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Artemisinin

Artemisinin (IPA: [arte’misinən]) is a drug Artemisinin


used to treat multi-drug resistant strains of
falciparum malaria. The compound (a
sesquiterpene lactone) is isolated from the
shrub Artemisia annua long used in
traditional Chinese medicine. Not all shrubs
of this species contain artemisinin.
Apparently it is only produced when the
plant is subjected to certain conditions. It
can be synthesized from arteminisic acid.[1] (3R,5aS,6R,8aS,9R,12S,12aR)-
octahydro-3,6,9-trimethyl-3,12-
Chemical name
epoxy-12H-pyrano[4,3-j]-
1,2-benzodioxepin-10(3H)-one
Chemical formula C15H22O5
Molecular mass 282.332 g/mol
Artemisinine
Synonyms
Qinghaosu
CAS number 63968-64-9
PubChem 68827
ATC code P01BE01
Density 1.24 ± 0.1 g/cm3
Melting point 152 - 157 °C
Boiling point decomp.
CC1CCC2C(C(=O)OC3
SMILES
C24C1CCC(O3)(OO4)C)C

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. 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 discovered artemisinin in the leaves of Artemisia annua. The drug is
named qinghaosu 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.

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

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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.

For many years, access to the purified drug and the plant it was extracted from were restricted
by the Chinese government. However, Artemisia annua is a common shrub and has been found
in many parts of the world, including along the Potomac River, in Washington, D.C.

Currently, artemisinin is widely used in China and Southeast Asia for treatment of malaria. It is
often used without taking precautions against conditions that might lead to resistance of the
malaria parasite to this drug, leading to concern that the effectiveness of artemisinin may be
reduced in the near future, as is the case with other classes of antimalarial drugs.

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. However, their activity is not long lasting, with significant decreases in
effectiveness after one to two hours. To counter this drawback, artemisinin is given alongside
lumefantrine to treat uncomplicated falciparum malaria. Lumefantrine has a half-life of about 3 to
6 days. Such a treatment is called ACT (artemisinin-based combination therapy); other
examples are artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, and
artesunate-sulfadoxine/pyrimethamine. Recent trials have shown that ACT is more than 90%
effective, with a recovery of malaria after three days, especially for the chloroquine-resistant
Plasmodium falciparum.

The World Health Organization has recommended that a switch to ACT should 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 they have proved to be safe and effective anti-malarial
drugs. They have minimal adverse side effects. Currently, artemisinin is not widely available in
the United States or Canada, but is easy to find in Africa and Asia. There have been some
concerns about the quality of some products on offer in Africa, but sticking to one of the
European (often Belgian) manufacturers could overcome this problem.

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 recent paper in Nature presented
a geneticly engineered yeast that created a closely related compound which can be efficently
converted into 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. There are also plans to have the plant grow in
other areas of the world (outside Vietnam and China).

Cancer Treatment

Artemisinin is under early research and testing for treatment of cancer. 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.

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Mechanism of Action

The specific mechanism of action of artemisinin is not well understood, and there is ongoing
research directed at elucidating it. When the parasite that causes malaria infects a red blood
cell, it consumes hemoglobin and liberates 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.[2]

Numerous studies have investigated the type of damage that these oxygen radicals may induce.
For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease
activity of malarial parasite by artemisinin.[3] These observations were further confirmed by ex
vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin,
suggesting inhibition of hemoglobin degradation. They found artemisinin to be a potent inhibitor
of hemeozoin formation activity of malaria parasite.

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. [4]

Artemisinins have also been shown to inhibit PfATP6, a SERCA-type enzyme (calcium
transporter) and artemisinin has been shown to compete with thapsigargin for SERCA binding,
though artemesinin is much less toxic to mammalian cells. Resistance to artemisinin is
conferred by a single mutation in the calcium transporter (PfATP6). This mutation has been
studied in the laboratory but recently a study from French Guiana in field isolates of malaria
parasites has identified a different mutation in the calcium transporter (PfATP6) that is
associated with resistance to artemether, lending support to the idea that PfATP6 is the target
for artemisinins.[5]

References

1. ^ Acton, N. & Roth, R.J. On the conversion of dihydroartemisinic acid into artemisinin. J.
Org. Chem. 57, 3610-3614 (1992)
2. ^ Cumming, Jared N.; Ploypradith, Poonsakdi; Posner, Gary H. Antimalarial activity of
artemisinin (qinghaosu) and related trioxanes: mechanism(s) of action. Advances in
Pharmacology (San Diego) (1997), 37 253-297.
3. ^ Pandey et al
4. ^ Li et al., PLOS Genetics, September 2005, Volume 1, Issue 3
5. ^ A.-C. Uhlemann et al. Nature Struct. Mol. Biol. 12, 628-629;2005

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Medicinal chemistry ring system (Fig. 1b). This was their first
breakthrough. Remarkably, not only were
A worthy adversary for malaria the resulting compounds stable, but when
tested against human strains of the malaria
Paul M. O’Neill parasite, they also had superior parasite-
killing properties even to artesunate and
A remarkable set of antimalarial drug candidates has been developed artemether.
by an international collaboration of scientists, using the age-old The first series of the compounds were
Chinese herbal medicine artemisinin as a template. poorly soluble in water, however, so the next
step was to increase the compounds’ water
solubility so that they could be more easily

N
early two billion people live in areas create a new class of endoperoxide anti-
where malaria is endemic, and the malarials that have superior properties to the absorbed from the gastrointestinal tract7.
incidence of this disease is increasing artemisinin derivatives. The team consisted Many potential drugs containing chemical
dramatically, mainly because many malaria- of chemists,parasitologists,pharmacokineti- groups that increase water solubility were
parasite strains have become resistant to the cists and toxicologists. examined, and this led to the discovery of
available drugs1. The devastating spread of The first stage of their drug discovery a candidate, OZ277 (Fig. 1c), that was
parasite resistance has prompted the world- process involved a systematic examination of well absorbed when administered orally to
wide search for new classes of effective anti- a chemical group known as secondary animals, and had outstanding antimalarial
malarial drugs. On page 900 of this issue, ozonides (or 1,2,4-trioxolanes; Fig. 1b). This properties both in vitro and in vivo. Unlike
Vennerstrom and colleagues2 describe the class of compounds is well known to organic the available artemisinin derivatives, OZ277
development of a new class of synthetic drug chemists as intermediates obtained by is structurally simple and its synthesis can be
related to the natural antimalarial product exposing alkenes to ozone. Although they scaled up in a way that is economically feasi-
artemisinin. have the requisite endoperoxide bridge, ble.What’s more,its toxicological profiles are
Artemisinin has been used in traditional these molecules tend to be highly unstable — satisfactory. Following the development of a
Chinese herbal fever remedies for more not a promising starting point, one might large-scale synthesis for OZ277, it has just
than 1,500 years3. It is extracted from sweet think.And unsurprisingly,some of the initial entered ‘first into man’studies.
wormwood (Artemisia annua), and is used ozonide compounds tested turned out to be Given the effectiveness of this new struc-
as the basis for synthesizing several modern very poor antimalarials. turally simple drug, the question arises: how
antimalarial drugs, such as artesunate and In artemisinin, the sensitive peroxide does it kill parasites? It seems probable that it
artemether. These artemisinin derivatives bridge is protected by bulky chemical rings, shares a common mechanism of action with
are increasingly important in the treatment and the team attempted to mimic this feature the artemisinins, where it is proposed that an
of drug-resistant malaria, as they are the by fusing a large, bulky group known as an interaction of the endoperoxide bridge with
most potent antimalarials available, rapidly adamantane ring onto the standard ozonide ferrous iron or haem from the red blood cell
killing all blood stages of the malaria parasite
Plasmodium falciparum. But the overall yield
of the artemisinin extraction process is poor, a
so that its derivatives, though inexpensive by
H
the standards of developed countries, are O
relatively expensive when put in the African O
O
context. In addition, the drugs only act for a H
H
short time, so the dosage regimen can lead to O
patient non-compliance and subsequent O
treatment failure. These shortcomings have Artemisinin
Endoperoxide bridge
prompted medicinal chemists to try to make
Adamantane ring
entirely synthetic analogues of artemisinin
b
with improved antimalarial properties4.
Artemisinins contain a structural feature R O O R O O O O
known as an endoperoxide bridge (Fig. 1a) O O
R R O
that is key to their antimalarial activity, and
one of the major challenges in the pursuit of The starting point — Relatively unstable Highly potent
a secondary ozonide and inactive antimalarial
synthetic analogues has been to introduce
this bridge into candidate drugs. Incor-
Endoperoxide bridge
porating the endoperoxide ‘warhead’ is c
now possible, but many of the candidate
O O
analogues produced have significant draw- NH2
O
backs, including poor antimalarial activity O
NH

and syntheses that are not stereoselective


or not amenable to being scaled up5,6. So, OZ277
although many research groups had focused
on the problem for some fifteen years, the
goal of a cheap, synthetic, endoperoxide- Figure 1 Artemisinin and its analogues. a, Chemical structure of artemisinin. The space-filled model
based antimalarial had not been realized. on the right shows how the sensitive endoperoxide bridge is shielded by the ring system. b, Drug
Vennerstrom et al.2 now provide the solu- prototypes. Vennerstrom and colleagues2 fused an adamantane ring system onto the basic ozonide
tions to many of these problems. They com- ring to produce a new class of antimalarial drug with superior activity to artemisinin. c, The clinical
piled a wish-list of ideal drug properties for candidate, OZ277. The adamantane system protects the endoperoxide bridge, and the boxed chemical
the target molecule and stuck strictly to it group is key to the compound’s improved water solubility and pharmaceutical properties. Carbon
through a process of drug-optimization to atoms, grey; hydrogen atoms, light blue; oxygen atoms, red; nitrogen atoms, dark blue.

838 NATURE | VOL 430 | 19 AUGUST 2004 | www.nature.com/nature


©2004 Nature Publishing Group
19.8 n&v AM 13/8/04 5:34 pm Page 839

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in which the parasite lodges generates toxic, Condensed-matter physics
carbon-centred free radicals8,9. Theoreti-
cally, these highly reactive molecules can
modify key parasite proteins, disabling Vortices weave a tangled web
essential biological targets and killing the David R. Nelson
parasite. Using a technique known as spin-
trapping, Vennerstrom and colleagues pro- In high-temperature superconductors, quantized vortex filaments can
vide evidence that trioxolanes can indeed be twisted up into a DNA-like double helix. An experiment is proposed
generate a carbon-centred free radical in a to test how easily these vortex lines cut through each other.
manner reminiscent of the artemisinins.
There are several proposed protein targets

I
nside a superconductor, electrical currents applications. Indeed, if vortices are allowed
for the noxious free radicals produced by flow without resistance.Almost as remark- to move in response to an applied current
artemisinin, one of which is an enzyme able as this electron flow without dissipa- (which exerts a force on them), their motion
known as PfATP6 (ref. 10). Future studies tion are the quantized, thread-like vortices of dissipates energy, and resistanceless flow in a
should reveal whether OZ277 and its chemi- charge that swirl like miniature tornadoes magnetic field is impossible. A vortex crystal
cal siblings target the same proteins as the around lines of magnetic field. Last year, resists shear deformations, so that pinning
artemisinin derivatives. Alexei Abrikosov shared the Nobel Prize in the Abrikosov flux lattice is relatively easy,
The development of OZ277 is a flagship Physics for his brilliant 1957 prediction like tacking a carpet to a slippery floor. How-
project for the Medicines for Malaria Ven- (made well before similar developments in ever, pinning the melted lattice in a vortex
ture11,12. It is an excellent example of how a high-energy theory and astrophysics) that, liquid is much more difficult — this requires
well-managed partnership between acad- in a class of materials called ‘type II’ a high viscosity, similar to the property that
emia and major pharmaceutical companies superconductors, a regular lattice of parallel allows us (temporarily, at least) to nail a
can have a significant impact on antimalarial vortex filaments, aligned with an external pancake of ‘silly putty’ to a wall. Silly putty is
product research and development. magnetic field, would form1. In high- composed of long, tangled polymer chains,
Basing the drug development process on temperature copper-oxide superconductors, and it is tempting to think of a melted
a chemically unstable entity such as a sec- discovered 30 years later, Abrikosov’s vortex liquid of Abrikosov vortices (Fig. 1) as a
ondary ozonide was a daring move. And lattice actually ‘melts’ over an appreciable related ‘directed polymer melt’ of entangled
the research that enabled ozonides to be range of magnetic field and temperature2,3. vortex filaments. Crucial to the high viscos-
redesigned, not only to increase the chemical Olson Reichhardt and Hastings4, writing in ity of real polymer melts, however, are large
and metabolic stability, but also to provide Physical Review Letters, now propose a key energy barriers to the polymer chains cross-
phenomenal antimalarial properties, is experiment that could unravel the physics of ing each other.
impressive. The subsequent tailoring of the these vortices as they become entangled in Do vortices, which are singularities in the
‘ozonide’ molecule to enhance its availability the melted state. underlying superconducting order, behave
to the body was hugely successful — the new A typical phase diagram for a high-tem- as impenetrable lines, or do they cut freely
synthetic analogues are more potent and perature superconductor is shown in Fig. 1, through one another? The answer depends
act for longer in vivo than artemether and overleaf, as a function of temperature and of on field and temperature. The energy barri-
artesunate by some margin. As such, when the magnetic field induced in the material5. ers against flux cutting are very small near the
combined with a second antimalarial, The Meissner phase of the diagram, in which critical field line (Fig. 1), where quantized
this new class could offer the best solution to surface currents completely exclude an vortices first form. However, when nearly
date for destroying drug-resistant malaria applied magnetic field, follows the horizon- parallel vortex lines cross, the ‘quantum of
parasites. ■ tal axis (where there is no magnetic induc- vorticity’ effectively doubles. The quantum
Paul M. O’Neill is in the Departments of Chemistry tion in the superconductor) and terminates of vorticity is a universal combination of
and of Pharmacology, University of Liverpool, at the temperature at which the material Planck’s constant, the speed of light and the
Liverpool L69 7ZD, UK. ceases to be a superconductor — its transi- electron charge, and determines the strength
e-mail: p.m.oneill01@liverpool.ac.uk tion temperature. According to Abrikosov’s of the swirling supercurrents around a
1. Winstanley, P. A., Ward, S. A. & Snow, R. W. Microbes Infect. 4, original theory, an applied magnetic field vortex. Well below the critical field line,
157–164 (2002). would penetrate the material as a regular this doubling leads to a very large crossing
2. Vennerstrom, J. L. et al. Nature 430, 900–904 (2004).
3. Klayman, D. L. Science 228, 1049–1055 (1985).
lattice of quantized vortex filaments when energy. Two entangled vortices can always
4. Borstnik, K., Paik, I. H., Shapiro, T. A. & Posner, G. H. the magnetic induction is greater than zero cut each other easily if the lines deform so as
Int. J. Parasitol. 32, 1661–1667 (2002). and below some critical field line (Fig. 1). to cross each other at a large angle, but this is
5. O’Neill, P. M. & Posner, G. H. J. Medicin. Chem. 47, 2945–2964
But thermal fluctuations melt this lattice resisted by the line tension. Although there
(2004).
6. Vroman, J. A., Alvim-Gaston, M. & Avery, M. A. Curr. Pharm. above the ‘coexistence region’ — where is some experimental evidence for a large
Design 5, 101–138 (1999). liquid and solid phases coexist at slightly viscosity in a vortex liquid, theoretical esti-
7. Haynes, R. K. Curr. Opin. Infect. Dis. 14, 719–726 (2001). different densities3. mates of the ratio of the melting temperature
8. Posner, G. H. & Oh, C. H. J. Am. Chem. Soc. 114, 8328–8329
(1992).
What is this melted liquid of fluctuating, and the crossing energy at that temperature
9. Wu, Y. K. Acc. Chem. Res. 35, 255–259 (2002). randomly braided vortex filaments like? An vary widely6,7.
10. Eckstein-Ludwig, U. et al. Nature 424, 957–961 (2003). important property is its shear viscosity, Olson Reichhardt and Hastings4 propose
11. Vennerstrom, J. L., Dong, Y., Chollet, J. & Matile, H. US Patent which determines the ease with which point- an elegant way to probe that all-important
6,486,199 (2002).
12. www.mmv.org/pages/page_main.htm
like, linear or planar defects can pin the vor- vortex crossing energy, using a magnetic
tices in place. These defects might be missing force microscope (MFM).An MFM is similar
Nature Outlook: Malaria atoms (for example, oxygen vacancies), to an atomic force microscope, except that it
More about the challenges posed by malaria columnar damage tracks from heavy-ion has a magnetized tip that pulls on the end of
appears in the collection of articles published radiation, or more extended objects such as an individual vortex line8. It should be possi-
as a Nature Outlook supplement, beginning grain boundaries or globules of a different ble to pin the entry points of two vortex
on page 923 of this issue. The articles cover atomic phase. The pinning of vortex lines, lines in place, and then use the MFM to
scientific, social and political problems, with thereby immobilizing them relative to the wind one vortex around another into a
the emphasis on Africa. host material, is crucial in many high-field double helix (Fig. 1). If the energy barriers to
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