Synthesis of a novel series of artemisinin dimers with potent anticancer activity involving Sonogashira cross-coupling reaction

Article abstract of DOI:10.1016/j.bmcl.2013.11.032

A series of C-10 acetal artemisinin dimers were synthesized using Sonogashira cross-coupling reaction. All these novel semisynthetic artemisinin dimers exhibited excellent growth inhibitory activity against Lung A-549 human cancer cell line.

Full text of DOI:10.1016/j.bmcl.2013.11.032

Bioorganic & Medicinal Chemistry Letters 24 (2014) 237–239
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of a novel series of artemisinin dimers with potent
anticancer activity involving Sonogashira cross-coupling reaction
b
b
Pori Buragohain a, Bishwajit Saikia a, Naresh Surineni a, Nabin C. Barua a, , Ajit K. Saxena , Nitasha Suri
⇑
a Natural Products Chemistry Division, CSIR-North-East Institute of Science & Technology, Jorhat 785006, Assam, India
b Pharmacology Division, Indian Institute of Integrative Medicine, Jammu 180001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of C-10 acetal artemisinin dimers were synthesized using Sonogashira cross-coupling reaction.
All these novel semisynthetic artemisinin dimers exhibited excellent growth inhibitory activity against
Lung A-549 human cancer cell line.
Received 14 August 2013
Revised 13 November 2013
Accepted 14 November 2013
Available online 23 November 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Artemisinin
Sonogashira cross-coupling
Artemisinin dimer
Anticancer
Dihydroartemisinin
Artemisinin (1) is the first natural endoperoxide containing ses-
quiterpene lactone isolated from Chinese herb Artemisia annua.
Artemisinin and its derivatives, such as artemether, arteether, arte-
suic acid, artelinic acid are worldwide used as chemotherapeutic
agents against multidrug-resistent malaria caused by Plasmodium
falciparum (Fig. 1).1–3 Artemisinins act more rapidly by killing par-
asites and by inhibiting their major metabolic processes, such as
glycolysis, nucleic acid and protein synthesis. The antimalarial
activities of artemisinin and its derivatives have been recognized
as therapeutic agents for malaria and applied clinically. Interest-
ingly, the recent revelation of artemisinins as anticancer agents
against various cancer cell lines have evoked many interests on
this class of compounds as evident from numerous publications
in various high ranking scientific journals.4–21
Artemisinin dimers are a new class of artemisinin derivatives
obtained by joining two artemisinin molecules without destroying
their endoperoxide bridge. A search of literature revealed that the
endoperoxide bridge in artemisinin is the key factor for its out-
standing medicinal value and its sensitive nature restricts wide-
spread use of stringent reaction conditions for its derivatization.
So far the majority of artemisinin analogues were synthesized via
chemical modification of artemisinin at its C-10/C-13 position.22,23
Thus, Beekman et al. have reported the anti-cancer activity of C-10
acetal dimers where two artemisinin units are connected through
an ether-linkage.24 Posner et al. have confirmed the role of linker in
affecting the biological activity of dimers and synthesized a series
of artemisinin C-10 acetal dimers linked through by a polyethylene
15
H
5
6
4
7
8
3
5a
12a
O
O
14
O
8a
9
12
10
O
13
O
1
Figure 1. Structure of artemisinin.
glycol or carbon chain link or disulfide linker, with varying length
and flexibility.25,26 Lee and co-workers have reported that intro-
duction of a sulfur atom to an artemisinin moiety affords new
derivatives with unique biological properties which selectively
control tumor related angiogenesis.27,28
With this background, we attempted to synthesize some C-10
acetal artemisinin dimers where two artemisinin units were con-
nected through aromatic ring. We recently synthesized a series
of artemisinin dimers involving dinitroaliphatic and triazole
moiety as a linkers.29–31 In continuation of our interest to maxi-
mize the structural diversity of artemisinin analogues for further
value addition we decided to synthesize artemisinin dimers using
Sonogashira cross-coupling reaction. Imperative need of highly
effective compounds with enhanced pharmacological properties
has resulted in the continuous search for simple and efficient
methods for generation of libraries for biological screening. Sono-
gashira-cross-coupling reaction has emerged as one of the most
powerful and reliable carbon–carbon bonds forming reaction for
the synthesis of novel compounds with desired chemistry.32–39
⇑
Corresponding author.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.11.032

238
P. Buragohain et al. / Bioorg. Med. Chem. Lett. 24 (2014) 237–239
in acetonitrile at room temperature to furnish the desired dimers
H
H
O
5a (67%), 5b (60%), 5c (50%), 5d (59%), 5e (57%), 5f (47%), 5g
(55%) and 5h (50%) in isolated yields (Scheme 2). Accordingly,
the stereochemistry of all the eight dimers remained intact as
C-10b acetal derivatives and was confirmed from the H-9/H-10
coupling constants in their 1H NMR spectra. The small H-9/H-10
coupling constant (J = 3.4 Hz in 1H NMR) and chemical shift
(12.9 ppm in 13C NMR) for the 13-methyl at C-9 of 5a showed that
it possesses 9b-methyl and 10b-acetal groups.41 Similarly structure
of the dimers are confirmed from their H-9/H-10 coupling constant
at 1H NMR spectra.
(a)
(b)
O
NaBH4, MeOH, 0 oC
HO
O
O
O
O
n
O
O
BF3.Et2O
CH2Cl2, rt
O
O
n
1
2 (n=1)
3 (n=2)
Scheme 1. Synthesis of terminal alkynes of artemisinin.
Due to its selectivity and mild nature, this cross-coupling reaction
is extensively used for the synthesis of natural products, drugs and
drug intermediates. In this communication we describe the appli-
cability of palladium catalysed Sonogashira cross-coupling reac-
tion of aryl halide and alkyne as a new approach in preparation
of artemisinin dimers in moderate to good yields.
Our synthetic strategy towards the target dimers was simple
and commenced with the synthesis of alkyne precursors according
to the literature procedure (Scheme 1).40 The requisite alkyne pre-
cursor 2 (56% yield) and 3 (57% yield) were prepared as 10b-acetal
derivatives from artemisinin and confirmed from NMR spectra.
Sonogashira cross-coupling reaction between the aromatic dihal-
ide and alkyne derivatives of artemisinin 2 and 3 were carried
out using DABCO as ligand with Pd(dba)2 and Cs2CO3 as the base
Eight novel artemisinin-derived dimers were synthesized and
were tested for in vitro cytotoxic activity against different human
cancer cell lines using Sulphorhodamine B Assay. Mitomycin-c,
Adriamycin, Paclitaxel, 5-Fluorouracil are used as the control
and the results are summarized in Table 1. Unmodified artemis-
inin shows only 26% growth inhibition against Lung A-549 hu-
man cancer cell line whereas compound 5a, 5b, 5c, 5d, 5e, 5f,
5g, 5h show 67%, 64%, 70%, 65%, 56%, 67%, 77%, 60% growth
inhibition in 10 lM concentration, which is comparable with that
of paclitaxel. However all the compounds show moderate result
against the prostate, neuroblastoma (IMR-32), cervix and breast
cancer cell lines. Overall compound 5c (70% GI) and 5g
(77% GI) has shown good activity against Lung A-549 cancer cell
line.
H
O
H
O
H
O
O
O
O
O
O
O
O
O
Pd(dba)2, Cs2CO3
DABCO, MeCN, rt
I
I
+
O
R
O
O
O
n
R
n
n
S
n = 1: 2
n = 2: 3
R:
n = 2, R = 4a: 5e
= 2, R = 4b: 5f
n = 1, R= 4a: 5a
= 1, R= 4b: 5b
= 1, R=
= 1, R= 4d: 5d
4a
4c
4c 5g
= 2, R =
:
4c 5c
:
= 2, R = 4d: 5h
4b
4d
Scheme 2. Synthesis of artemisinin dimers.
Table 1
Proliferation inhibition assay against different human cancer cell lines using (% growth inhibition)a
Comound
Concn (lM)
Prostate (PC)
Neuroblastoma (IMR-32)
Lung (A-549)
Cervix (Hela)
Breast MCF-7
Artemisinin
Artemisinin
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
5f
5f
5g
5g
10
50
10
50
10
50
10
50
10
50
10
50
10
50
10
50
10
50
10
10
10
10
35
40
56
68
46
68
44
47
50
65
48
55
41
47
49
53
45
60
65
—
24
34
50
56
34
43
54
83
40
45
11
37
04
27
26
28
10
30
—
26
38
67
69
64
69
70
73
65
70
56
72
67
74
77
78
60
65
—
51
66
34
43
47
57
35
37
—
25
36
36
45
30
32
25
29
—
—
—
20
24
18
50
51
52
—
—
—
—
—
26
41
24
38
31
41
—
—
—
—
—
5h
5h
Mitomycin-c
Adriamycin
Paclitaxel
5-Fluorouracil
69
—
—
—
56
—
—
—
62
—
a
No entries (—) are shown for compounds that were not tested against the indicated cell lines.

P. Buragohain et al. / Bioorg. Med. Chem. Lett. 24 (2014) 237–239
239
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We would like to thank the Director, NEIST, Jorhat for providing
necessary facilities to carry out this work. P.B. and B.S. thank CSIR
for award of senior research fellowship. N.S. thanks UGC for award
of senior research fellowship.
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