Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives as anti-prostate cancer agents

Article abstract of DOI:10.1016/j.bmcl.2017.01.065

The structural modification and molecular docking-based screening approaches on thiazole-based isoindolinediones were imposed to find the novel 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives. The best fit compounds (6a-n) were synthesized and evaluated their antiproliferative activities on the prostate cancer cell lines (PC-3 & LNCaP). Among them, the compound, 6m exhibited good activity, particularly on LNCaP (IC₅₀?=?5.96?±?1.6?μM), moderately active against PC-3 cell lines as compared to bicalutamide. The compound, 6m decreased the androgen-mediated transcription of ARE-mRNA in PSA, TMPRSS2, c-myc and cyclin D1 than R-bicalutamide. The compounds, 6e and 6f were reconfirmed through single crystal XRD analysis. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters. These findings may provide vital information for the development of anti-prostate cancer agents.

Full text of DOI:10.1016/j.bmcl.2017.01.065

Accepted Manuscript
Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl) isoin-
doline-1,3-dione derivatives as anti-prostate cancer agents
K. Saravanan, R. Elancheran, S. Divakar, S. Athavan Alias Anand, M.
Ramanathan, Jibon Kotoky, N.K. Lokanath, S. Kabilan
PII:
S0960-894X(17)30077-X
http://dx.doi.org/10.1016/j.bmcl.2017.01.065
BMCL 24641
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 September 2016
8 January 2017
23 January 2017
Please cite this article as: Saravanan, K., Elancheran, R., Divakar, S., Anand, S.A.A., Ramanathan, M., Kotoky, J.,
Lokanath, N.K., Kabilan, S., Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl)
isoindoline-1,3-dione derivatives as anti-prostate cancer agents, Bioorganic & Medicinal Chemistry Letters (2017),
doi: http://dx.doi.org/10.1016/j.bmcl.2017.01.065
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Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl) isoindoline-1,3-
dione derivatives as anti-prostate cancer agents
K. Saravanana, R. Elancheranb, S. Divakarc, S. Athavan Alias Ananda, M. Ramanathanc,
Jibon Kotokyb, N. K. Lokanathd, S. Kabilana, *
a Drug Discovery Lab, Department of Chemistry, Annamalai University, Annamalai Nagar -
608002, Tamil Nadu, India
b Drug Discovery Laboratory, Life Sciences Division, Institute of Advanced Study in Science
and Technology, Guwahati-781035, Assam, India
c
Department of Pharmacology, PSG College of Pharmacy, Coimbatore - 641004, Tamil
Nadu, India
d Department of Studies in Physics, University of Mysore, Manasagangotri, Mysuru-570 006,
India
*Corresponding author: Tel: 04144-238641
E-mail address: profdrskabilanau@gmail.com
Abstract
The structural modification and molecular docking-based screening approaches on thiazole-
based isoindolinediones were imposed to find the novel 2-(4-phenylthiazol-2-yl) isoindoline-
1,3-dione derivatives. The best fit compounds (6a-n) were synthesized and evaluated their
antiproliferative activities on the prostate cancer cell lines (PC-3 & LNCaP). Among them,
the compound, 6m exhibited good activity, particularly on LNCaP (IC50 = 5.96 ± 1.6 µM),
moderately active against PC-3 cell lines as compared to bicalutamide. The compound, 6m
decreased the androgen-mediated transcription of ARE-mRNA in PSA, TMPRSS2, c-myc
and cyclin D1 than R-bicalutamide. The compounds, 6e and 6f were reconfirmed through
single crystal XRD analysis. The ADME profiling of the test compounds was evaluated to
find the drug-likeness and pharmacokinetic parameters. These findings may provide vital
information for the development of anti-prostate cancer agents.

Keywords
Androgen Receptor
Prostate Cancer
AR antagonist
Isoindolinediones
Molecular docking
Prostate cancer (PCa) is the second leading causes of cancer-related deaths in men
in the United States. The American Cancer Society has estimated that the diagnosis of
1
1,80,890 new cases and 26,120 deaths due to PCa in the United States in 2016 and still
the incidence is rising. PCa magnification is mainly prompted by androgen and androgen
receptor (AR), initially respond to standard androgen deprivation therapies usually relapse
into a more truculent, castration-resistant prostate cancer (CRPC). Antiandrogens, such as
abiraterone acetate, bicalutamide, cyproterone acetate, flutamide, enzalutamide, galeterone,
hydroxyflutamide and nilutamide (Fig.1) have been utilized for the androgen signal blockage,
but they have several side effects.2
Ultimately, AR antagonist therapy is more efficacious for prostate cancer patients,
results in castration-resistant due to gene mutations such as T877A mutation is activated by
3,4
hydroxyflutamide and W741C mutation is found in bicalutamide-resistant PCa patients.
Despite these current therapeutic options, CRPC still presents a great clinical challenge due to
the inevitably ineluctable development of drug resistance. The drawbacks of currently
available drugs accentuate the desideratum for the development of incipient candidates with
high anti-prostate cancer activities and low unpropitious effects. Aforetime, we have reported
the design and development of oxobenzimidazoles as novel androgen receptor antagonists.5
In recent years, the development of various five-membered heterocyclic predicated scaffolds
has been reported as anti-prostate cancer agents.6,7 However, the search of incipient novel

antiandrogens found that thiazole derivatives were associated with sundry biological
activities such as anticonvulsant, antimicrobial, antidiabetic and anticancer activities.8-11
Several reports revealed the characteristic properties of thiazole and isoindolinedione
scaffolds to attribute various pharmacological properties. In particular, the 4-aromatic
substituent on the 1,3-thiazole core could be considered as more potent and selective
antitumor agents.12 Therefore, these findings prompted our further investigations on the anti-
tumor effects of thiazole-based isoindolinedione derivatives (Fig.1).
CF3
CF3
O
S
HO
O
O
O
H
NC
O2N
S
O
N
F3C
NC
O
NH
F3C
O2N
N
N
N
N
F
HN
H
O
R= H : Flutamide
R= OH: Hydroxyflutamide
O
F
Bicalutamide
Nilutamide
Enzalutamide (MDV3100)
O
O
N
N
N
O
H
H
H
O
H
H
H
H
H
H
HO
O
O
H
Cl
Galeterone ( VN/124-1)
Abiraterone acetate
Cyproterone acetate
OCH3
O
N
OCH3
H2N
N
N
H
S
N
N
S
R
R
S
O
3
O
OCH2CH3
2
1
R1
O
N
N
S
R2
O
6a-n
Figure 1. Structure of novel antiandrogens for the treatment of PCa & structural
modification of novel and designed thiazole-based isoindolinediones
Taking into account the intriguing properties of these thiazole-based
isoindolinedione derivatives and in continuation of our research, we designed a series of

novel 2-(5-phenylthiazol-2-yl)isoindoline-1,3-dione utilizing the Schrödinger (Maestro
9.5) software.13 The available AR crystal structures were either in agonist or partial agonist
conformation which has helix 12 closed towards the ligand binding pocket. The 3D
structure of AR co-crystallized with SARM inhibitor (4-[(4R)-4-(4-hydroxyphenyl)-3,4-
dimethyl- 2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile) (PDB: 3V49) as a
partial agonist was utilized in this study.14
A
B
C
D
Figure 2. Predicted binding mode of the compounds (6m & 6n) in AR LBD (PDB: 1Z95)
highlighting the H-Bond interaction with Arg752, HOH and Met745 (HOH bridged) and π-π
stacking with Trp741 (Fig. 2A & 2B: coloured by atom types- C light gray, F green, N blue,
O red, S yellow, H white).
The Arg752, HOH, Met745 were present deep inside the binding pocket while the Thr877
lies more proximate to the helix 12.15 The phthalimides which have methoxyphenyl,
cyanophenyl, and nitrophenyl nucleus could form H-Bond interaction with the deep

residues, and none of the phthalimides formed H-Bond interaction with amino acids that
were nearer to helix 12. Also, it was observed that the phthalimide group was found to be
closer towards the helix 12 and the fluorine atom in the phthalimide has a steric class with
helix-12 amino acids Val903 and Ile899. So, it is possible that the bulkiness of the 6m & 6n
might have obviated the binding with AR where the helix 12 is only partially unfolded
(Fig. 2). The ligands which could bind with helix 12 closed AR might have less bulkiness to
completely displace the helix 12 away from the ligand binding pocket, and hence those
ligands could function as an agonist or partial agonist.16
Table 1
Docking score and H-Bond interactions of test and standard compounds
H-Bonding
π-π interaction
Dock score
(Kcal/mol)
ID
Arg752 Met745* HOH Thr877 Phe764 Hie874 Trp741
-8.317
-9.113
-8.378
-8.260
-8.364
-8.437
-8.777
-9.051
-8.757
-8.377
-8.499
-8.942
-8.999
-8.470
-8.348
6a
6b






















































6c



6d





6e






6f









6g
6h
6i







6j



6k



6l












6m
6n



R-BIC
* H-Bond mediated through HOH
# Docking carried out using helix 12 truncated androgen receptor
Bridged H-bond interaction
 No Bridged H-bond interaction
The compounds (6a-n) have shown binding affinity to AR and their docking scores were
quite kindred to the standard (R)-bicalutamide (Table 1). Predicated on the molecular

docking results, the synthesis of the molecules was considered to be consequential. The
compounds (5a-g) were synthesized by using commercially available 2-bromo-1-(4-
substituted phenyl)ethanone and thiourea in ethanol were refluxed in the presence of
triethylamine.17 Further, the compounds (6a-n) were obtained by refluxing the compounds
(5a-g) with the respective phthalic anhydride in acetic acid, in good to excellent yield (60–
90 %), 8–12 h.8,18 The general synthesis of 2-(4-phenylthiazol-2-yl)isoindoline-1,3-dione
derivatives (6a-n) is depicted in Schemes 1.
O
R1
R1
O
O
S
O
R2
N
S
Br
H2N
NH2
O
N
N
NH2
R2
AcOH
TEA, EtOH
R1
S
O
6a (R1 = H, R2 = H)
6b (R1 = F, R2 = H)
6c (R1 = Cl, R2 = H)
6d (R1 = CH3, R2 = H)
6e (R1 = OCH3, R2 = H)
6f (R1 = CN, R2 = H)
6g (R1 = NO2, R2 = H)
4a (R1 = H)
4b (R1 = F)
4c (R1 = Cl)
4d (R1 = CH3)
6h (R1 = H, R2 = F)
6i (R1 = F, R2 = F)
6j (R1 = Cl, R2 = F)
6k (R1 = CH3, R2 = F)
6l (R1 = OCH3, R2 = F)
6m (R1 = CN, R2 = F)
6n (R1 = NO2, R2 = F)
5a (R1 = H)
5b (R1 = F)
5c (R1 = Cl)
5d (R1 = CH3)
5e (R1 = OCH3)
5f (R1 = CN)
5g (R1 = NO2)
4e (R1 = OCH3)
4f (R1 = CN)
4g (R1 = NO2)
Scheme 1. Synthesis of thiazole derivatives
The synthesized compounds (6a-n) were well characterized by IR, NMR, and
HRMS, and all the data are in accordance with the proposed structures. Single crystals of
the compounds, 6e and 6f were obtained from ethyl acetate solvent by slow evaporation at
room temperature.19,20 The compound, 6e belongs to monoclinic with space group, P21/c, a
=7.004 (9) Å, b = 14.054 (17) Å, c = 15.275 (19) Å, β = 90.368° (12) and Z= 4. Similarly,
the compound, 6f belongs to triclinic system, space group P-1, a =7.915 (7) Å, b = 12.1641
(10) Å, c = 17.255 (14) Å, α = 69.51° (2), β = 79.50° (2), γ = 82.93° (3) and Z=4. The
molecular structure and atomic connectivity of the compounds, 6e and 6f were illustrated
in Fig. S3.

All the synthesized compounds (6a-n) were evaluated the anticancer activities
against prostate cancer cell lines (PC-3 & LNCaP) and their cytotoxicities using non-
cancerous cell line (3T3) as compared with the standards by using the standard MTT
assay. Cellular viability in the presence and absence of the compounds was determined as
described in the earlier methods.5,21 The results indicate that the compounds (6a-n) were
shown the cytotoxic potential in the IC50 range of 5-36 µM in LNCaP, 37-44 µM in PC-3
and 36-50 µM in 3T3 cell lines. The range of IC50 values indicates that the compounds
were more selective towards T877A AR expressing LNCaP cell line. Of these, the
compound, 6m showed 4.6 fold greater activities than R-bicalutamide and 7.4 fold better
than bicalutamide in LNCaP cell line. The results demonstrated that the compound, 6m
(IC50 = 5.96 ± 1.6 µM) showed the highest anticancer activities among the series especially
selective against LNCaP. It is evident that the substitution at position R1 and R2 were
influencing the activity in the cell-based assay. In particular, the compound 6m, the
fluorine at R2 was incrementing the antagonist activity compared to the compound 6f.
Similarly, the groups OCH3, CN and NO2 at position R1 were influenced by the better
activities compared to other groups. Also, the previous studies endorsed that 4-substituted
phenyl-1,3-thiazole core showed the greater anticancer activities compared to aromatic
substitution on 1,3-thiazole at 5th position.12
Table 2
IC50 of test and standard compounds
R1
O
N
N
R2
S
O
Selectivity
Safety
a
ID
R1
R2 LNCaP (μM)*, PC3 (μM)a 3T3 (μM)a
AR-/AR+ 3T3/LNCaP
H
F
H
H
36.84 ± 2.1
28.56 ± 3.3
43.94 ± 1.2 46.46 ± 2.8
37.19 ± 4.0 38.9 ± 27
1.19
1.30
1.26
1.36
6a
6b

Cl
CH3
OCH3
CN
H
H
H
H
H
F
26.24 ± 2.3
29.04 ± 4.7
13.67 ± 0.7
10.96 ± 0.4
13.17 ± 1.5
22.59 ± 0.4
21.51 ± 1.5
27.96 ± 3.9
25.82 ± 1.6
8.17 ± 0.2
5.96 ± 1.6
7.78 ± 1.8
27.71 ± 7.2
44.94 ± 3.3 50.2 ± 0.9
38.38 ± 1.8 50.51 ± 4.2
42.93 ± 3.1 45.06 ± 1.7
40.30 ± 5.5 39.19 ± 6.7
41.8 ± 4.8 41.56 ± 5.6
1.71
1.32
3.14
3.67
3.17
1.17
1.8
1.91
1.73
3.29
3.57
3.15
1.90
2.04
1.59
1.51
5.04
7.09
4.69
2.27
6c
6d
6e
6f
NO2
H
6g
40.2 ± 1.1
42.96 ± 3
6h
F
F
39.49 ± 2.6 43.98 ± 1.8
37.95 ± 2.2 44.53 ± 1.2
44.4 ± 4.1 39.03 ± 4.4
41.3 ± 3.3 41.2 ± 6.2
43.12 ± 4.3 42.3 ± 6.4
39.88 ± 4.9 36.5 ± 4.3
59.83 ± 6.9 63.1 ± 5.9
6i
Cl
F
1.35
1.71
5.05
7.23
5.12
2.15
6j
CH3
OCH3
CN
NO2
F
6k
F
6l
6m
F
F
6n
R-BICb
BICb
44.26 ± 1.5
60.69 ± 5.1 54.9 ± 7.5
1.37
1.2
*IC50 of the compounds stimulated by 1nM DHT
a
The values are the mean ± standard deviation (SD) of three independent experiments
performed in triplicate
b Positive control
In recent studies, it was reported that gal suppressed castration-resistant and
enzalutamide-resistant prostate cancer growth in vitro and also blocked nuclear
translocation and decreased AR-dependent genes (PSA, TMPRSS2, and Nkx3.1).23 The
active molecule 6m was further analyzed for AR specific activity by evaluating the mRNA
expression of androgen regulated response elements (AREs), PSA and TMPRSS2 in
LNCaP cell line. The LNCaP cells also express ER-β which shares similar binding
characters as of AR. There are several reports on ER response element, pS2 gene in
prostate cancer. But, the compound, 6m had not decreased the mRNA expression of ER
response gene, pS2. We also measured the androgen responsive oncogenes, c-myc and
cyclin D1. The c-myc and cyclin D1 were highly expressed in androgen-independent
prostate cancer. The LNCaP cell has 50 times more expression of c-myc than normal cell
lines, indicating the significant contribution by these oncogenes in deregulating the

androgen-mediated homeostatic control on prostate cells. The 1 nM DHT increased the
mRNA expression of PSA (4 fold), TMPRSS2 (3 fold), c-myc (2 fold) and cyclin D1 (2
fold) than the solvent control (Fig. 3).
Figure 3. Gene expression
The significant symbol (#) represents the comparison between control and DHT. The
significant symbol (*) represents the comparison between the DHT (negative control) and
standard (R-BIC) and test (6m) ligands. (***P<0.001, **P<0.01, *P<0.05); (R)-BIC: (R)-
Bicalutamide.
The standard R-bicalutamide and test compound 6m had decreased the androgen-
mediated transcription of ARE mRNA (PSA, TMPRSS2) and oncogene c-myc. The
notable difference is that the test compound 6m was more potent in antagonizing the

androgen-mediated mRNA expression of ARE and oncogenes. Also, the test compound
6m could significantly decrease the mRNA expression of cyclin D1 while the standard R-
bicalutamide did not. The cyclin D1 is responsible for G1/S transition during cell division.
This indicates that the test compound could limit the cell division better than the standard
R-bicalutamide. None of the tested compounds had changed the expression of ER response
elements, pS2. This indicates that the anti-prostate cancer activity of the tested compound
was mediated through AR. The absorption, distribution, metabolism and elimination
(ADME) properties of the synthesized compounds (6a-n) were evaluated for the
pharmacokinetic and pharmaceutical relevant properties as described earlier.5 The qikpro
v3.5 was used for the evaluation ADME parameters, and its permissible ranges are listed in
the supporting information (Table S2).
Thanks to the recent disclosure of the hARLBD X-ray structure, we were able to
perform a structure-based design of a novel class of AR antagonists. The 2-(4-phenylthiazol-
2-yl)isoindoline-1,3-dione derivatives were designed by using ligand-receptor docking, and
the Glide scores were in good agreement with the observed IC50 values. It is evident from the
docking calculations that the isoindoline-1,3-dione group has enhanced the binding affinities
of the compounds (6a-n) than the phenylthiazol-2-amine (5a-g). The compounds, 6a-n
demonstrated the significant anti-prostate cancer activities. In particular, the compound, 6m
was discovered as the most promising of the series, especially selective against the LNCaP
cell line. Also, the compounds, 6l & 6n were moderately active against the LNCaP cell line.
The investigation of the target site and the in vivo anticancer activity of the active compounds
will be further examined.
Acknowledgements
This work was supported by Govt. of India funded by the Ministry of Science & Technology,
Department of Biotechnology (DBT) (HC-95).

Supplementary data
Supplementary data associated HRMS & NMR spectra of compounds, 6a-6n. The
Crystallographic data for compounds, 6e & 6f has been deposited with the Cambridge
Crystallographic Data Centre, CCDC No. 1488161 & 1491736 respectively. Copies of the
data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: +44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
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