Design, synthesis and anticancer screening of 3-(3-(substituted phenyl) acryloyl)-2H-chromen-2ones as selective anti-breast cancer agent

Article abstract of DOI:10.1016/j.biopha.2017.02.089

By utilizing concept of molecular hybridization, involving combination of various Pharmacophore, novel substituted coumarin-chalcone hybrids was synthesized and evaluated for anti-proliferative activity against estrogen receptor-positive MCF-7 and negativ

Full text of DOI:10.1016/j.biopha.2017.02.089

Biomedicine & Pharmacotherapy 89 (2017) 966–972
Available online at
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Original article
Design, synthesis and anticancer screening of 3-(3-(substituted
phenyl) acryloyl)-2H-chromen-2ones as selective anti-breast cancer
agent
*
Santosh N. Mokale , Afreen Begum, Nikhil S. Sakle, Vishakha R. Shelke, Swati A. Bhavale
Dr. Rafiq Zakaria Campus, Y.B. Chavan College of Pharmacy, Aurangabad 431001, Maharashtra, India
A R T I C L E I N F O
A B S T R A C T
Article history:
By utilizing concept of molecular hybridization, involving combination of various Pharmacophore, novel
substituted coumarin-chalcone hybrids was synthesized and evaluated for anti-proliferative activity
against estrogen receptor-positive MCF-7 and negative MDA-MB-435 breast cancer cell lines. In-vivo
study was carried out by N-methyl nitrosourea (MNU) induced mammary carcinoma in virgin female
Spraque Dawly (SD) rats. The compound 5b has highest potential than standard drug Adriamycin,
comparable against Tamoxifen against ER-positive MCF-7 breast cancer cell lines. Docking study was
Received 4 October 2016
Received in revised form 11 February 2017
Accepted 11 February 2017
Keywords:
Coumarin
Chalcone
SERM
Breast cancer
Molecular docking
performed to study the binding orientation and affinity of synthesized compounds on the ER-a enzyme.
© 2017 Elsevier Masson SAS. All rights reserved.
1. Introduction
Among diverse biological activities of coumarin the most
intriguing bioactivity is effective against breast cancer. The
literature reveals that coumarin containing compound neo-
tanshin lactone which is 10 fold more potent and 20 fold more
selective than TAM against estrogen receptor positive human
breast cancer [7]. Several coumarin derivatives have been
identified as nuclear hormone receptor modulator [8]. Chromane
derivatives were found to possess Raloxifene like activity on serum
cholesterol and bone mineral density, which explains beneficial
estrogenic effect of coumarin containing compound [9].
Despite immense advances in the field of basic and clinical
research of new aggressive therapeutics, breast cancer, still
remains a leading killer among women worldwide. Estrogens
are well known to play crucial role in breast cancer development.
ER-a is well characterized as a mediator of cell proliferation in
breast cancer cells [1]. Tamoxifen (TAM) is the first selective
estrogen receptor modulator (SERM) approved for the prevention
of breast cancer [2].
Due to the development of drug resistance, undesired side
effects, relapses and recurrences of cancer, there is a need to
develop safe, potent and tissue selective anti-breast cancer agents
with novel mode of action [3,4]. For many years important research
studies have been devoted to natural phytoestrogens and to their
synthetic analogues. These derivatives can bind to the ERs and lead
to agonist or antagonist activities.
Chalcones (1,3-diphenyl-2-propen-1-ones) considered as the
precursor of flavonoids and isoflavonoids are widely distributed in
nature from ferns to higher plants [10]. Chalcone derivatives are
associated with some important biological activity such as
antitubercular, anthelmintic, fungicidal, antioxidant, antimalarial,
anti-inflammatory, anti-cancer agents and anti-tumouragent [11–
14].
Coumarins are heterocyclic organic compounds known as
benzo-2-pyrone derivatives. It is an important group of natural
occurring products having varied activities [5]. The biological
activities include anticoagulation, antibiotic, antifungal, antipsor-
iasis, antitumor, anti-HIV, anti-inflammatory [6].
Both coumarin and chalcone are chemopreventive agents. Their
chemopreventive efficacy includes their ability to interrupt or
reverse the carcinogenesis process by acting on intracellular
signalling network molecules involved in the initiation and or
promotion of cancer or their potential to arrest or reverse the
progression stage of cancer. They may also trigger apoptosis in
cancerous cells through modulation of a number of key elements in
cellular signal transduction pathways linked to apoptosis [15].
In recent years, combination chemotherapy was adopted to
* Corresponding author.
E-mail address: santoshmokale@rediffmail.com (S.N. Mokale).
treat cancer. A single molecule containing more than one
http://dx.doi.org/10.1016/j.biopha.2017.02.089
0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.

S.N. Mokale et al. / Biomedicine & Pharmacotherapy 89 (2017) 966–972
967
pharmacophore, each with different mode of action could be
beneficial for the treatment of cancer [16].
2.3. General procedure for synthesis of substituted p-hydroxy chalcone
[19] (2–4)
In view of these observations, it was thought of interest to
combine different pharmacophore to produce novel compounds
with effective breast cancer treatment. This strategy has resulted in
a combination of pharmacophoric moieties of different bioactive
substances such as coumarin, chalcone and amine side chain [17]
led us to discover a novel class of substituted coumarin-chalcone
hybrids (Fig. 1) which could be with an improved affinity, efficacy
and modified selectivity profile with different mode of action and
reduce undesirable side effects.
An equimolar mixture of 3-acetyl-2H-chromen-2-one, substi-
tuted benzaldehydes and KOH (2 mmol) was stirred in PEG-400
(15 ml) at 40 ꢀC for 2–3 h. After the completion of the reaction
(monitored by TLC), the crude mixture was worked up with ice-
cold water (100 ml). The resultant product was separated out and
recrystallized from absolute ethanol.
2.4. General procedure for the synthesis of 3-(3-(substituted phenyl)
acryloyl)-2H-chromen-2ones [20] (5a–7c)
2. Experimental section
A mixture of substituted chalcone (0.625 mmol), anhydrous
K2CO3 (3.12 mmol), amino hydrochloride chain (0.93 mmol), and
dry acetone (10 ml) was refluxed for 24 h. K2CO3 was filtered off
and acetone was distilled out. The residue was diluted with water
and extracted with ethyl acetate. The organic layer was washed
with water, brine, and dried over anhydrous Na2SO4. The
precipitate was recrystallized from absolute ethanol.
2.1. Chemistry
Melting points were recorded in open capillaries with electrical
melting point apparatus. IR spectra of all synthesized compounds
in KBr were recorded using a (JASCO FT-IR 4000) spectrophotom-
eter. 1H and 13C NMR spectra were recorded on the Bruker Advance
(400 MHz) Spectrometer in CDCl3 solutions, with TMS as an
internal reference. Mass spectra were recorded on a Varian Inc, 410
Prostar Binary LC with 500 MS IT PDA Detectors. All the reagents
and solvents used were of analytical grade.
2.5. In-vitro anticancer screening
In vitro testing done using SRB assay protocols [21], each drug is
tested at
4
dose levels (1 ꢁ10ꢂ7 M, 1 ꢁ10ꢂ6M, 1 ꢁ10ꢂ5 M,
2.2. Synthesis of 3-acetyl-2H-chromen-2-one [18] (1)
1 ꢁ10ꢂ4 M, or 10, 20, 40, 80
mg/ml). Appropriate positive controls
are run in each experiment and the experiment is repeated thrice.
Results are given in terms of GI50, TGI and LC50 values.
To a cold mixture of salicylaldehyde (2.1 ml, 20.051 mmol), ethyl
acetoacetate (3.16 ml, 25.064 mmol) in 2.5 ml absolute ethanol,
1.0 ml piperidine was added drop wise. It was stirred vigorously on
a magnetic stirrer. By continuing the stirring mixture started
thickening, to it was added 2.5 ml absolute ethanol in order to
facilitate stirring. After 30 min, added 5 ml absolute ethanol and
stirred vigorously for further 30 min. Then 50 ml of ethanol was
added and warmed just to dissolve fine particles. It was then
allowed to crystallize into needle by cooling in freezer for 10–
15 min. Then washed with cold ethanol and recrystallized with
100 ml distilled water to get cream colour needles crystals m.
p. = 124–126 ꢀC, yield = 2.07 g.
2.6. In-vivo anticancer screening
Female virgin SD rats were obtained from Wockhardt Pvt. Ltd.
(Aurangabad) at 35 days of age. Rats were housed at 3 per cage and
maintained at (25 ꢃ 2) ꢀC under 12 h dark/light cycle with access to
standard diet and water ad libitum.
The NMU was purchased from Sigma (USA). An aqueous
solution at a concentration of 10 mg/ml was made by wetting the
NMU powder with 3% acetic acid and then dissolving it in 0.9% NaCl
solution; a fresh solution was prepared for each injection. Rats
were given intra peritoneal (i.p.) 50 mg/kg of NMU on the 50th and
57th day. Animals were divided into different groups with six
animals in each group. Group I (intact control) received 0.9% NaCl
solution Groups II–V was introduced with MNU. Two weeks after
MNU treatment, animals were treated with synthesized com-
pounds (5 mg/kg) and TAM (10 mg/kg in 1% Tween 80) by gavage
once per day for six weeks. Animals in intact control group and
untreated MNU group were given vehicle (Tween 80) according to
experimental protocol. After MNU treatment the animals were
palpated weekly to detect the presence of mammary tumors. MNU
yields a high incidence of estrogen receptor positive mammary
tumors. The time of appearance of first tumor (latency period), the
number of tumors/rat (tumor burden) and relative size of every
tumor was recorded. The tumor diameter was measured by
micrometer caliper, and volume was calculated using the formula:
V = 4/3
B
r3
Where, r is half of the average diameter.
After completion of treatment, blood was collected from retro
orbital puncture and analyzed for estrogen level measurement.
2.7. Histopathological studies
Tumors larger than 0.5 cm in diameter were removed from the
mammary gland and washed with ice cold buffered saline solution
(pH 7.4) and preserved in 4% formaldehyde in 0.1 mol/l phosphate
Fig. 1. Designed pharmacophor of substituted coumarin–chalcone hybrids.

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S.N. Mokale et al. / Biomedicine & Pharmacotherapy 89 (2017) 966–972
buffer solution (PBS, pH 7.4). They were fixed overnight in 10%
phosphate buffered formalin, dehydrated in alcohol, cleared of fat
grid of protein structure. The results of molecular docking studies
indicated an acceptable reliability of the parameters specified in
Maestro-Glide in reproducing the binding mode for these
compounds.
with toluene, rehydrated and tumor sections (5
H&E.
mm) stained with
In order to better describe the possible binding modes of
2.8. Docking study
chalcone compounds with hER-
(LBD) with non-steroidal antagonists, i.e. raloxifene (RAL) was
used. The crystal structure of hER- LBD (PDB entry: 1ERR) was
a, hER-a ligand-binding domain
In order to explore the main interactions with the target ER-
a
a
receptor of the chalcone derivatives was subjected to molecular
docking studies using Glide v5.8 (Schrödinger, LLC). The coor-
obtained from the Protein Data Bank (PDB) (http://www.rcsb.org/
pdb/). To identify the binding modes for the chalcone compounds,
the docked states (ligand conformation and orientation relative to
the estrogenic receptor; hereafter referred to as poses) of each
compound were compared.
dinates for ER-a receptor was taken from RCSB Protein Data Bank
and prepared for docking using protein preparation wizard. Water
molecules in the structures were removed and termini were
capped by adding ACE and NMA residue. The bond orders and
formal charges were added for hetero groups and hydrogens were
added to all atoms in the structure. Side chains that were not close
to the binding cavity and do not participate in salt bridges were
neutralized. After preparation, the structures were refined to
optimize the hydrogen bond network using OPLS_2005 force field.
The minimization was terminated when the energy converged or
the RMSD reached a maximum cutoff of 0.30 Å. Grids were then
defined around refined structure by centering on ligand using
default box size. The extra precision [22] (XP) docking mode for
compounds, optimized by Ligprep, was performed on generating
3. Result and discussion
3.1. Chemistry
We describe herein a convenient approach to the synthesis of 3-
acetylcoumarin (1), intermediate hydroxychalcones(2, 3, 4) and
the target compound 3-(3-(3–4-subtitutedphenyl) acryloyl)-2H-
chromen-2one (5, 6, 7) [as shown in Scheme 1].
The key reactions involved in the formation of compound 1 are
Knoevenagel condensation reaction, the intermediate formation of
O
O
OH
O
O
Piperidene
Ethanol
O
OCH3
HO
HO
O
O
1
O
O
O
OH
O
O
O
OH
O
O
OH
O
O
OH
2
O
O
3
OCH3
4
NR
NR
NR
O
N
N
O
O
O
O
O
O
N
N
O
O
O
O
O
O
O
O
7a
OCH3
OCH3
5a
6a
O
O
N
N
O
O
O
O
O
O
O
5b
7b
6b
O
N
O
O
O
O
N
N
O
O
O
O
O
O
O
5c
OCH3
6c
7c
Scheme 1. Synthesis of designed compounds.

S.N. Mokale et al. / Biomedicine & Pharmacotherapy 89 (2017) 966–972
969
Chalcone is based on Claisen-Schmidt condensation on 3-
3.5. Detection of estrogen level
acetylcoumarin with three different aldehydes (4-hydroxybenzal-
dehyde,2-hydroxy benzaldehyde and 4-hydroxy-3-methoxy ben-
zaldehydes). The synthesis of target compounds involves
alkylation of chalcones.
Hormone concentrations measured in rat serum on days 30 and
45 of intoxication were compared with the control and MNU group
values which shows prominent selectivity on estrogen receptor.
Mean of the concentrations of all groups is depicted in Table 3. The
result shows that the compound 5b has selectivity as standard TAM
(tamoxifen) towards estrogen receptor. All the synthesized
compounds show marked antagonistic activity.
3.2. Biological evaluation
The target compounds were evaluated for their anti-breast
cancer activity against the MCF-7 and MDA-MB-435 cell line and
Adriamycin and Tamoxifen was taken as the standard. LC50, TGI and
GI50 value of in-vitro anticancer activity profile was shown in
Table 1.
3.6. Docking study
The level of ER-a inhibition and anti-proliferative activities of
synthesized compounds prompted us to perform molecular
3.3. Structural activity relationship
docking studies to understand the ligand–protein interactions in
detail. Docking of compounds was done with ER-a and the results
The results from in-vitro screening suggest that, anti-prolifer-
ative activity increases with newly synthesized compounds
substituted with amine side chain containing piperidine ring.
The compounds 5b, 6b, 7b were found to be more active against
the MCF-7 than MDA-MB-435 cell line. The highest anti-prolifer-
not only validated our docking protocol but also established the
following findings. The docking studies showed that the com-
pounds 5–7(a–c) were binding to the binding site of Raloxifen in
the co-activator groove. Amongst the analogues synthesized
significant interactions were seen in a few cases. Foremost
amongst them was compound 5b. The comparison of compound
ative activity with GI50 value below 10 mg/ml obtained with
compound 5b.
5b docked with ER-a shows that it has a binding site similar to RAL
in the co-activator groove (Fig. 2a–c).
3.4. In-vivo anticancer screening
In general, it is observed that the coumarin fragment of the
compounds fitted into the cavity formed by Phe404, Glu353,
Leu387, Leu428, Met388 and Met421 while the other amine side
chain fitted into the other cavity formed by Thr347, Asp351, Trp383,
Met543, Leu536 and Met528. Compound 5b produces a deep,
It is observed that administration of synthesized compounds
shows the protective effect on mammary tumorigenesis. The
animals treated with 5b, 6b, 7b prolonged the latency, reduced
tumor burden and volume compared to that of MNU treated rats.
The effect of treatment on tumor latency, burden and volume is
given in Table 2. Histomorphological examination of rat mammary
gland revealed that the normal architecture was disturbed by
carcinogen. Rat mammary gland adenocarcinoma and tumor
response to treatment is given in Fig. 3.
moving into the hydrophilic pocket of ER-
a with which the
coumarin and 4-ethoxy piperidine side chain fragments are able to
reach the hydrophilic pocket and was involved in strong hydrogen
bonding with Asp351 (C
and TAM. In addition to this compound 5b shows
¼
Oꢄ ꢄ ꢄNH; 2.74 Å) as similar to that of RAL
p-p
stacking
interaction with Phe404 which was also observed in the TAM
interaction (Fig. 2a andc). Substitution/removal of the N-substi-
tuted piperidine/pyrrolidine ring by an alkyl group in the side
chain resulted in weaker binding affinity and no significant
interactions with the receptor were observed. The compound 5b
shows the same binding pattern as that of standards which fails in
the other compounds. This difference in the binding modes may
lead to distinct activities.
Table 1
In-vitro anticancer activity (mg/ml) of synthesized compounds.
Comp No.
MCF-7
LC50
MDA-MB-435
LC50 TGI
TGI
GI50
GI50
4. Conclusion
5a
5b
5c
6a
6b
6c
7a
7b
7c
ADR
TAX
>80
74.5
>80
>80
>80
>80
>80
>80
>80
>80
29.4
>80
40.2
>80
>80
62.9
>80
70.6
>80
>80
54.5
11.2
65.2
<10
>80
>80
18.9
38.8
35.1
32.5
>80
<10
<10
>80
>80
>80
>80
>80
>80
>80
>80
>80
>80
54.2
>80
78.2
>80
>80
77.1
>80
>80
>80
>80
61.8
21.5
>80
75.3
>80
>80
>80
>80
>80
54.2
>80
<10
<10
The synthesis and characterization of new series of 3-(3-
(substituted phenyl)acryloyl)-2H-chromen-2one derivatives were
carried out and all the compounds were evaluated for their anti-
breast cancer activity against the MCF-7 and MDA-MB-435 cell
line. The majority of the tested compound possessed antiprolifer-
etive activity against the tested cancer cell line. Compound 5b was
fond to be similar effect compared to TAM and ADR against the
MCF-7 cell line, having GI50 value less than 10
induced mammary carcinomas express functional ER
m
g/ml. NMU-
and are
a
Table 2
Effect of treatment on mammary tumorigenesis.
Group
Treatment
Tumor Latency (week)
Tumor burden
Tumor volume (mm3)
I
II
III
IV
V
MNU
TAM
5b
6b
7b
4.5 ꢃ 0.6
6.2 ꢃ 1.0c
5.5 ꢃ 0.7c
4.7 ꢃ 0.2c
3.8 ꢃ 0.4a
4.45 ꢃ 0.1
2.8 ꢃ 0.21c
3.1 ꢃ 0.22c
3.6 ꢃ 0.12c
4.25 ꢃ 0.13c
4.8 ꢃ 0.14
2.5 ꢃ 0.16c
3.3 ꢃ 0.27c
3.9 ꢃ 0.14b
4.5 ꢃ 0.16a
The results are expressed as Mean ꢃ SEM. The data is analyzed using One-way Analysis of Variance (ANOVA) followed by Tukey’s test. (n = 6). aP < 0.001, bP < 0.01, cP < 0.05.

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S.N. Mokale et al. / Biomedicine & Pharmacotherapy 89 (2017) 966–972
Fig. 2. Ligand interaction diagrams of – a) Tamoxifen, b) Raloxifene & c) Compound 5b respectively.

S.N. Mokale et al. / Biomedicine & Pharmacotherapy 89 (2017) 966–972
971
Fig. 3. Histomorphology of mammary gland adenocarcinoma in rats treated with NMU (A) Histology of the normal mammary gland. ꢁ100. (B) Cribiform carcinoma in a NMU
control animal. Masses of proliferating epithelial cells surround acinar spaces of varying size and shape, a few of which contain secretion. ꢁ200. (C) Benign tubular adenoma in
a tumor responded to 5b treatment. The tumor is composed of simple tubular structures separated by only a small amount of stroma. ꢁ200. (D) Benign pericanalicular
fibroadenoma in TAM treated tumor. Bands of fibrous tissue surround islets of secretory epithelium and myoepithelium with loss of lobular structure. ꢁ200.
Table 3
Appendix A. Supplementary data
Estrogen levels (pg/ml) of animals on day 30 and 45.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.
biopha.2017.02.089.
Group
Compound No.
Estrogen level on
30th Day
(mean ꢃ SE)
45th Day
(mean ꢃ SE)
I
II
III
IV
V
Control
MNU
5b
6b
7b
9.9 ꢃ 1.22
9.7 ꢃ 1.36
References
18.96 ꢃ 2.09
11.08 ꢃ 1.36
12.84 ꢃ 2.58
14.22 ꢃ 1.03
11.06 ꢃ 1.18
20.77 ꢃ 1.98
11.14 ꢃ 1.88
13.36 ꢃ 2.12
14.12 ꢃ 1.46
11.28 ꢃ 1.69
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