The potential role of anibamine, a natural product CCR5 antagonist, and its analogues as leads toward development of anti-ovarian cancer agents

Article abstract of DOI:10.1016/j.bmcl.2012.05.127

Chemokines and their receptors play important roles in the development of primary tumors and their metastases. Particularly CC chemokine receptor 5 (CCR5) and its ligand CC chemokine ligand 5 (CCL5/RANTES) seem to be critical in proliferation and invasion of ovarian cancer, the leading cause of death from gynecological malignancies in the United States. Anibamine, the first natural product CCR5 antagonist, and its analogues were examined for their effects on proliferation of the OVCAR-3 ovarian cancer cells in order to validate their candidacy as leads to develop novel anti-ovarian cancer agents. Acting as CCR5 antagonists, anibamine and its analogues significantly suppressed CCL5-induced intracellular Ca²⁺ flux. The compounds also inhibited the proliferation of OVCAR-3 at micromolar to submicromolar range. Moreover, anibamine and several analogues did not show significant cytotoxicity in NIH 3T3 cells at concentrations up to 20 μM. Based on these results, anibamine and one of its synthetic analogues were defined as potential leads to develop novel agents against ovarian cancer.

Full text of DOI:10.1016/j.bmcl.2012.05.127

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5093–5097
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The potential role of anibamine, a natural product CCR5 antagonist,
and its analogues as leads toward development of anti-ovarian cancer agents
Yan Zhang a,b, , Christopher K. Arnatt a, Feng Zhang a, Jiannan Wang a, Kendra M. Haney a, Xianjun Fang b,c
⇑
a Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA
b Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
c Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Chemokines and their receptors play important roles in the development of primary tumors and their
metastases. Particularly CC chemokine receptor 5 (CCR5) and its ligand CC chemokine ligand 5
(CCL5/RANTES) seem to be critical in proliferation and invasion of ovarian cancer, the leading cause of
death from gynecological malignancies in the United States. Anibamine, the first natural product CCR5
antagonist, and its analogues were examined for their effects on proliferation of the OVCAR-3 ovarian
cancer cells in order to validate their candidacy as leads to develop novel anti-ovarian cancer agents. Act-
ing as CCR5 antagonists, anibamine and its analogues significantly suppressed CCL5-induced intracellular
Ca2+ flux. The compounds also inhibited the proliferation of OVCAR-3 at micromolar to submicromolar
range. Moreover, anibamine and several analogues did not show significant cytotoxicity in NIH 3T3 cells
Received 12 April 2012
Revised 22 May 2012
Accepted 29 May 2012
Available online 16 June 2012
Keywords:
Ovarian cancer
Chemokines
CCR5
at concentrations up to 20
lM. Based on these results, anibamine and one of its synthetic analogues were
Anibamine
defined as potential leads to develop novel agents against ovarian cancer.
Published by Elsevier Ltd.
Ovarian cancer is the second most common (affecting about
every one out of seventy women) and the deadliest (1% of all
women die of it) gynecological cancer in the United States, and it
is also the fifth leading cause of cancer related deaths in women.1,2
factors produced by tumor cells that are essential to tumor cell
proliferation or survival.23–26 In view of their chemotactic proper-
ties, it has been suggested that chemokines may mediate the
recruitment of tumor-associated leukocytes to tumor sites,27–34
a
Ovarian cancer is called
a
‘silent killer’ because symptoms
process postulated to accelerate the progression of several malig-
nant diseases.
normally won’t be evident until the disease has advanced and
the chance of cure or remission becomes very slim.3 Therefore,
identification of factors and pathways responsible for the ovarian
cancer development and progression is of critical importance and
such effort may lead to development of novel therapeutic agents.
Tumor cell growth can be directly regulated, among others, by
chemokines, a family of small proteins inducing directed cell
migration (chemotaxis), via specific G-protein coupled recep-
tors.4–10 Initially, chemokines are considered to be pro-inflamma-
tory which can be induced during an immune response as
regulating leukocyte recruitment at sites of inflammation. During
the last decade, it has become increasingly clear that chemokines
also have the capacity to mediate several other functions and
therefore are more than simple trafficking controllers. Recently, a
number of reports demonstrated that a complex network of che-
mokines and their receptors influence the development of primary
tumors and their metastasis.11–15 For example, the expression of
chemokines was detected in several types of human and murine
tumors.16–22 In some cases, chemokines were found to be autocrine
The C–C chemokine receptor CCR5 is a G-protein coupled recep-
tor. The ligands of this receptor include monocyte chemoattractant
protein 2 (MCP-2), macrophage inflammatory protein 1 alpha
(MIP-1 alpha), macrophage inflammatory protein 1 beta (MIP-1
beta), and RANTES (Regulated on activation normal T expressed
and secreted protein), which is also known as CCL5. Along with
other chemokine receptors, CCR5 has been characterized for its po-
tential role in cancer development,35 particularly, in ovarian onco-
genesis. For instance, analysis of the levels of the chemokine in
plasma of patients at different stages of the disease revealed an
association between CCL5 and ovarian carcinoma progression
while it appeared that CCL5 protein levels were higher in ovarian
cancer patients than in patients diagnosed with benign ovarian
cysts, and elevated in stages III–IV of ovarian cancer compared to
stages I–II.36,37 This suggested that intrinsic CCL5 levels could be
useful for detection of malignant ovarian tumors. Another study
showed that interleukin-12 (IL-12) induced the regression of xeno-
grafts of the OV-HM ovarian carcinoma cells, which was mediated
by the chemokine receptor CCR5, while the CCR5 antagonist
TAK-779 in tumor-bearing mice prevented IL-12 induced T-cell
migration.38 This certainly suggested a therapeutic opportunity of
⇑
Corresponding author.
E-mail address: yzhang2@vcu.edu (Y. Zhang).
0960-894X/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2012.05.127

5094
Y. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5093–5097
using CCR5 antagonist in ovarian cancer. Meanwhile ovarian tu-
mors have been observed to over-express CCR5 and inhibition of
CCL11 (one of the CCR5 endogenous agonists) signaling by the
combination of neutralizing antibodies against CCL11 and its
receptors significantly increased the ovarian carcinoma cell sensi-
tivity to cisplatin.39 Overall, these findings suggested that develop-
ment of appropriate chemokine receptor CCR5 antagonists could
provide a novel strategy to treat ovarian cancer.
been demonstrated to correlate well with their affinity in radioli-
gand competition binding assays.52,53 Anibamine showed moder-
ate inhibition of calcium flux at an IC50 of 5.4 lM, which was in
line with its reported binding affinity to the CCR5 receptor.40
Anibamine was then evaluated for its ability to inhibit growth
of the OVCAR-3 ovarian cancer cells through a cell proliferation as-
say. In the initial experiments, CCL5 was not added in the protocol
in the consideration of avoiding possible non-specific stimulatory
effect of CCL5 on other chemokine receptors. It turned out that
anibamine effectively inhibited the proliferation of OVCAR3 cells
Anibamine, a unique pyridine quaternary alkaloid recently
isolated from Aniba panurensis, was found to bind to CCR5 with
an IC50 of 1
l
M in competition with 125I-gp120, an HIV viral envel-
at an IC50 around 1 lM, which again was in line with its binding
op protein.40 As the first natural product CCR5 antagonist, anib-
amine provides a structural skeleton that is remarkably different
from all previously identified lead CCR5 antagonists (Fig. 1) derived
from extensive high throughput screening studies. The chemokine
receptor CCR5 has mainly been employed in AIDS therapies since it
was first cloned more than a decade ago.41–44 To date only one
drug, maraviroc, has been approved by the FDA in 2007 while con-
cerns remained that maraviroc could be associated with increased
risks of liver damage, lymphoma, infections and heart attack.45
Apparently, there is an urgent need to explore new chemical struc-
tures and templates with a wider range of structural features to de-
velop novel CCR5 antagonists. Compared to those high-throughput
screening hits, lead compounds derived from natural products, of-
ten contain more diverse skeletons with wider ranges of shape,
chemical features, and specific biological activities.46,47 Thus, natu-
ral products are desirable and useful resources for drug discovery
and development.
Recent studies showed that anibamine inhibited proliferation of
prostate cancer cell lines at micromolar to submicromolar concen-
trations and prevented adhesion and invasion of the highly meta-
static M12 prostate cancer cell line.48 Meanwhile the total
synthesis of anibamine has been reported a couple of years ago49
while an updated synthetic route was made available very re-
cently.50 A homology modeling based docking study of anibamine
and other known CCR5 antagonists further verified the possible
binding mode of anibamine in the CCR5.51 The development of
these synthetic pathways and modeling studies provided the
opportunity to prepare diversified anibamine derivatives in order
to investigate the structure–activity relationship of anibamine as
a CCR5 antagonist and potential anti-cancer agent.
affinity to the CCR5 receptor and the inhibitory effect on the
CCL5 stimulated calcium flux (Table 1).
Since it has been reported that CCR5 and CCL5 were expressed
on OVCAR3 cells,39 it would be interesting to see if CCL5 could act
as a cancer cell growth stimulator. Therefore, different concentra-
tions of CCL5 were applied to the OVCAR3 cells and its effect on cell
proliferation was determined as illustrated in Figure 3. Interest-
ingly, at the lower concentrations (0.3 nM–3 nM), CCL5 signifi-
cantly promoted the growth of OVCAR3 cells by at least 50%
(P <0.01) while higher concentrations of CCL5 tested (10 nM and
30 nM) showed some but not very significant effect (Fig. 2). Such
observation was in coincidence with the reported stimulatory pat-
tern of CCL5 on several prostate cancer cells.22
To examine whether the inhibitory effect of anibamine on the
OVCAR3 cells observed previously was in correlation to its antago-
nist activity on the CCL5/CCR5 system, its inhibitory effect on the
proliferation of OVCAR-3 cells was further tested in the presence
of CCL5 (1 nM). Under such condition, anibamine showed rela-
tively stronger inhibitory effect on the OVCAR3 cell proliferation
(IC50 at 0.9 lM) than the condition without CCL5 stimulation,
which implied that the inhibitory effect of anibamine on ovarian
cancer cell growth may be mediated through its antagonist activity
on the CCR5 receptor (Table 1).
Afterwards, the basal cytotoxicity assay was performed using
the NIH 3T3 cells under similar proliferation conditions (WST-1
as the proliferation agent) to determine whether the inhibitory
effect of anibamine on cancer cells was due to its basal cytotoxic-
ity. It turned out that much higher concentration of anibamine
(IC50 = 23.5 lM) was required to inhibit the growth of 3T3 cells,
suggesting a very promising selectivity of anibamine in inhibiting
Characterization of anibamine as the lead for anti-ovarian cancer
agent. To validate anibamine’s function as a CCR5 antagonist, its ef-
fect on the intracellular calcium mobilization stimulated by CCL5
(RANTES) in MOLT4/CCR5 cells was first examined by following
the reported procedure50 since the inhibitory effects of CCR5
antagonists in chemokine-induced calcium ion mobilization have
the growth of cancer cells.
Application of ‘deconstruction-reconstruction-elaboration’ method
to study the structure–activity relationship of anibamine as anti-ovar-
ian cancer lead compound. The initial structural modification of
anibamine was conducted by following the ‘deconstruction-recon-
struction-elaboration’ method. This method has been successfully
H
N
N
O
N
+
O
TFA
TAK 779
Anibamine
O
N
N
N
N
F
N
N
N
N
F
N
O
HN
Maraviroc
F3C
O
Vicriviroc
Figure 1. Anibamine and some known CCR5 antagonists.

Y. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5093–5097
5095
Table 1
Biological characterization of anibamine and its analogs
Compound
CCR5 antagonism MOLT-4/CCR5 IC50
(l
M)
Anti-proliferation OVCAR3 IC50
M)
Basal cytotoxicity NIH 3T3 TC50 (lM)
(
l
w/o CCL5
w/CCL5
1, Aanibamine 5.4 0.9
1.1 0.3
1.3 0.2
0.4 0.1
NDa
0.86 0.1
0.9 0.1
1.0 0.1
ND
23.5 2.4
6.9 1.6
7.8 1.5
ND
2
9.2 0.4
16.3 4.2
>100
3
4
5
>100
ND
ND
ND
6
7
8
9
10
11
12
13
14
15
6.5 1.8
7.8 1.4
10.1 3.9
9.2 0.6
10.0 0.4
8.4 0.9
4.6 1.6
48.1 21.7
15.2 7.9
37.6 5.4
0.8 0.3
0.6 0.1
0.9 0.1
0.9 0.1
1.7 0.4
1.2 0.3
2.4 1.2
3.6 0.9
1.7 0.6
2.1 0.4
0.7 0.2
0.3 0.1
0.5 0.1
0.6 0.1
0.3 0.1
0.7 0.1
3.4 2.0
0.4 0.2
0.4 0.1
0.8 0.1
4.4 0.6
5.1 2.4
3.3 0.3
4.0 0.3
29.1 0.6
10.1 1.1
17.5 4.6
4.8 0.6
3.8 0.5
11.7 1.5
a
ND, not determined.
applied to improve the pharmacological activities of both synthetic
agents and natural products.54–57 In our case (Fig. 3), each struc-
tural component of the lead compound, anibamine, was ‘removed’
one at a time in order to test the influence of that component on its
CCR5 antagonism and anti-ovarian cancer activity. Once the essen-
tial structural components were defined, they were retained in the
core structure. Further modification was then done on the core
structure to improve its activities.
Total fourteen analogues of anibamine were prepared following
the synthetic route of anibamine with appropriate modifications
(See the Supplementary data for details).49,50 Similar to the charac-
terization of anibamine, all of its analogues were first evaluated in
a CCL5-induced Ca2+ mobilization experiment to see if they act as
antagonists to the CCR5 receptor and inhibit the calcium ion flux
induced by CCL5. These analogues were then tested in the cell pro-
liferation assay against OVCAR3 cells in the absence or presence of
CCL5. Similarly, 3T3 cells were adopted to characterize the basal
cytotoxicity of these analogues.
Anibamine deconstruction analogues and their activity studies.
Two side chain deconstruction analogues of anibamine, compound
2 and 3, were prepared to study the necessity of the side chains for
the binding to the CCR5 receptor and potential anti-ovarian cancer
activity (Table 1). The fact that both of them showed significantly
decreased inhibition to the receptor function of calcium flux com-
pared to the parent anibamine indicated that both side chains
should be retained to facilitate the binding to the receptor
complementarily.
On the other hand, compound 2 and 3 showed similar or some-
what higher activity than the parent natural product in the anti
proliferation assay in OVCAR3 cells. Considering their relatively
lower affinity to the receptor CCR5 as indicated by the calcium
mobilization inhibition activity, such improved anti-proliferative
effect on OVCAR-3 cells may be conferred in part by interaction
with other off-target proteins. This was further supported by their
significantly higher cytotoxicity in the 3T3 cells compared with the
parent lead compound.
To test if the core ring system would be essential, compound 4
and 5 were prepared (Fig. 3). In compound 4, a methyl group was
retained at position 2 to minimize the steric hindrance alteration
due to the removal of the fused ring part. The second molecule,
compound 5, was designed to retain the same number of the car-
bon atoms from the aliphatic core ring system in order to minimize
the change of hydrophobicity. To facilitate the synthesis, a methox-
yl group was applied to cap the end of the new side chain. The fact
that these two core ring deconstruction analogues carried no sig-
nificant antagonism to the receptor CCR5 (calcium flux inhibition
IC50 higher than 100 lM, Table 1) demonstrated that the positively
charged nitrogenous center was critical for binding to the receptor,
which was consistent with the observation from the molecular
modeling studies reported previously.48 Therefore this ring system
needs to be retained for the future operation.
Anibamine elaboration analogues activity study. Four analogues of
anibamine were prepared to evaluate the possible influence of
double bond configurations to the recognition of the receptor
and potential anti cancer activity (Fig. 3). Among these four com-
pounds, 6 through 9, it seemed that in general, the double bond
configurations (either trans, cis, or saturated) on the two side
chains did not influence the functional inhibition to the receptor
significantly based on the calcium mobilization assay results. They
also showed either similar or slightly higher anti-proliferation
activity as indicated by their IC50 values compared with the parent
anibamine. In the presence of CCL5 stimulation, all of them showed
significantly higher anti-proliferation activity against the OVCAR3
cells, indicating that they inhibited OVCAR3 cells through targeting
the CCR5 receptor. On the other hand, their higher basal cytotoxic-
ity compared with the parent natural product was somehow dis-
couraging (Table 1).
0.8
*
*
**
0.6
0.4
0.2
0.0
0
0.1
0.3
1
3
10
30
To further evaluate the core ring size influence on the receptor
CCR5 affinity as indicated by their functional inhibition to calcium
flux as well as the potential anti-ovarian cancer activity, six core
ring size modified analogues were prepared and studied (Fig. 3,
CCL5 (nM)
Figure 2. CCL5 stimulation of OVCAR3 cell proliferation. The statistical analysis was
conducted by ANOVA.

5096
Y. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5093–5097
Side chain
N
N
deconstruction
N
Cl
Cl
2
4
3
5
Ring system
deconstruction
N
O
N
N
Cl
Cl
Side chain
elaboration
6
7
N
N
Cl
N
Cl
Cl
Anibamine (1)
8
9
Ring system
elaboration
N
N
Cl
Cl
10
11
N
N
Side chain/ring
elaboration
Cl
Cl
Cl
12
14
13
15
N
N
Cl
Figure 3. The application of ‘deconstruction-reconstruction-elaboration’ concept to design the analogues of the lead compound, anibamine.
and Table 1). In general, it seemed that six-member ring analogues
of anibamine (compound 10, 12 and 14) showed relatively higher
receptor affinity than the seven-member ring analogues (com-
pound 11, 13, and 15). By comparing their anti-proliferative activ-
ity against OVCAR3 cells, it seemed that they all showed very
similar profile. Given the fact that the relatively lower receptor
affinity and higher basal cytotoxicity pattern, the seven-member
ring analogues probably interacted with some off-target protein(s).
A closer look at compound 10 and 12, both of which showed rel-
atively lower basal cytotoxicity profile with reasonable anti-prolif-
erative activity against OVCAR3 cells, provided some insight into
the potential role of the ring size combined with the side chain
configuration. Compound 10, which showed the lowest basal
cytotoxicity among all the analogues, also carried similar
a
anti-proliferative effect compared with the natural product lead,
anibamine. More importantly, the presence of CCL5 dramatically
increased its anti-proliferative activity, indicating its specific
antagonistic interaction with the CCR5. For compound 12, no sig-
nificant difference was observed in its anti-proliferative activity
with or without the stimulation of CCL5. Therefore compound 10
was considered our next generation lead compound based on its
biological activity profile.
In summary, the natural product CCR5 antagonist, anibamine,
was characterized as a lead to develop novel anti-ovarian cancer

Y. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5093–5097
5097
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