Synthesis, biological evaluation and molecular docking study of 1-amino-2-aroylnaphthalenes against prostate cancer

Article abstract of DOI:10.1016/j.bmcl.2018.03.057

A series of functionalized naphthalene was synthesized and screened against human prostate cancer cell line (PC-3). The in vitro antiproliferative activity of the synthesized compounds was evaluated by monitoring their cytotoxic effects against PC-3 cells by using MTT assay. We observed that compound 5f resulted in more than 50% cell death at 14 μM. Treatment of PC-3 cells with 5f provides apoptosis by flow cytometry. Western blotting showed decreased expression of pro-caspase 8 and 9. Our study shows that cancer cell treated with 5f has higher concentration of reactive oxygen species as compare to untreated sample, which facilitate cancerous cell to enter apoptosis. Exact mechanism by which ROS is generated after 5f treatment is still under study. Molecular docking study further strengthens the results obtained from in vitro experiments. Compound 5f can be considered as a promising leads for anticancer agent against prostate cancer cells due to its potent cytotoxic activity and apoptotic effect.

Full text of DOI:10.1016/j.bmcl.2018.03.057

Accepted Manuscript
Synthesis, biological evaluation and molecular docking study of 1-amino-2-ar-
oylnaphthalenes against prostate cancer
Reeta Rai, Roshan Kumar Dutta, Surjeet Singh, Dharmendra Kumar Yadav,
Seema Kumari, Harpreet Singh, Rinkoo Devi Gupta, Ramendra Pratap
PII:
S0960-894X(18)30252-X
https://doi.org/10.1016/j.bmcl.2018.03.057
BMCL 25711
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 December 2017
10 March 2018
21 March 2018
Please cite this article as: Rai, R., Dutta, R.K., Singh, S., Yadav, D.K., Kumari, S., Singh, H., Gupta, R.D., Pratap,
R., Synthesis, biological evaluation and molecular docking study of 1-amino-2-aroylnaphthalenes against prostate
cancer, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.03.057
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Synthesis, biological evaluation and molecular docking study
of 1-amino-2-aroylnaphthalenes against prostate cancer
Reeta Rai#,a, Roshan Kumar Dutta#,b, Surjeet Singhc, Dharmendra Kumar Yadavc, Seema
Kumarid, Harpreet Singhe, Rinkoo Devi Guptab,*, Ramendra Pratapc,*
aDepartment of Biochemistry, AIIMS, Ansari Nagar, New Delhi-110029
bFaculty of Life Sciences and Biotechnology, South Asian University, New Delhi-110021, India
cDepartment of Chemistry, University of Delhi, North Campus, Delhi-110007
dBiochemistry Division, Central Drug Research Institute, Lucknow-226001, U.P., India
eIndian Council of Medical Research, Ansari Nagar, New Delhi-110029
#Equal Contribution
*Corresponding Authors
Abstract: A series of functionalized naphthalene was synthesized and screened against human
prostate cancer cell line (PC-3). The in vitro antiproliferative activity of the synthesized
compounds was evaluated by monitoring their cytotoxic effects against PC3 by using MTT
assay. We observed that compound 5f resulted in more than 50% cell death at 14µM. Treatment
of PC-3 cells with 5f provides apoptosis by flow cytometry. Western blotting showed decreased
expression of pro-caspase 8 and 9. Our study shows that cancer cell treated with 5f has higher
concentration of reactive oxygen species as compare to untreated sample, which facilitate
cancerous cell to enter apoptosis. Exact mechanism by which ROS is generated after 5f treatment
is still under study. Molecular docking study further strengthens the results obtained from in
vitro experiments. Compound 5f can be considered as a promising leads for anticancer agent
against prostate cancer cells due to its potent cytotoxic activity and apoptotic effect.
Key words: Naphthalene; Prostate cancer; oxidative damage; apoptosis; cytotoxicity
Prostate cancer is the fifth leading cause of cancer-related deaths in men worldwide and this
disease is frequently observed in males at the age between 65-74 years [1]. A report in 2014 says
that approximately 24 lac men in USA suffered from prostate cancer and was the cause of their
mortality [2]. Prostate cancer are androgen sensitive in the beginning which respond to anti-
1

hormonal therapy, later they turn out to be refractory and develop without androgen. This cancer
is known as castrate resistant prostate cancer (CRPC), and difficult to treat. Recently, US Food
and Drug Administration have approved various new molecules for the treatments of prostate
cancer patients with castration resistant prostate cancer, but very few have provided survival
benefits [3, 4]. Recently, a review have been published on drug designing for prostate cancer
[4]. Thus search of new molecules with effective therapeutic properties for prostate cancer is
much more required.
Various skeletons have been studied for their anticancer properties. Some of the naphthalene
based molecules like naphthalenediimide (NDI) is present in various anticancer agents and they
can intercalate with DNA during the interaction [5-9]. Various molecules containing 2-
aminodiaryl ketones as a main or substructure showed activity as antitubulin agents. Some of the
reported compounds like Phenstatin I and Hydroxyphenstatine (II) [10] and 2-
aminobenzophenone analogues (III) act as antitubulin agents [11]. 2-Amino-1-aroylnaphthalene
and 2-hydroxy-1-aroylnaphthalene were studied for their anti-proliferative activity against
human cancer cell and their activity was almost comparable to the potency of colchine [12].
Molecules containing aminated phenyl aryl ketones as substructure like suitably substituted 4H-
imidazo [1, 5-a] [1, 4] benzodiazepines and related compounds act as central benzodiazepine
receptor (CBR) ligands (Fig. 1) [13]. Another naphthalene based compound neo-transhinlactone
O
R1
MeO
MeO
R2
O
(IV)
OMe
N
OMe
N
(I) R1 = H, R2 = OH, Phenstatin
(II) R1 = R2 = OH, Hydroxyphenstatin
N
O
NH2
MeO
MeO
R1
R2
Cl
R4
(IV)
OMe
R3
(III) 2-Aminobenzophenone analogues
Fig. 1. Structure of phenstatin I, hydroxyphenstatine II, 2-aminobenzophenone analogues III 3-
substituted 6-aryl-4H-imidazo-[1,5-a]benzodiazepines (IV)
2

is reported as anticancer compound and is isolated from Salvia miltiorrhiza [14-16]. Since
naphthalene based molecules exhibit very good anticancer activity, we became interested in the
synthesis of some differently functionalized naphthalene and to study their effect against prostate
cancer cell line.
In order to perform the study, we have synthesized various functionalized naphthalene by two
methods. Compound 1 was synthesized by reaction of acetophenone, carbon disulphide and
methyl iodide under basic conditions at low temperature. Similarly, compound 3 can be
synthesized by using 2-cyanomethylbenzonitrile instead of acetophenone. Under method A, we
have used 4,4-bis-methylsulfanyl-arylethanone as a precursor and perform the reaction with 2-
cyanomethylbenzonitrile under basic condition to achieve the desired product in good yield.
CN
O
CN
CN
O
S
Ar
SMe
Ar
SMe
2 CN
CH3
4
Ar
Mehod A
SMe
Method B
S
CN
NH2
5
O
1
3
NH2
CN
O
NH2
O
NH2
CN
O
S
SMe
Me
SMe
SMe
O
5c
CN
5b
5a
NH2
O
NH2
O
NH2
CN
SMe
Br
SMe
SMe
CN
CN
5e
5f
5d
NH2
O
NH2
CN
O
O
SMe
SMe
Cl
CN
CH3
5h
5g
.
Scheme 1. Synthesis of various 4-amino-3-aroyl/heteroaroyl-2-methylsulfanylnapthalene-1-
carbonitriles (5a-h)
3

While in alternative method B 2-(1-cyano-2,2-bis-methylsulfanyl-vinyl)-benzonitrile was used as
a starting material. Stirring mixture of 2-(1-cyano-2,2-bis-methylsulfanyl-vinyl)-benzonitrile and
acetophenone under basic conditions provided the desired functionalized naphthalenes (Scheme
1). All the synthesized compounds are characterized by spectroscopic technique and the results
obtained are reported earlier [17].
We have synthesized a number of compounds but on the basis of results obtained from molecular
docking studies, we have selected this series (5a-h) for further studies.
Table 1: Growth inhibition values of all the compounds measured by MTT assaya
Growth
Inhibition (%)
24.76
S.No.
Compound
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
23.36
22.42
15.88
13.08
84.24
24.76
63.97
87.27
cisplatin
aResults expressed are Mean of three independent experiments.
100
90
80
70
60
cisplatin
50
40
30
20
10
0
5f
concentration (M)
Fig 2. Cytotoxicity of 5f and cisplatin was measured by MTT assay. PC-3 cells were treated with
different concentration of Cisplatin and compound 5f (1µM, 5µM, 10µM, 20µM, 40µM, 80µM
and 100µM).
4

The in vitro antiproliferative activity of synthesized compounds mentioned in Table 1 was
evaluated by monitoring their cytotoxic effects on human prostate cancer (PC-3) cell line. In the
initial screening 5f emerged as a potential antiproliferative compound. At tested concentration
(100μM) compound 5f showed 84.24% growth inhibition. For the calculation of IC50 value of
compound 5f, PC-3 cells were cultured with varied concentration of 5f solubilised in DMSO. We
estimated the cytotoxicity of a known anticancer drug cisplatin also on PC-3 cells as a reference
compound. Due to cytotoxicity of DMSO, its concentration was kept below 0.1% throughout the
experiments and also the control reaction was set with and without DMSO. After 72 hours, the
compound showed 50% cell growth inhibition at 14 µM concentration (IC50), however the IC50
value for cisplatin was found to be 10 µM (Fig 2).
A
B
Fig. 3. (A) Colony formation assay; After 24 hours of seeding, cells were treated with 14 µM of
compound 5f and incubated for 14 days (with change of media with fresh media supplemented
with compound every 48 hours). Light microscopy Nikon 6000i image was used to visualize the
5

cells of a) Control; b) DMSO and c) compound 5f. GelDocX+ image of control, DMSO control
and compound treated of same well plate in lower panel. (B) DNA fragmentation assay was
performed in time dependent manner by taking 200 ng of pUC19 DNA incubated with 14 µM of
compound 5f in 15 µl reaction mixture. The fragmentation was analyzed by resolving the
samples on Agarose gel.
Clonogenic assay is the ability of a single cell to grow into a colony and tests every cell in the
population for its ability to form tumor. For this, PC-3 cells were seeded and treated with 14µM
of the compound. After 14 days, cells were washed and fixed with 3.8 % formaldehyde and
stained with crystal violet dye and observed for the clonogenic ability. Fig 3A shows significant
decrease in the clonogenic ability after drug treatment as compare to control. These observation
suggests that 5f might reduce the ability of PC-3 cells to form colony i.e. tumorogenic ability and
along with cell death, cells morphology was also changed. We also noticed chromosomal
aberrations indicated by large number of necrotic and apoptotic cells after treatment. To check
the effect of compound on DNA, DNA cleavage assay was performed by agarose gel
electrophoresis using supercoiled pUC18 plasmid DNA. DNA degradation was observed after 45
minutes of incubation with 5f (Fig 3B). This assay also confirms the presence of endonuclease
activity in the compound which might be due to generation of reactive oxygen species.
Encouraged from result of 5f induced apoptosis in PC-3 cells, we further investigated the effect
of the compound on cell cycle by flow cytometry after treatment of PC-3 cells. PC-3 cells were
treated with 14 µM of the compound and after 48h were fixed and stained with propidium iodide.
The different phases of cell cycle were analyzed by flow cytometry and it is observed that the
cell cycle was arrested in G1 phase and indicate that compound has capability to induce G2/M
arrest and progress to apoptosis (Fig 4A). To further verify its pro-apoptotic function, flow
cytometry analysis was carried out after double staining with propidium iodide and annexin V-
FITC. As shown in Fig 4B, treatment of PC-3 cell lines with 14µM of the compound resulted in
significant increase in apoptosis as compared to control. Further, to confirm that 5f treated PC-3
cells show cell death which is primarily due to apoptosis, we measured the level of apoptotic
markers in treated and untreated samples by western blotting. Decreased expression of pro-
caspases 8 and 9 was observed in 5f treated samples as compared to control (Fig 4C), indicating
that these pro-caspases are converted to caspase 8 and 9 respectively. These results suggest an
enhancement in both intrinsic as well as extrinsic apoptotic pathways. The kinase Akt, an
6

oncoprotein correlated to cell survival and proliferation is upregulated in several cancers and is
responsible for resistance to apoptotic cell death. In this study, the decreased level of
phosphorylated Akt in presence of 5f in comparison to control indicates inhibition in cell
proliferation as activated Akt overcome the cell cycle arrest in G1 and G2 phases. These results
collectively suggest that the compound 5f inhibit the growth of PC-3 cell line by inducing
apoptosis. The assay revealed that the rate of apoptosis increased in a time dependent manner
when compared with control groups (Table 2). Naphthalene based thiosemicarbazone derivatives
are also reported to cause cell death of LNCaP Prostate cancer cell line via apoptosis [18].
A
120
Control
DMSO
ss134f
100
80
60
40
20
0
7

B
C
Figure 4 Cell death analysis of PC-3 cells in control, DMSO treated and 5f (14µM) treated
samples. Flow cytometry was performed to detect whether cell death occurred due to Apoptosis
8

or Necrosis. In Fig 4B Y-axis shows propidium Iodide level and X-axis shows Annexin V. Panel
A and B shows results obtained after 48 h and 72 h respectively after treatment with compound
5f. Lowest panel shows the comparison between percentage changes in cell death after 48h and
72h of treatment. Fig 4C Immunoblotting analysis of procaspase 8 and 9 and pAkt1, 2, 3 after 20
h of treatment with compound 5f (14µm); Samples were collected at different time points.
Table 2. Apoptotic percentages of the control and compound 5f treated groups (n=3). Results are
expressed as Mean±SD.
48 hours
72 hours
Early Apoptosis Control
9.48± 1.46
3.61±0.66
DMSO
7.80 ± 1.58 4.64±2.05
25.48± 5.07 37.9±3.06
1.17±0.181 1.54±0.08
5f
Late Apoptosis Control
DMSO
5f
0.82±0.14
1.80±0.15
14.52±1.48 16.46±1.30
0.05±0.034 3.14±0.621
Necrosis
Control
DMSO
5f
0.06±0.02
0.36±0.08
2.27±0.32
8.52±0.84
As it was observed that 5f has apoptotic as well as necrotic effect on PC-3 cell line and showed
DNA damage, we hypothesize that this could be mediated through generation of reactive oxygen
species (ROS). To find the effect of this compound on generation of ROS in the cell, we
estimated SOD levels in cell lysate. SOD assay was done because it is one of the indirect
methods to detect the ROS level inside the cell. The result shows (Fig. 5) significant time
dependent decrease in SOD level and after 48 hours of treatment, the SOD level in control was
approximately 80% whereas in 5f treated cells, it was approximately 50%. High SOD level in
control denotes higher superoxide concentration, whereas low SOD level in treated sample
reflects that superoxide concentration is less and thus the ROS level is higher as compare to
untreated sample. However the exact mechanism by which ROS is generated after 5f treatment is
yet to be understood.
9

Fig. 5. SOD levels in PC-3cell lysate after treatment with compound 5f (14µM). SOD level was
measured at different time intervals (12 h, 24 h and 48 h). (p≤ 0.05).
The aim of the molecular docking study was to elucidate whether the newly synthesized
compound 5f as well as cisplatin, a known drug currently used in the treatment of prostate cancer
modulates the cell survival by prostate cancer protein receptor cytochrome P450 17A1
(P450c17), and to study their possible mechanisms of action. Molecular docking simulation
results revealed that both compounds were able to interact with the enzyme, and binds strongly
with the cytochrome P450 receptor.
The docking results for compound 5f showed high binding affinity docking score indicated by -
7.136 with the anticancer target cytochrome P450 receptor and also showed the formation of a
H-bond of 2.0Å with acidic amino acid residue Aspartic acid 298 (Fig. 6A). Within the 5f-
cytochrome P450 complex, the chemical nature of binding site residues within a radius of 4 Å
was basic (polar, hydrophobic, positive charged), for example, Arg-239 (Arginine); acidic (polar,
negative charged), for example, Glu-305 (Glutamic acid) and nucleophilic (polar, hydrophobic),
for example, Thr-306 and Ser-106 (Threonine); aromatic (hydrophobic), for example, Phe-114
(Phenylalanine); aliphatic (hydrophobic), for example, Gly-301(Glycine), Leu-214 (Leucine),
Val-236, Val-482, Val-483, Val-366 (Valine), Ile-205, Ile-206, Ile-371(Isoleucine); aromatic
(hydrophobic), for example, Phe-114 (Phenylalanine);aliphatic hydrophobic, for example, Ala-
113, Ala-105, Ala-302, Ala-367 (Alanine); as a result, the bound compound showed a strong
hydrophobic interaction with anticancer target protein cytochrome P450 receptor, thus leading to
more stability and activity of this compound (Fig. 6B). The docking results for the control
compound cisplatin with the anticancer target protein cytochrome P450 receptor showed a low
10

binding affinity docking score, indicated by a -3.687 without any H-bond (hydrogen bond)
formation. Thus, the docking procedure of Glid software (Maestro10.7, Schrödinger) in
reproducing the experimental binding affinity seems reliable, and therefore predicted as true
positive.
A
B
Fig. 6A: 2D Ligand interaction diagram of compound 5f with anticancer target protein
cytochrome P450 using Maestro (Schrödinger) program with the essential amino acid residues at
the binding site are tagged in circles. Fig. 6B: The 3D docking pose showing interaction for
compound 5f binding model with anticancer target protein cytochrome P450. 5f docked on to
11

cytochrome P450 (PDB: 3RUK) with high binding affinity, as indicated by a docking score of -
7.136.
In conclusions, we have synthesized and studied eight naphthalene functionalized with amino
and aroyl group and screened them for antiproliferative potential against prostate cancer (PC-3)
cell line. MTT assay indicated that, out of eight compounds tested, compound 5f showed 50% of
cell death on PC-3 cells. To understand the mechanism of action Flow cytometry analysis was
performed which showed that compound 5f causes apoptosis of PC-3 cells. We also studied the
effect of this compound for ROS production in the cell, and used indirect methods to detect the
ROS level inside the cell. We observed significant time dependent decrease in SOD level in 5f
treated cells indicate the ROS level is higher. We have also performed the molecular docking
study of compound 5f exhibit high binding affinity docking score about -7.136 with the
anticancer target cytochrome P450 receptor, which suggest that further modification may provide
the lead molecule.
Acknowledgements
RKD and RDG thank South Asian University for providing infrastructure and financial support.
RDG thanks Department of Science and Technology, India for financial assistance. RP thanks
University of Delhi and DST, New Delhi for DST-DU purse grant. RR thanks DST, New Delhi
for providing Women Scientist Fellowship. SS thanks CSIR, New Delhi for providing financial
support in the form of SRF.
RP also thank CSIR, New Delhi and ICMR, New Delhi for providing research funding.
Conflict of Interest
The Authors declare no competing interests.
Supporting Information
1H and 13C spectra for all the reported compounds are provided in the SI.
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Graphical abstract
Synthesis, biological evaluation and molecular docking study of 1-amino-2-
aroylnaphthalenes against prostate cancer
Reeta Rai, Roshan Kumar Dutta, Surjeet Singh, Dharmendra Kumar Yadav, Seema Kumari,
Harpreet singh, Rinkoo Devi Gupta and, Ramendra Pratap
100
90
NH2
O
80
70
60
50
40
30
20
10
0
cisplatin
5f
SMe
Br
CN
5f
 IC50 value for 5f = 14 µM
concentration (M)
 IC50 value for cisplatin = 10 µM
 Cytotoxicity of 5f and cisplatin was measured by MTT assay
15