting materials, using basic organic
reagents, many times. The first two total syntheses were a "remarkable... stereoselective synthesis" by Schmid and Hofheinz at Hoffmann-La Roche in Basel
starting from (−)-isopulegol (13 steps, ≈5% overall yield) and a concurrent synthesis by Zhou and coworkers at the Shanghai Institute of Organic Chemistry from
R-(+)-citronellal (20 steps, ≈0.3% overall yield).[73]
Key steps of the Schmid-Hofheinz approach included an initial Ohrloff stereoselective
hydroboration/oxidation to establish the "off-ring" methyl stereocenter on the propene side chain; two sequential lithium-reagent mediated alkylations thatintroduced all needed carbon atoms and that were, together highly diasteroselective; and further reduction, oxidation, and desilylation steps performed on this
mono-carbocyclic intermediate, including a final singlet oxygen-utilizing photooxygenation and ene reaction, which, after acidic workup closed the three
p y p p p g
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(http://www.the-scientist.com/2005/3/28/42/1). The Scientist 19 (6): 42.
Research on the use of artemisinin for cancer treatment (http://depts.washington.edu/bioe/about/news/artemisinin.html)
Artemisinin — Researchers blend folk treatment, high tech for promising anti-cancer compound (http://www.uwnews.org/article.asp?articleID=8139)
BBC Horizon documentary about artemisinin (http://www.bbc.co.uk/sn/tvradio/programmes/horizon/malaria_prog_summary.shtml)Artemisia Annua, by Memorial-Sloan Kettering Cancer Center (http://www.mskcc.org/mskcc/html/11571.cfm?RecordID=650&tab=HC)
Use of Artemisinin for Cancer Treatment and Bacterial Infection, Henry Lai, Ph.D., University of Washington (streaming video, Spring 2005)
(http://www.bioeng.washington.edu/video/#spring05/bioe599jL5.wmv)
Assured Artemisinin Supply System, support the global production of sufficient Artemisia/artemisinin to meet the expanded needs (http://www.a2s2.org)
Artemisinin latest patents (http://tgs.freshpatents.com/Artemisinin-bx1.php), covering use in fighting infections, including viral infections; fighting cancer;
various novel derivatives and ACTs; high-yielding Artemisia plants; and extraction methods.
Retrieved from "http://en.wikipedia.org/w/index.php?title=Artemisinin&oldid=632131797"
Categories: Antimalarial agents Chinese inventions Experimental cancer drugs Organic peroxides Sesquiterpene lactones Trioxanes
Oxygen heterocycles
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