Artemisinin-indole and artemisinin-imidazole hybrids: Synthesis, cytotoxic evaluation and reversal effects on multidrug resistance in MCF-7/ADR cells

Article abstract of DOI:10.1016/j.bmcl.2019.02.021

A series of artemisinin derivatives with MDR reversal activity were designed and synthesized. All hybrids were screened to anticancer activities against four human cancer cell lines (A549, MCF-7, HepG-2, MDA-MB-231) and normal human hepatic cell (L02) in vitro. Most of the new compounds showed higher anticancer activities than artemisinin, among which compounds 11a and 11c displayed superior potency with IC₅₀ 6.78 μM and 5.25 μM against MCF-7, respectively. The further research indicated that the most potent 11c induced cell cycle arrest at G2 phase in MCF-7. Additionally, compound 11c showed remarkable MDR reversal activity which reversed adriamycin against MCF-7/ADR cells with IC₅₀ 0.76 μM.

Full text of DOI:10.1016/j.bmcl.2019.02.021

Accepted Manuscript
Artemisinin-indole and artemisinin-imidazole hybrids: Synthesis, cytotoxic
evaluation and reversal effects on multidrug resistance in MCF-7/ADR cells
Yanping Hu, Na Li, Jiayao Zhang, Ying Wang, Li Chen, Jianbo Sun
PII:
S0960-894X(19)30105-2
https://doi.org/10.1016/j.bmcl.2019.02.021
BMCL 26301
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 January 2019
13 February 2019
19 February 2019
Please cite this article as: Hu, Y., Li, N., Zhang, J., Wang, Y., Chen, L., Sun, J., Artemisinin-indole and artemisinin-
imidazole hybrids: Synthesis, cytotoxic evaluation and reversal effects on multidrug resistance in MCF-7/ADR
cells, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.02.021
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Artemisinin-indole and artemisinin-imidazole hybrids: Synthesis,
cytotoxic evaluation and reversal effects on multidrug resistance in
MCF-7/ADR cells
Yanping Hu, Na Li, Jiayao Zhang, Ying Wang, Li Chen* and Jianbo Sun*
State Key Laboratory of Natural Medicines, Department of Natural Medicinal
Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical
University, 24 Tong Jia Xiang, Nanjing 210009, China.
*Corresponding author. Tel.: +86-25-83271415; e-mail: chenli627@cpu.edu.cn (L.
Chen)
*Corresponding author. Tel.: +86-25-83271415; e-mail: sjbcpu@gmail.com (J.B. Sun)

ABSTRACT
A series of artemisinin derivatives with MDR reversal activity were designed and
synthesized. All hybrids were screened to anticancer activities against four human
cancer cell lines (A549, MCF-7, HepG-2, MDA-MB-231) and normal human hepatic
cell (L02) in vitro. Most of the new compounds showed higher anticancer activities
than artemisinin, among which compounds 11a and 11c displayed superior potency
with IC50 6.78 μM and 5.25 μM against MCF-7, respectively. The further research
indicated that the most potent 11c induced cell cycle arrest at G2 phase in MCF-7.
Additionally, compound 11c showed remarkable MDR reversal activity which
reversed adriamycin against MCF-7/ADR cells with IC50 0.76 μM.
Keywords: artemisinin, indole, imidazole, anticancer activities, MDR reversal
activity

Cancer, with uncontrolled, rapid and pathological proliferation of abnormal cells,
is one of the refractory diseases in the world 1. The chemotherapy of cancer remains a
2
severe challenge because of the drug resistance and severe side effects . Therefore,
looking for drugs with better pharmacological activity, reversal resistance, high
selectivity and safety has been the goal of scientific research.
Drug repurposing is described as applying known drugs or compounds with
proven clinical safety to new diseases or indications 3-4. For example, sildenafil was
first used to dilate blood vessels but made poor efficacy. Later, FDA approved it for
impotence treatment in 1998. Recently, studies found that it had the potential as a lung
cancer therapy chemoadjuvant5. Aspirin first used as pain reliever and then as
anti-inflammatory drug6. In recent years, researchers found that it also had
antithrombotic effects7. Repurposed drugs are typically approved for clinical which
result in significant time and cost savings. Hence, drug repurposing has become one
of the important strategies for drug research. Artemisinin (ART, Fig. 1), a traditional
Chinese medicine, has been used for treat malaria for decades and showed excellent
safety in clinical 8-9. The structure of artemisinin contains endoperoxide, acetal,
lactone, seven chiral carbons and the tetracyclic system which accounts for its poor
solubility both in oil and water. Therefore, it is extremely important to modify the
structure of artemisinin. Dihydroartemisinin (DHA) and artesunic acid (ATS) (Fig. 1),
the first generation of artemisinin, improved the solubility and enhanced their
antimalarial activities 10-11
.

Fig.1. Structures of artemisinin and its semisynthetic derivatives.
Not until 1993 did researchers find that artemisinin had the potential in antitumor
12. After that, artemisinin and its derivatives have received much attention for
searching antitumor agents 13-15. A great number of artemisinin derivatives had been
synthesized. The synthetic strategies mainly focused on the C-9 and C-10. What’s
more, the group of Soomro Shahid found that the C-10 derivatives were more active
16
than C-9 derivatives . As shown in Fig.2, compound 2 was 179 fold and 48.9 fold
stronger than 4 against CCRF-CEM cells and CEM/ADR5000 cells, respectively16.
Thus, the structure modification was at C-10 position of artemisinin in this study.
Fig.2. The structure-activity research from Soomro Shahid group (Based on
reference 16).
N-heterocycles are widely present in various materials, especially biologically

17
18
active molecules . N-heterocyclic moieties exhibit improved solubility . Nitrogen
atom can influence the interaction between the molecule and its target because it can
19
act as a hydrogen bond acceptor or donor . Indole scaffold was considered as the
feature of many pharmacologically active compounds derivatives. Researchers have
embarked on the development of indole derivatives as potent anticancer agents20-21
.
For instance, the Bcl-2 antagonist obatoclax (5, Fig. 3) could antagonize MCL-1 and
overcome MCL-1-mediated resistance to apoptosis22. Indibulin (6, Fig. 3), a
multi-targeted receptor tyrosine kinase inhibitor, has been progressed to clinical
trials23-24. Another nitrogen heterocyclic compound imidazole shows various
biological activities such as antitumor, antifungal, antiparasitic, etc.25. Imidazole
could combine with a variety of enzymes and protein receptors in the biological
system26-27. This interaction could be enhanced when a nitro substituted on
imidazole28. Nitroimidazole derivatives are easy to bind to many macromolecules
such as DNA, enzymes and receptors in organisms29. The clinical used drug
glycididazole sodium (7, Fig. 3) has been confirmed as effective radiotherapy and
chemotherapy sensitizer30. Additionally, imidazole derivatives (8, 9, Fig. 3) had been
confirmed as efficacious multidrug resistance (MDR) modulator31-32. Hence, indole
and imidazole moieties were introduced respectively to artemisinin to form
artemisinin-indole and artemisinin-imidazole hybrids in this study.

Fig. 3. Structures of compounds bearing indole-based and imidazole-based moieties.
Herein, 19 of DHA-indole and ATS-imidazole hybrids were designed and
synthesized. Their activities were evaluated against several human cancer cell lines by
MTT assay. Moreover, cell cycle arrest of 11c was biologically examined to reveal the
mechanisms of activation of these hybrids. Besides, MDR reversal activity in
MCF-7/ADR cells was assayed to investigate the reversal of drug resistance.
The synthesis of target compounds 11a-d, 13a-n were outlined in Scheme 1.
33
DHA (2) was synthesized according to the literature by reacting with artemisinin
o
and NaBH4 at 0 C for 3 h with high yield. The intermediates 12a-n were prepared
from
2-bromoethanol/3-bromo-1-propanol/4-bromo-1-butanol at 55 C for 12 h. Then the
target compounds (Table and 2) were synthesized by using
1-ethyl-3-(3-d-im-ethylaminopropyl) carbodiimide (EDCl) and
4-dimethyl-aminopyridine (DMAP) stirring at room temperature for 8 h.
the
corresponding
imidazole
by
heating
with
o
1

Scheme 1. Reagents and conditions: (i) EDCl/DMAP, dry DCM, r.t. 8 h; (ii)
2-bromoethanol/3-bromo-1-propanol/4-bromo-1-butanol, K2CO3, KI, acetone, reflux,
12 h.
Table 1. Structures of artemisinin derivatives (11a-11d).

Table 2. Structures of artemisinin derivatives 13a-13o.
Compd.
13a
n
1
1
1
1
1
2
2
2
R1
NO
H
R2
R3
H
H
H
H
Compd.
13i
n
2
2
3
3
3
3
3
R1 R2
R3
H
H
H
H
H
H
H
H
NO
13b
13c
Br
13j
Cl CN
H
NO
CN
13k
N
H
O
H
13d
13e
Cl
H
13l
Br
NO
CN CN 13m
H
13f
NO
H
H
H
H
H
13n
13o
Cl CN
13g
Br
NO
H
CN CN
13h
H
The synthesized compounds 11a-d, 13a-o were evaluated their anticancer
activities against human breast cancer cell line MCF-7, human non-small-cell lung

cancer cell line A549, human hepatocellular carcinoma cell line HepG-2 and human
normal liver cell line L02 in vitro. It was reported that artemisinin was resistant in the
highly metastatic MDA-MB-231 breast cancer cell line 34. Therefore, the activity
against MDA-MB-231 was tested. The result was summarized in Table 3. Evidently,
most of the tested compounds displayed superior activities than artemisinin,
dihydroartemisinin and artesunic acid. All of the hybrids exhibited higher cytotoxicity
to MCF-7 than A549, HepG-2 and MDA-MB-231. Particularly, compounds 11a and
11c showed high cytotoxicity against three cancer cell lines (MCF-7, A549, HepG2),
especially 11c exhibited specific cytotoxicity against MCF-7 with IC50 5.25μM which
was 10-fold more than artemisinin. However, the length of linker of
artemisinin-imidazole seemed to have no effect on cytotoxicity. Importantly, all the
active compounds were screened for the toxicity against human normal liver cell line
L02 and showed weak antiproliferative activities with IC50 ranging from 31.00 to
72.82μM while adriamycin displayed high toxicity with IC50 0.79 μM.
Table 3. Anti-proliferative effects of new artemalogues against human cancer cell
lines.
IC50 (μM)a
Compd.
MCF-7
A549
HepG-2
MDA-MB-231
58.91±2.50
70.42±4.36
>100
L02
11a
11b
11c
11d
13a
6.78±0.50
14.48±0.36
5.25±0.39
>50
12.92±0.35
13.39±1.12
6.17±0.26
>50
15.21±0.37
27.67±2.20
10.83±0.26
>50
42.59±2.57
36.35±2.31
31.00±1.82
>100
>100
16.37±0.56
14.01±1.40
23.72±3.36
39.35±2.56
50.20±3.43

24.74±2.33
31.94±0.31
13b
13c
13d
13e
13f
13.09±2.47
13.97±0.58
17.46±0.88
10.75±0.63
12.86±0.31
12.40±0.38
12.69±0.30
13.80±0.31
16.23±0.37
9.78±0.15
11.64±0.38
15.40±1.49
13.61±1.81
15.17±0.40
>50
>100
66.88±3.88
56.21±1.68
61.25±1.23
49.05±2.86
46.37±5.21
>100
12.70±0.38
20.68±0.62
12.36±1.35
20.95±0.41
26.02±0.24
19.97±1.61
19.61±2.43
26.71±2.13
16.53±0.39
18.88±1.17
25.79±2.22
23.31±5.33
17.92±2.31
>50
34.92±3.84
44.30±2.91
25.59±0.35
39.30±2.29
41.59±4.12
33.33±4.26
>50
82.26±5.58
66.44±1.88
>100
>100
13g
13h
13i
80.92±5.38
80.92±3.33
>100
34.32±4.57
72.82±1.41
66.18±2.55
45.74±3.26
41.30±1.70
77.52±1.24
52.33±3.07
42.92±5.98
>100
13j
>50
93.15±8.37
85.20±6.15
>100
13k
13l
21.25±1.21
35.85±3.52
30.19±6.50
40.22±4.49
32.34±4.12
>50
13m
13n
13o
ART
DHA
ATS
56.98±4.49
>100
50.82±6.40
>100
34.29±2.85
38.71±5.73
45.33±1.27
50.68±3.34
1.13±0.28
31.71±8.41
39.93±3.38
0.85±0.18
58.69±5.20
75.69±3.29
2.94±0.06
40.21±1.02
72.17±1.14
0.79±0.02
adriamycin b 0.67±0.11
aMTT methods, cells were incubated with corresponding compounds for 48 h. IC50
values (means ± SD, n = 3).
bAdriamycin as the positive control.
Previous studies have shown that artemisinin could inhibit the proliferation of
tumor cells by inducing arrest of the cell cycle35-37. To investigate the mechanism of
cytotoxicity of these derivatives, 11c was selected to examine the effect on cell cycle
using propidium iodide (PI) staining. MCF-7 cell was treated with different
concentrations of 11c for 48 h. As a result, compound 11c reduced the cells at G1
phase from 52.44% to 39.61% and cells at S phase from 24.31% to 21.41%. However,

it made a significant increase at G2 phase from 23.25% to 38.97% (Fig. 4). These
results showed that compound 11c induced MCF-7 cell cycle arrest at G2 phase.
Fig. 4. Compound 11c induce cell cycle arrest in MCF-7. The cells were treated with
0, 2.5 μM, 5 μM and 10 μM of 11c for 48 h. Cell cycle analysis was evaluated via PI
fluorescence and flow cytometry.
Lack of cytotoxicity is an important requirement to clearly distinguish any
38-39
potential effects from synergism of an active compound with adriamycin (ADR)
.
Therefore, cytotoxicity assay was carried out to determine the activity of all new
hybrids in parental ADR-sensitive MCF-7 cells. As show in Table 4, the result
suggested that all of the tested compounds were inactive at the concentration of 5 μM,
which leading to the following MDR reversal experiment.
The MDR reversal activity was performed by combination of 5 μM of compounds
and different concentrations of ADR using MCF-7/ADR cells which exhibited high
resistance to ADR with resistance index (RI) being 133 folds (Table 5). The result was
listed in Table 6. All of the tested compounds at 5 μM and ADR displayed increasing
cytotoxic effects with reversal fold (RF) ranging from 4.10 to 117. Compounds that

exhibited reversal fold values greater than 15.0 were classified as potential MDR
modulators40. Among these compounds, 13b, 13d, 13e, 13g, 13i, 13j, 13k, 13l, 13n
and 13o showed moderate reversal activity (1<RF≤15). Surprisingly, potential
activities were observed in compounds 11a, 11b, 11c, 11d, 13a, 13c, 13f, 13h and
13m (RF>15). Especially compound 11c possessed remarkable MDR reversal activity
than the positive control (verapamil) against MCF-7/ADR cells. The structure-activity
relationship studies suggested that the reversal activity of artemisinin-indole
derivatives were better than that of artemisinin-imidazole derivatives. As shown in
Table 6, compound 11a-d contains an indole moiety showed superior MDR reversal
activity with RF values ranging from 61.05 to 117, while the RF values of 13a-o only
ranging from 4.10 to 27.09. For the reversal activity of artemisinin-imidazole
derivatives, the 4-nitro substitution was better than 2-nitro substitution on imidazole
group, while the bromine or cyano substitution was the worst. Compounds with two
carbons in linker were more active than compounds contained three or four carbons in
linker.
Table 4. Cytotoxicity of compounds in MCF-7 cells.
Compd. IRa (%) at 5 μMb
Compd.
IRa (%) at 5 μMb Compd.
IRa (%) at 5 μMb
11a
11b
11c
11d
13a
18.85
19.84
32.07
5.38
13d
13e
13f
21.30
13.70
22.28
23.23
22.31
13k
13l
19.76
8.95
13m
13n
13o
20.25
16.60
11.25
13g
13h
13.46

13b
13c
12.41
7.78
13i
13j
12.75
15.00
aIR: Inhibitory rate.
bMTT methods, cells were incubated with corresponding compounds for 48 h at a
concentration of 5 μM. Values are mean of three independent experiments.
Table 5. Resistance to ADR in MCF-7/ADR cell.
Sensitive MCF-7
IC50 (μM)a
MCF-7/ADR
IC50 (μM)a
Reversal index
(RI)b
ADR
0.67±0.11
89.14±4.89
133
aMTT methods, cells were incubated with corresponding compounds for 48 h. IC50
values (means ± SD, n = 3).
bReversal index (RI)= IC50(MCF-7/ADR)/ IC50(MCF-7).
Table 6. Reversal activity of tested compounds towards MCF-7/ADR cells.
Compd.
ADR
+11a
+11b
+11c
+11d
+13a
+13b
+13c
+13d
+13e
+13f
IC50 (μM)a
89.14±4.89
0.93±0.05
1.24±0.11
0.76±0.02
1.46±0.08
3.29±0.13
13.99±1.42
2.05±0.33
9.65±0.50
16.47±0.61
5.34±0.18
RFb
Compd.
+13g
+13h
+13i
IC50 (μM)a
15.93±0.84
5.67±0.57
10.48±0.21
20.38±1.54
6.06±0. 28
16.04±0.78
3.42±0.19
7.98±0.32
21.76±0.88
2.25±0.09
RFb
5.60
95.85
71.89
117
15.72
8.51
+13j
4.37
61.05
27.09
6.37
+13k
+13l
14.71
5.56
+13m
+13n
+13o
+VRPc
26.06
11.17
4.10
43.48
9.24
5.41
39.62
16.69

aMTT methods, cells were incubated with corresponding compounds for 48 h.
IC50 values (means ± SD, n = 3).
bReversal fold (RF)= IC50(ADR)/ IC50(ADR + compounds).
cVerapamil (VRP) as the positive control.
In conclusion, a series of new artemisinin derivatives were synthesized and their
biological activities were evaluated. Most of the new compounds showed enhanced
antiproliferative activities against MCF-7, A549 and HepG-2 cells than artemisinin
and lower cytotoxicity to L02 cells than positive control (adriamycin). Notably,
compound 11c showed the most potential against MCF-7 with IC50 5.25 μM. The
study on cell cycle arrest indicated that compound 11c induced MCF-7 cells cycle
arrest at G2 phase. It is worthy that all the tested compounds could reverse MDR in
MCF-7/ADR cells with reversal fold values ranging from 4.10 to 117. Especially
compound 11c possessed remarkable MDR reversal activity which reversed
adriamycin against MCF-7/ADR cells with IC50 0.76 μM. According to the result
above, compound 11c was identified as a potential anticancer and MDR reversal
candidates.
Acknowledgments
This research was financially supported by "Double First Class" Subject
Innovation Team Construction Project of China Pharmaceutical University
(CPU2018GY12).
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Highlights
• A series of artemisinin derivatives were designed and synthesized..
• Most of the hybrids showed better anticancer activities than artemisinin.
• Cell cycle research indicated that 11c induced MCF-7 cell cycle arrest at G2
phase.
•Compound 11c showed remarkable MDR reversal activity which reversed
adriamycin against MCF-7/ADR cells with IC50 0.76 μM.
Graphical abstract
19 novel artemisinin-indole and artemisinin-imidazole hybrids have been designed and synthesized. The
in vitro anti-tumor activity screening results showed that the indole-based hybrids of artemisinin were the
effective chemical modification to improve the anticancer activity of artemisinin. The study on cell cycle
arrest indicated that compound 11c induced MCF-7 cells cycle arrest at G2 phase. The MDR reversal
activity in MCF-7/ADR cells indicated that artemisinin-based compounds could reverse multidrug
resistance.