artemisinin - wiki

8/10/2019 Artemisinin - Wiki

http://slidepdf.com/reader/full/artemisinin-wiki 1/19

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

Artemisinin - Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Artemisinin

1 of 19 2014/11/05 09:26 PM



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)

(what is this?) (verify)

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


2 of 19 2014/11/05 09:26 PM



A t i i i Wiki di th f l di htt // iki di / iki/A t i i i



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


4 of 19 2014/11/05 09:26 PM



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

8 of 19 2014/11/05 09:26 PM




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

9 of 19 2014/11/05 09:26 PM



(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

This page was last modified on 2 November 2014 at 12:41.Text is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. By using this site, you agree to the Terms of Use and Privacy Policy. Wikipedia® is a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization.

19 of 19 2014/11/05 09:26 PM

artemisinin - wiki

Documents