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134 Fluorine in Medicinal Chemistry and Chemical Biology
To address the tumor specifi city issue, various tumor - targeting anticancer drug conju-
gates, consisting of a tumor - targeting molecule, a functional linker, and a highly potent
cytotoxic drug, have been developed. Such a drug conjugate should have a high affi nity to
tumor cells through the tumor - targeting module, promoting effi cient endocytosis of the
whole conjugate. The functional linker moiety of the conjugate should be intelligently
designed and engineered so that the conjugate is stable in the circulation but the linker is
readily cleaved in tumors to release the potent cytotoxic drug effi ciently. Monoclonal anti-
bodies (mAbs), hyaluronic acid, folic acid, biotin, and somatostatin peptide mimic are among
the tumor - targeting molecules most commonly used [57, 58] . For example, mAbs specifi -
cally bind to antigens that are overexpressed on the surface of tumor tissues or cells, distin-
guishable from normal tissues. Therefore, in principle, mAb – cytotoxic drug conjugates can
be specifi cally delivered to the tumor and internalized via receptor - mediated endocytosis,
releasing the cytotoxic drug [57, 59, 60] . Mylotarg ® (gemtuzumab - ozogamicin) [61] was
approved by the US FDA for the treatment of acute myelogenous leukemia (AML), provid-
ing the fi rst mAb – drug immunoconjugate for the treatment of cancer in clinic use. Several
other mAb – drug conjugates have reached human clinical trial stage [60, 62 – 65] .
Our investigation in this area led to the development of novel mAb – taxoid conjugates
as tumor - targeting anticancer agents that exhibited extremely promising results in human
cancer xenografts in SCID (severe combined immunodefi ciency) mice. The results clearly
demonstrated tumor - specifi c delivery of a taxoid anticancer agent without any noticeable
toxicity to the animals, curing all animals tested [66] . As the linker for these mAb – taxoid
conjugates, we used a disulfi de linker that was stable in blood circulation but effi ciently
cleaved by glutathione or other thiols in the tumor [ Note: The glutathione level is known
to be 1000 times higher in tumor tissues than in blood plasma [67] . However, in this
fi rst - generation of mAb - taxoid conjugates, the original taxoid molecule was not released
because of the compromised modifi cation of the taxoid molecule for attachment the disul-
fi de linker. Accordingly, the cytotoxicity of the taxoid released in these conjugates was
8 – 10 times weaker than that of the parent taxoid [66] .
To address this problem, we have been developing second - generation mechanism -
based disulfi de linkers. One of our approaches is the glutathione - triggered cascade drug
release, forming a thiolactone as a side - product as illustrated in Scheme 5.6 . This mecha-
nism - based drug release concept has been nicely demonstrated in a model system by
monitoring the reaction with
19
F NMR using fl uorine - labeled compounds (see Figure 5.6 )
[68] . The strategic incorporation of a fl uorine substituent at the para position to the disul-
fi de linkage would direct the cleavage of this linkage by a thiol to generate the desirable
thiophenolate or sulfhydrylphenyl species for thiolactonization. In addition, the incorpora-
tion of a fl uorine substitution may increase the metabolic stability of the conjugate. This
type of linkers is highly versatile and readily applicable to any tumor - targeting drug con-
jugates, including fl uoro - taxoids.
Moreover, combination of a fl uorine - containing linker and a fl uoro - taxoid may
provide fl uorine probes for monitoring the internalization and drug release of these con-
jugates in the tumor cells and tissues by
19
F NMR as an alternative method to the use of
fl uorescence - labeled probes with confocal fl uorescence microscopy [69] .
Further applications of the strategic incorporation of fl uorine into medicinally active
substances as well as compounds useful as tools for biomedical research are actively under
study in these laboratories.
Fluoro-Taxoid Anticancer Agents 135
S
OO
OH
O
OAc
HO
O
O
O
O
R
1
Rf
O
O
NHO
O
O
SS
HN
O
F
Glutathione
S
HN
O
S-Glutathione
O
F
OO
OH
O
OAc
HO
O
O
O
O
R
1
Rf
O
OH
NHO
O
TTM
X
X
TTM
Scheme 5.6 Glutathione - triggered cascade drug release for tumor - targeting of fl uoro - taxoid
conjugates.
F
A
F
B
S
O
O
MeS
F
B
F
A
S
O
F
A
'
MeS-S-Cysteine
HO F
B
'
F
A
'
F
B
'
+
HS-Cysteine
Figure 5.6 A model system for mechanism - based release.
( Source: Reproduced with permission, from Ojima, I. Use of fl uorine in the medicinal chemistry
and chemical biology of bioactive compounds – a case study on fl uorinated taxane anticancer
agents. ChemBioChem , (2004) 5, 628 – 635. Copyright Wiley-VCH Verlag GmbH & Co.
KGaA.)
136 Fluorine in Medicinal Chemistry and Chemical Biology
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Fluoro-Taxoid Anticancer Agents 139
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6
Antimalarial Fluoroartemisinins:
Increased Metabolic and
Chemical Stability
Jean - Pierre B é gu é and Dani è le Bonnet - Delpon
6.1 Introduction
Malaria continues to be one of the most important infectious diseases in the world [1] . Of
the four human malaria parasites, Plasmodium falciparum is the one overwhelmingly
responsible for severe clinical malaria and death. A major cause of malaria morbidity and
mortality is the current increasing resistance of malaria parasites, in particular P. falci-
parum , to the most prescribed antimalarial drugs (chloroquine, pyrimethamine, proguanil,
halofantrine, etc.) [2] . Facing this alarming decline in the effi cacy of antimalarial drugs,
a broad consensus on the need to develop new antimalarial drugs is now well established
[3] . Artemisinin 1 (see Figure 6.1 ), which was isolated from a plant, Artemisia annua L.,
and has been used to treat high fever over 2000 years in Chinese traditional medicine [4] ,
has emerged as a desirable drug. Artemisinin is a sesquiterpene lactone that contains an
endoperoxide bridge, as a part of a 1,2,4 - trioxane core. This very unusual functional group
in medicinal chemistry is an absolute requirement for the antimalarial activity. When the
endoperoxide is lacking, as in the reduced desoxoartemisinin, the compound is devoid of
antimalarial activity [5] . Consequently, the peroxide function has become a focus for
experiments aimed at understanding the mode of action of artemisinin and other trioxanes.
Numerous hypotheses have been proposed as possible mechanisms of action for artemis-
inin derivatives ( “ artemisinins ” ). They were supported by a large number of studies
seeking an understanding at the molecular level [6] . However, the conclusion of these
Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima
© 2009 Blackwell Publishing, Ltd. ISBN: 978-1-405-16720-8
142 Fluorine in Medicinal Chemistry and Chemical Biology
complementary but often contradictory experiments is that the in vivo activity is probably
multifactorial: that is, artemisinins interacts with several targets [7] .
The therapeutic value of artemisinin is limited by its low solubility in both oil and
water. However, artemisinin provides a unique key molecular framework from which
medicinal chemists can attempt to prepare more effi cacious antimalarial drugs by retaining
the pharmacologically essential 1,2,4 - trioxane core [8] .
The fi rst - generation semisynthetic analogues, dihydroartemisinin 2 , artemether,
arteether ( “ ethers of artemisinin ” ) and sodium artesunate, were prepared in the 1980s
(Figure 6.1 ) [5a, 9] . These artemisinin derivatives have made a substantial impact on the
treatment of malaria [10 – 12] . They are fast - acting and potent antimalarial drugs against
all Plasmodium parasites, in particular the multidrug - resistant P. falciparum [13] . They act
at the early stages of development of parasites once the parasites have invaded red cells
[14] . Artemisinins are gametocytocidal, but they do not kill the hepatic stages of parasites
[15] . No clinical case of resistance to artemisinins has been reported so far [16] .
These derivatives have poor oral bioavailability, but fortunately this is partially coun-
tered by their very high intrinsic activities. Furthermore, they all possess a short half - life
in the body, which can lead to recrudescence of parasitemia [17] . According to Scheme
6.1 , the human metabolism of an ether of artemisinin, such as artemether, involves fi rst
an oxidation in the liver by cytochrome P450 enzymes. This produces dihydroartemisinin
(DHA) as the main metabolite, which retains the antimalarial activity [11] . DHA is then
rapidly eliminated through phase II metabolism via generation of water - soluble conjugates
such as α - DHA - β - glucuronides [18] . These two processes are responsible for the short
plasma half - life of ethers of artemisinin [8] . A second important factor is the low stability
of the acetal group under acidic conditions, such as those found in the stomach upon oral
administration.
[ Note: In artemisinin series, conventional designation of stereochemistry is used (e.
g., α is below the plane, while β is above the plane), but the stereochemistry at C - 10 is
opposite to that used for glycosides.]
The use of these artemisinin derivatives in combination with an antimalarial drug
with a longer half - life, as recommended by WHO, can not only delay emergence of resis-
tance but also partially overcome the problem of short plasma half - life [19] . Nevertheless,
chemically and metabolically more stable artemisinins would bring improvement in
malaria therapy and bitherapy (or combination therapy) [20] .
In order to improve the oral bioavailability, a huge number of compounds have been
synthesized from artemisinin, which is a readily available naturally occurring compound
[8] . Large - scale isolation and purifi cation of artemisinin from wild or cultivated Artemisia
O
O
O
O
O
O
O
O
O
OH
O
O
O
O
O
CH
3
O
O
O
O
O
CH
3
O
O
O
O
O
O
CO
2
Na
Artemisinin
Dihydroartemisin (DHA)
Artemether
Arteether
Sodium artesunate
1
2
6
3
7
8
9
10
12
5a
14
15
16
12a
5
8a
4
Figure 6.1 First - generation antimalarial artemisinins.
Antimalarial Fluoroartemisinins: Increased Metabolic and Chemical Stability 143
O
O
O
O
O
COOH
O
O
O
N
O
R
O
O
O
O
N
S
O O
O
O
O
O
N
N
CF
3
O
O
O
O
R
O
O
O
O
O
R
3
4
5
Artemisone
6
8
7
10
16
Figure 6.2 Main structural variations of the artemisinin skeleton for antimalarial drug
discovery.
O
O
O
O
OH
O
O
O
O
O
CH
3
O
O
O
O
O
CH
2
OH
O
O
O
O
O
O
OH
HO
OH
O
COOH
DHA (α + β)
Artemether
P450
enzymes
H
2
O
Oxidation sites
Glucuronidation
Oxidation
Proteolyse
H
+
10
5
6
7
9
16
2
α-DHA-glucuronide
Scheme 6.1 Metabolism of artemether in humans.
annua are rather easy (more than 10 tonnes/year is produced in south - east Asia). The two
main objectives of medicinal chemists have been to obtain more stable derivatives and to
increase water solubility by introducing polar or ionizable functional groups.
Numerous chemical modifi cations of artemisinin have been extensively investigated
and reviewed [8, 20a, 21, 22] . The most effective approaches include the design of
oxidation - resistant ethers of DHA 3 (see Figure 6.2 ), of 10 - aza analogues 5 [23, 24] , and of
10 - carba analogues 6 [8, 20a, 21, 22, 25] . From these various “ robust ” artemisinins, current
efforts are focused on incorporating functional groups in order to increase water solubility
and to decrease log P . Good examples are artemisone 5 , developed by Bayer and MMV
[26] , and the piperazine derivative 6 , a potent in vitro and in vivo antimalarial [8, 27] .
144 Fluorine in Medicinal Chemistry and Chemical Biology
All structural modulations described above are concerned with the C - 10 site. Arte-
misinin derivatives functionalized at C - 16 ( 7 , 8 ) are more diffi cult to prepare, and the
natural precursors, artemisitene and artemisinic acid, are less readily available than arte-
misinin [18c, 28, 29] .
6.2 Fluoroartemisinins: Control of Metabolism
To prevent oxidative metabolism and/or to increase hydrolytic stability, ten years ago we
initiated our approach to designing a metabolically more stable artemisinin using fl uorine
substitution. This approach is now classical in medicinal chemistry and has been validated
by numerous examples [30, 31] . The decreased rate of metabolism as a result of fl uorine
substitution is a consequence of the intrinsic properties of the fl uorine atom – the electronic
structure and strong electronegativity of fl uorine impart great chemical inertia to the C – F
bond, in particular toward oxidation. Furthermore, the electronegativity of fl uorine confers
a strong electron - withdrawing character on fl uoroalkyl substituents. This disfavors devel-
opment of positive charge on the α - carbon, and hence the generation of cationic species
involved in hydrolytic processes [30, 32] .
We present here an overview of our approaches to and results on new potent antima-
larial fl uoro - artemisinins. The effects of fl uorine substitution on chemical reactivity make
the synthesis of fl uoro - artemisinins not always straightforward. These specifi c synthetic
challenges will be highlighted.
6.2.1 Fluoroalkyl Ethers of Dihydroartemisinin
6.2.1.1 Synthesis
As indicated in Scheme 6.1 , in vivo or in liver homogenates, ethers of DHA undergo rapid
hydroxylation by cytochrome P450 enzymes to generate a hemiacetal, which decomposes
to produce DHA 2 and an aldehyde [18c, 33] . A feasible approach to prolonging the half -
life of DHA ethers is to design poorer substrates for cytochrome P450 by introduction
of a fl uorinated substituent (R
f
) at the α - methylene carbon of the alkoxy group (see
Scheme 6.2 ). A slower rate of oxidative dealkylation would be expected since it has been
O
O
O
CH
2
R
f
H
H
O
O
Oxidation slowed down by
the protecting Rf group
Scheme 6.2 Design of fl uoroalkyl ethers of artemisinin.