Synthesis of Tamoxifen-Artemisinin and Estrogen-Artemisinin Hybrids Highly Potent Against Breast and Prostate Cancer

Article abstract of DOI:10.1002/cmdc.202000174

In the search for new and effective treatments of breast and prostate cancer, a series of hybrid compounds based on tamoxifen, estrogens, and artemisinin were successfully synthesized and analyzed for their in vitro activities against human prostate (PC-3) and breast cancer (MCF-7) cell lines. Most of the hybrid compounds exhibit a strong anticancer activity against both cancer cell lines – for example, EC₅₀ (PC-3) down to 1.07 μM, and EC₅₀ (MCF-7) down to 2.08 μM – thus showing higher activities than their parent compounds 4-hydroxytamoxifen (afimoxifene, 7; EC₅₀=75.1 (PC-3) and 19.3 μM (MCF-7)), dihydroartemisinin (2; EC₅₀=263.6 (PC-3) and 49.3 μM (MCF-7)), and artesunic acid (3; EC₅₀=195.1 (PC-3) and 32.0 μM (MCF-7)). The most potent compounds were the estrogen-artemisinin hybrids 27 and 28 (EC₅₀=1.18 and 1.07 μM, respectively) against prostate cancer, and hybrid 23 (EC₅₀=2.08 μM) against breast cancer. These findings demonstrate the high potential of hybridization of artemisinin and estrogens to further improve their anticancer activities and to produce synergistic effects between linked pharmacophores.

Full text of DOI:10.1002/cmdc.202000174

Accepted Article
Title: Synthesis of Tamoxifen-Artemisinin and Estrogen-Artemisinin
Hybrids Highly Potent Against Breast and Prostate Cancer
Authors: Tony Fröhlich, Christina Mai, Roman Bogautdinov, Svetlana
N. Morozkina, Alexander G. Shavva, Oliver Friedrich, Daniel
Gilbert, and Svetlana B. Tsogoeva
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1/2020

ChemMedChem
10.1002/cmdc.202000174
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Synthesis of Tamoxifen-Artemisinin and Estrogen-Artemisinin
Hybrids Highly Potent Against Breast and Prostate Cancer
Tony Fröhlich,[a] ‡ Christina Mai,[a] ‡ Roman P. Bogautdinov,[b] Svetlana N. Morozkina, Alexander G.
[b]
Shavva,[b] Oliver Friedrich, Daniel F. Gilbert,* and Svetlana B. Tsogoeva*
[c]
[c]
[a]
[
a]
Dr. T. Fröhlich, C. Mai, Prof. Dr. S. B. Tsogoeva
Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM)
Friedrich-Alexander University of Erlangen-Nürnberg
Friedrich-Alexander University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058 Erlangen, Germany
E-mail: svetlana.tsogoeva@fau.de
[
[
b]
c]
R. P. Bogautdinov, Prof. Dr. S. N. Morozkina, Prof. Dr. A. G. Shavva
Kronverkskiy prospekt
ITMO University
197101 St. Petersburg, Russia
Prof. Dr. O. Friedrich, PD Dr. D. F. Gilbert
Institute of Medical Biotechnology
Friedrich-Alexander-Universität Erlangen-Nürnberg
Paul-Gordan-Straße 3, 91052 Erlangen, Germany
E-mail: daniel.gilbert@fau.de
‡
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document
Abstract: In search for new and effective treatments of breast and
that the cure of these cancer types remain a challenging health
problem.
prostate cancer, a series of hybrid compounds based on tamoxifen,
estrogens and artemisinin were successfully synthesized and
analyzed towards their in vitro activities against human prostate (PC-
Natural product artemisinin (1, Figure 1) and its semisynthetic
derivatives dihydroartemisinin (DHA, 2), artesunic acid (3)
(Figure 1) initially were known to possess a high activity against
3
) and breast cancer (MCF-7) cell lines. Most of the hybrid
malaria,[ were found to have also an anti-cancer potency,
3]
[4]
compounds exhibit a strong anti-cancer activity against both cancer
cell lines e.g., EC50 (PC-3) down to 1.07 µM and EC50 (MCF-7) down
to 2.08 µM, thus showing higher activities than their parent
compounds 4-hydroxytamoxifen (Afimoxifene, 7) (EC50 (PC-3) = 75.1
µM and EC50 (MCF-7) = 19.3 µM), dihydroartemisinin (2) (EC50
including activities against breast and prostate cancer.[5]
Estrogens have remarkable and diverse pharmacological
properties, including anticancer activities.[6],[7] For instance, the
estrogen fulvestrant is an efficient estrogen receptor antagonist,
which was approved for the treatment of hormone-related breast
cancer,[ or abiraterone which is a known steroidal therapeutic
against prostate cancer.[9] Another class of anti-cancer drugs are
selective estrogen receptor modulators (SERMs), including
tamoxifen (5, Figure 1), which has been used for over 30 years
in treatment of hormone-dependent breast cancer.[
Nonetheless, the development of new effective medications for
the treatment of breast and prostate cancer is urgently needed,
as most of the currently available drugs are no longer effective
due to enhanced drug resistance in tumors (e.g., resistance to
tamoxifen[ and to abiraterone[12]) and many unwanted side
effects.[
(PC-3) = 263.6 µM and EC50 (MCF-7) = 49.3 µM) and artesunic acid
8]
(3) (EC50 (PC-3) = 195.1 µM and EC50 (MCF-7) = 32.0 µM). The most
potent compounds were the estrogen-artemisinin hybrids 27 and 28
EC50 (PC-3) = 1.18 µM and 1.07 µM, correspondingly) against
(
prostate cancer and hybrid 23 (EC50 (MCF-7) = 2.08 µM) against
breast cancer. These findings demonstrate the high potential of
hybridization of artemisinin and estrogens to further improve their
anticancer activities and to produce synergistic effects between
linked pharmacophores.
10]
11]
1a, 13]
Introduction
One of the most promising, time- and cost-effective drug
discovery approaches to obtain new anticancer compounds with
improved pharmacological properties is the hybridization of
existing drugs. The concept of hybridization means covalent
binding via linker of two or more bioactive compounds with
different mechanisms of action, which can result in the discovery
of new and potent drug candidates, able to exceed parent
compounds in the corresponding activities (by possible
Cancer is a leading cause of death worldwide, with breast cancer
being the most common cancer type in women and prostate
cancer being the second most frequent malignancy (after lung
cancer) in men.[ The fact that anti-cancer therapeutics have the
1]
[
2]
lowest clinical trial success rate of all major diseases, shows
1
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ChemMedChem
10.1002/cmdc.202000174
FULL PAPER
synergistic effects of subunits in a multifunctional hybrid drug),
even able to overcome drug resistance and being an alternative
to the standard drugs.[14]
Results and Discussion
Chemistry
While tamoxifen (5, Figure 1) has been used since its approval
to treat millions of women and men diagnosed with hormone-
receptor-positive breast cancer,[ recently tamoxifen-resistance
was reported.[11] We hypothesized, therefore, that linking
artemisinins with tamoxifen derivatives might result in novel
therapeutic agents with a decreased chance of developing
resistance.
10]
H
H
O
H
O
O
O
H
H
H
O
O
O
O
O
O
O
O
O
O
O
R1 R2
Z-N-desmethyl-tamoxifen (Z-DMT, 6) and 4-hydroxytamoxifen
(4-OHT, 7), which we used for the synthesis of novel hybrids 10-
OH
OH
O
1
: R /R2
1
2
=
O
1
3 (Figure 2), are active metabolites of tamoxifen (5). Estrone (8)
3
4
: R1 = OH, R2 = H
and ten of its synthetic analogues 35-42, 48 and 53 were chosen
to present estrogenic moieties of the designed estrogen-
artemisinin hybrid molecules 14-29 (Figure 3). The estrogen
analogues were chosen due to their different substituents in their
skeleton to elucidate the structure-activity relationship.
R3
N
N
O
HO
O
5
6
(Tamoxifen): R3 = CH3
(Z-DMT): R3 = H
7 (4-OHT, Afimoxifene)
We recently reported a new fluorescent artemisinin-derived
antiviral hybrid, containing an ester linker, which was studied for
its cellular uptake using confocal laser-scanning microscopy.[19]
H
O
O
H
O
O
No degradation of ester-linked hybrid under assay conditions
was observed. Another new artemisinin based hybrid with ester
linker was recently evaluated by us in vitro against P. falciparum
strains and in vivo in P. berghei-infected mice.[20] Notably, this
ester-linked hybrid was not only more potent in comparison to its
derivatives with amide and/or triazole linker, it has also
demonstrated high thermal, hydrolytic, and enzymatic
stability.[20] Other groups also reported in vivo studies of
O
O
O
OH
O
H
H
N
H
H
H
H
H
HO
O
8
(E1)
9
Figure 1. Structures of artemisinin (1) and its semisynthetic derivatives
dihydroartemisinin (DHA, 2), artesunic acid (3) and artemisinin-derived acid
), SERMs (tamoxifen (5), Z-DMT (6), 4-OHT (7)), estrone (8) and the first
(
4
artemisinin based hybrids containing an ester linker where no
problems of stability or cleavage are reported.[21] Based on these
[
15]
estrogen-artemisinin hybrid 9
.
previous results with artemisinin-derived hybrids with ester
linkers and ease of ester synthesis, we choose ester linker for
the preparation of most new hybrids in this work.
Notably, several successful attempts have been made already
to apply the method of hybridization in the development of new
medications against hormone-dependent breast[16] and
prostate[17] cancer.[18] Recently, our group reported the synthesis
Z-DMT (6) and 4-OHT (7) were first synthesized using a McMurry
reductive coupling[
22]
as a key step (Scheme 1). Thus,
propiophenone (31) was coupled with either benzophenone
derivative 30 or 33, yielding the triphenylethylenes 32 and 34.
of the first five estrogen-artemisinin hybrids (e.g., hybrid 9,
Figure 1), which were investigated for their in vitro anticancer
potential, and indeed, most of them were highly potent against a
panel of human malignant cells of gynecological origin
containing breast (MCF-7, MDA-MB-231, MDA-MB-361, T47D)
and cervical tumor cell lines (HeLa, SiHa, C33A).[ These hybrid
molecules can be regarded as potential lead compounds for
development of new improved anticancer agents. Following this
investigation and in order to obtain additional compounds for
structure-activity relationship (SAR) studies, we herein present
the synthesis of the first four tamoxifen-artemisinin hybrids and
sixteen estrogen-artemisinin hybrids and their investigation
against breast (MCF-7) and prostate (PC-3) cancer.
Compound 32 was then alkylated in order to obtain a 1:1 E/Z
mixture of 4-OHT (7).[
22]
Since pure Z-4-OHT is known to
equilibrate rapidly into E/Z equimolar mixture under physiological
conditions,[
16a]
the separation of E/Z isomers was considered
pointless, and, therefore, the mixture was used for further
coupling reactions. On the contrary, compound 34 was isolated
by crystallization from i-PrOH as pure Z-isomer (such derivatives
are much more stable towards isomerization under physiological
conditions) and reacted with methylamine, yielding Z-DMT (6).[
The compounds 6 and 7 were suitable for coupling with the
artemisinin derivatives 3 and 4 using carbodiimide activation.
Thus, starting from 7, hybrids 10 and 11 were obtained by
Steglich esterification with DCC.[24]
15]
23]
2
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ChemMedChem
10.1002/cmdc.202000174
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H
O
H
O
O
H
O
H
O
O
O
O
O
O
O
O
N
O
O
O
O
N
10
11
H
O
H
H
O
O
H
O
O
O
O
O
O
O
O
N
N
O
1
2
13
O
O
Figure 2. Structures of the synthesized tamoxifen-artemisinin hybrids 10-13.
However, later EDC was shown to have some superiority
concerning yields and simplicity of final purification, and it was
used in all subsequent couplings. The amidation reactions
artemisinin derivative 3 or 4. Finally, the phenolic hydroxyl is
deprotected using TBAF and converted to the desired sulfamate
group, yielding the five different hybrids 23-25 and 27-28.
involving
3
and 4, activated by this reagent gave the
This route had to be slightly modified in order to obtain hybrid 29
(Scheme 2), because in this case the starting material 53 bears
a methoxy moiety instead of the phenolic hydroxyl group as the
other starting materials 8, 35 and 48. Therefore, the first step
involves the reduction of the carbonyl group and demethylation
to give a phenolic hydroxyl group which is then protected by
silylation in the next step. The newly formed aliphatic hydroxyl
group is then used in an esterification with artesunic acid (3) and
again, the final sulfamate containing artemisinin-estrogen hybrid
29 is obtained by deprotection and conversion of the phenolic
hydroxyl group to a sulfamate moiety. This procedure was further
improved for the synthesis of hybrid 26, where no protection of
the phenolic hydroxyl group was performed. Thus, hybrid 26 was
obtained after only two steps, instead of five or six as previously
described, involving firstly, a conversion of the alcohol to the
sulfamate group and secondly, reduction of the carbonyl
group,[28] followed by an esterification reaction[24] between 57
and artesunic acid (3). The stability of the hybrid compounds 10-
29 was assessed by exposition to heat (65°C/60°C/40°C) for
24 h to 48 h (see the Supporting Information for more details).
[
25]
corresponding amide-bond linked hybrids 12 and 13. Hence,
the diverse set of tamoxifen-based hybrids was synthesized
(Figure 2). All of them are supposed to have different chemical
and enzymatic stability depending on the type of linker. The next
class of hybrids was based on estrogen-derivatives. As such,
new hybrids 14-22 (Figure 3) were synthesized by reacting
artesunic acid (3) in an esterification reaction, using EDC as
carbodiimide activator, with the corresponding estrogen
derivatives 8 or 35-42 (Scheme 2).[24] Hybrids 14-22 were
obtained in good to excellent yields of 79% to 95%. Furthermore,
estrogen-derivatives bearing a sulfamate moiety were used as
building blocks for a hybridization reaction with artemisinin
derivatives providing the new hybrid molecules 23-29 (Figure 3).
Sulfamate based estrogen analogues are a well-known new
class of potential medications against hormone-dependent
diseases,[26] and for that reason we decided to evaluate the
potency of their hybrids with artemisinin against breast and
prostate cancer. Starting with
transforming the phenolic hydroxyl group in 8, 35 and 48 to a
tert-butyldimethylsilyl ether,[ the subsequent reduction of the
a protection reaction by
27]
1
After applying these conditions, H NMR showed less than 5%
carbonyl group with NaBH
4
gives the hydroxyl moiety which is
decomposition indicating a sufficient stability of all hybrids.
necessary for the following coupling reaction with either
3
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ChemMedChem
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FULL PAPER
H
H
O
H
O
O
O
O
O
O
H
H
O
H
O
O
O
O
O
O
H
H
H
H
H
O
O
O
O
O
O
O
O
H
H
H
H
H
H
H
H
O
H
O
O
O
O
H
1
4
15
16
H
H
O
O
O
O
O
O
H
H
O
O
O
O
O
O
O
O
H
H
O
O
O
F
O
O
O
O
O
H
H
O
H
H
O
H
O
O
O
H
O
O
O
O
H
1
7
18
19
H
H
O
H
O
O
O
O
H
O
O
O
O
O
O
H
H
O
O
O
O
O
O
O
O
H
H
H
H
H
O
O
O
O
O
O
O
2
0
21
22
H
O
H
H
O
O
O
H
H
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
O
H
H
O
O
H
H
O
O
O
S
H
H
O
H
H
S
S
O
H N
O
O
2
H
2
N
2
H N
23
24
25
H
O
O
H
O
O
O
O
H
O
O
H
O
O
O
O
H
O
O
O
O
O
H
H
O
S
N
H
2
6
H
H
O
H
O
O
O
O
H
H
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
O
O
O
O
H
O
H
O
H
O
H
S
S
S
O
O
O
H
2
N
H
2
N
2
H N
2
7
28
29
Figure 3. Structures of the synthesized estrogen-artemisinin hybrids 14-29.
4
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O
Cl(CH
Cs
2
)
2
NMe
2
3 or 4
DCC, DMAP
O
3
1
CO
2
3
1
0/11
TiCl , Zn
4
DMF
THF
HO
OH
THF
N
80% / 78%
HO
OH
HO
O
3
0
3
2
4-OHT (7)
24% (E/Z 1:1)
9
4%
O
3 or 4
EDC, DMAP, TEA
O
3
1
MeNH
2
1
2/13
TiCl , Zn
THF
4
EtOH
Cl
H
N
O
THF
75% / 68%
Cl
O
O
3
3
34
2%
6
82%
4
Scheme 1. Synthesis of tamoxifen-artemisinin hybrids 10-13.
Biological evaluation
measurement of intracellular ATP content. Average (mean ± SD)
agonist dose–responses were constructed by pooling results
from wells exposed to different solutions and are shown in the
Supporting Information in Figure S2 – S3. The determined half-
maximal inhibition concentration (EC50) for 4-OHT (7), DHA (2),
artesunic acid (3), estrogen precursor 57 and the hybrids 10-29
are shown in Table 1. These data demonstrate that most of
hybrids are more active against PC-3 and MCF-7 than their
parent compounds DHA (2), artesunic acid (3) and selected
estrogen 57 (precursor of hybrid 26). Additionally, a combination
of estrogen 57 and artesunic acid (3) was analyzed, which
showed an activity similar to that of artesunic acid (3) alone.
Furthermore, most of hybrids are more active than 4-OHT (7),
excepted hybrids 17, 19 and 20, which are based on steroidal
phenols. Comparing the tamoxifen based hybrids, it is interesting
that, the hybrids 11 (EC50 = 16.0 µM) and 13 (2.74 µM), with the
artemisinin-derived acid 4, are more active than the hybrids 10
(EC50 = 45.6 µM) and 12 (EC50 = 6.38 µM) containing artesunic
acid (3) as building block, while, in general, the hybrids 12 and
13 based on Z-DMT (6) are more active.
Following the synthesis of hybrid molecules, we intended to
evaluate their chemotherapeutic potential. To evaluate the
potential of hybrid molecules in the context of breast cancer, we
aimed to assess the cellular fitness of MCF-7 cells in response
to compound exposure. MCF-7 is a common and estrogen
receptor-positive breast cancer in vitro model that has been used
for more than 40 years in breast cancer research. [29] To analyze
the cell line specificity of the hybrid molecules, we aimed to
assess their cytotoxic activity also in PC-3 cells. Notably, PC-3
cells do not respond to androgens, glucocorticoids, or epidermal
or fibroblast growth factors and are thus, suitable to identify
estrogen receptor-dependent cytotoxic activity of the
synthesized molecules.[30] To assess the chemotherapeutic
potential, i.e. the cytotoxic activity of the hybrid molecules, we
employed
quantification of the intracellular ATP concentration [ATP]
Noteworthy, [ATP] serves as an energy carrier that basically
drives all cell functions. Persistent depletion of [ATP] causes a
a common assay type, which is based on
i
.
i
i
cell to die and, in turn, cell death is indicated by low ATP levels.
Due to its simple accessibility, e.g. by an ATP-dependent
luciferase-luciferin reaction, intracellular ATP has been a long-
serving indicator of cellular fitness.[ Cell fitness screening in
MCF-7 and PC-3 cells was conducted in 384-well plates as
described in the Methods section. Each chemical was tested in
increasing concentrations (0.001, 0.01, 0.1, 1, 10, 100 and 300
µM) and was incubated for 24-36 h with at least three replicates
per concentration. The cytotoxic activity was assessed based on
Besides these, the hybrids 23-25 and 29, with EC50 values
ranging from 3.94 to 2.04 µM, are very active and 27 (EC50
=
31]
1.18 µM) and 28 (EC50 = 1.07 µM), containing a naphthalene
moiety, are most active. Besides PC-3, all hybrids and parent
compounds were also tested towards their biological activity
against MCF-7. Within the experiments, the two hybrids 15 and
28 showed no activity at all against MCF-7, whereas hybrid 28
exhibited a very high activity against PC-3.
5
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ChemMedChem
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FULL PAPER
.
H
O
H
H
O
O
O
O
H
O
H
H
O
O
O
O
O
O
H
A3
A4
=
=
X
Z
EDC, DMAP, TEA
THF
O
O
O
+
14 - 22
9-95%
O
O
Z
n
H
Y
H
O
HO
OH
7
O
O
3
4
3
8 or 35-42
A3/4
O
OH
O
1) TBSCl
3 or 4
imidazole, THF
EDC, DMAP
1) TBAF, THF
2) NH SO Cl
H
H
H
2
3 - 25
2) NaBH4
THF
2
2
H
H
H
H
H
H
MeOH/THF
DMA
6
9-75%
HO
TBSO
TBSO
4
5/46
47
88%
8
:
C8-H
43 or 44
or
8
9%/64%
35: C8-H
A3
O
OH
O
1
) TBSCl
3
imidazole, THF
DCC, DMAP
1) TBAF, THF
2) NH SO Cl
2
7, 28
2
) NaBH
4
THF
2
2
H
H
H
MeOH/THF
DMA
6
0%, 21%
HO
TBSO
TBSO
4
9
50
21%
51
80%
52
98%
48
or
or
33%
A3
O
OH
OH
O
1) NaBH
4
TBSCl,
3
THF/H O
imidazole
DCC, DMAP
1) TBAF
2
2) NH SO Cl
2
H
H
H
2
9
H
2) DIBAL
THF
THF
2
H
H
H
H
H
H
toluene
DMA
H
H
67%
O
O
HO
O
TBSO
O
TBSO
O
56
5
3
5
5
4
0%
55
64%
95%
O
OH
1
) NH
DMA
2
SO
2
Cl
3
H
H
EDC, DMAP, TEA
2
6
H
H
2) NaBH
MeOH/THF
4
H
H
THF
HO
H NSO
2 3
33%
8
57
Scheme 2. Synthesis of estrogen-artemisinin hybrids 14-29 using enantiopure estrone (8) and racemic estrogens 35-42, 48, 53.
Nevertheless, many compounds showed higher activity than
their parent compounds artesunic acid (3) and DHA (2), but only
ten of them are even more active than 4-OHT (7) (EC50 =19.3
µM) with EC50 values between 20.0 and 2.08 µM, where hybrid
showed relatively high SD values. Due to the fact, that the
averaged data with relatively higher SD values confirm the dose-
dependent effects of the tested molecules, those compounds
were not subjected to re-testing. The reason for the observed
higher SD values was not evaluated in detail but may be due to
errors during liquid handling using multi-channel pipetting
devices.
1
0 (EC50 = 20.0 µM) showed a similar activity as 7. The highest
activity was seen with the hybrids 13, 23-25 and 29 (EC50 = 3.91
2.08 µM). Although we observed an overall high reproducibility
–
in our in vitro study with MCF-7 and PC-3 cells, some of the
conducted experiments, depicted in the supporting information,
6
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Table 1. EC50 values for DHA (2), artesunic acid (3), Afimoxifene (4-OHT, 7), precursor 57 and hybrids 10-29 against human prostate (PC-3) and breast cancer
(
MCF-7) cell lines
PC-3
MCF-7
MW
compound
(g/mol)
EC50 (µM)
75.1
263
SD
EC50 (µM)
19.3
49.3
32.0
20.0
15.7
22.1
3.91
27.7
> 1000
14.8
17.4
51.8
23.8
56.7
7.03
5.23
2.08
3.09
2.84
22.3
165
SD
Afimoxifene (7)
DHA (2)
387.52
284.35
384.43
753.93
695.90
723.90
665.87
636.78
636.78
650.81
654.77
638.75
680.79
650.81
664.84
678.86
717.87
717.87
659.84
1084.28
351.46
81.5
82.5
72.4
4.29
4.58
8.90
2.17
4.01
19.3
119
17.5
6.33
5.67
1.65
4.95
57.1
4.15
7.54
-
Artesunic acid (3)
195
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
57
45.6
16.0
6.38
2.74
14.3
20.7
41.8
179
3.75
5.22
44.6
5.04
61.2
4.19
3.76
0.45
0.85
1.52
3.48
50.6
176
10.5
114
14.4
31.6
70.2
10.0
0.82
1.72
0.61
0.85
1.72
-
111
14.1
5.62
3.23
2.04
3.76
33.7
>1000
5
(
7 + 3
1:1)
351.46 + 384.43
156
45.4
33.7
6.03
27
28
29
755.92
755.92
747.90
1.18
1.07
3.94
1.44
0.18
1.44
52.7
>1000
3.86
154
-
1.85
7
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Sekar, R. G. Correa, Y. Wang, X. Gu, M. Bashin, K. Chibale, T. A.
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We gratefully acknowledge the financial support from Deutsche
Forschungsgemeinschaft (DFG) by grant TS 87/16-3. We also
thank the Interdisciplinary Center for Molecular Materials (ICMM),
the Graduate School Molecular Science (GSMS) for research
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Keywords: artemisinin • estrogen • tamoxifen • hybrid • anti-
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Entry for the Table of Contents
The synthesis and biological investigations of 4 novel tamoxifen-artemisinin and 16 new estrogen-artemisinin hybrid molecules
exceeding in most cases their parent compounds, as well as reference drug in anticancer activities, are presented. The
developed hybrids exhibit an excellent in vitro activity against human prostate (PC-3) and breast cancer (MCF-7) cell lines.
1
0
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