Design, synthesis and biological evaluation of novel arylpiperazine derivatives on human prostate cancer cell lines

Article abstract of DOI:10.1016/j.cclet.2015.09.016

A series of novel arylpiperazine derivatives was synthesized. The in vitro cytotoxic activities of all synthesized compounds against three human prostate cancer cell lines (PC-3, LNCaP, and DU145) were evaluated by a CCK-8 assay. Compounds 8, 10, 13, 17 a

Full text of DOI:10.1016/j.cclet.2015.09.016

Chinese Chemical Letters 27 (2016) 277–282
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Design, synthesis and biological evaluation of novel arylpiperazine
derivatives on human prostate cancer cell lines
a,b,1
b,1
b,1
b
b
b
Hong Chen
, Fang Xu , Bing-Bing Xu , Jing-Yi Xu , Bin-Hao Shao , Bi-Yun Huang ,
b,
Mu Yuan *
a
College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022, China
Pharmaceutical Research Center, Guangzhou Medical University, Guangzhou 510182, China
b
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of novel arylpiperazine derivatives was synthesized. The in vitro cytotoxic activities of all
synthesized compounds against three human prostate cancer cell lines (PC-3, LNCaP, and DU145) were
evaluated by a CCK-8 assay. Compounds 8, 10, 13, 17 and 20 exhibited strong cytotoxic activities against
Received 7 April 2015
Received in revised form 9 June 2015
Accepted 15 June 2015
the tested cancer cell lines (IC50 <3
mmol/L). In addition, these compounds exhibited weak cytotoxic
Available online 28 September 2015
effects on human epithelial prostate normal cells WPMY-1. The structure–activity relationship (SAR) of
these arylpiperazine derivatives was also discussed based on the obtained experimental data.
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Synthesis
Arylpiperazine derivatives
Cytotoxic activity
CCK-8
Structure–activity relationship
1
. Introduction
normal tissue, because most drugs can show some selective
toxicity toward rapidly dividing cells compared to noncycling cells
Prostate cancer is the most common non-skin cancer in men
and is the second-leading cause of cancer-related deaths in the US
1]. Generally, the incidence rate of prostate cancer in Western
[7]. So, drugs designed are expected to have high affinity with the
novel targets, and they not only inhibit the proliferation but also
differentiation of tumor cells and speed up their death [8].
Studies have shown that compounds with arylpiperazine
moieties have anti-proliferative properties [9–11]. Naftopidil, an
[
countries is higher than that in Asian countries [2,3]. Prostate
cancer mortality typically results from metastasis to the bone and
lymph nodes, as well as the progression from androgen-dependent
to androgen-independent prostatic growth [4]. Although various
chemotherapeutic agents are used solely or in combination with
radiotherapy to treat advanced diseases, none of the conventional
approaches to cancer therapy have been proven to be highly
successful for prostate cancer [5]. Therefore, inventing and
developing more effective, safe and selective anti-prostate cancer
drugs are urgently needed. The selective targeting of tumor cells is
the goal of modern cancer chemotherapy aimed at overcoming the
nonspecific toxicity of most anticancer agents against normal cells
arylpiperazine ether derivative, is a specific
receptor antagonist [12,13], and it is one of the most widely
used -adrenergic receptor antagonists in Japan for the
a1d-adrenergic
a
1
treatment of benign prostatic hyperplasia (BPH) [14,15]. Recent
studies have shown that naftopidil could possibly exert an
anticancer effect and inhibit prostate cancer cell growth by
arresting the G1 cell cycle phase [16,17], as well as inducing
apoptosis in malignant mesothelioma cell lines [18]. In our
previous works [19,20], we reported anti-prostate cancer activi-
ties of a series of arylpiperazine ether derivatives. In this work, we
report the synthesis of a series of novel arylpiperazine amide
derivatives (Scheme 1) with the intention of identifying much
more effective anti-prostate cancer drugs. All synthesized
compounds were evaluated for their cytotoxic activities against
three human prostate cancer cell lines PC-3, LNCaP and DU145
cell line, and human prostate epithelial cell line WPMY-1. The SAR
was further discussed on the basis of the obtained experimental
[
6]. At present, much of successful cancer chemotherapy probably
lies in utilizing differences in cell kinetics between tumor and
*
Corresponding author.
E-mail address: mryuanmu838@sina.com (M. Yuan).
These authors contributed equally to this work.
1
http://dx.doi.org/10.1016/j.cclet.2015.09.016
001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
1

2
78
H. Chen et al. / Chinese Chemical Letters 27 (2016) 277–282
Scheme 1. Synthetic route of compounds 7–23. Reagents and conditions: (a) BH
salt, K CO , CH CN, reflux, 16 h; (c) TsCl, Et N and 4-dimethylaminopyridine, Cl CH
temperature, 16 h; (f) acids, DIPEA, HATU, Cl CH , room temperature, 16 h; (g) HCl, AcOEt, room temperature, 0.5 h; (h) acid anhydrides, toluene, reflux, 16 h.
3
.S(CH
3
2
) , THF, 0 8C for 1 h, and then room temperature for 10 h; (b) phthalimide potassium
2
3
3
3
2
2
, 0 8C, 16 h; (d) N-phenylpiperazine, K
2
CO , CH CN, reflux, 16 h; (e) N .H O, EtOH, room
3
3
2
H
4
2
2
2
data. As we expected, some arylpiperazine amide derivatives
exhibited strong anti-prostate cancer activities against the tested
cancer cells and potency superior to naftopidil.
(C, H, N) were performed on an Elementar Vario EL elemental
analyzer and the analytical results were within ꢀ0.4% of the
theoretical values for the formula given unless otherwise listed.
Flash column chromatography was performed with silica gel (Qing
Dao Ocean Chemical Factory, 300–400 mesh) eluted with petro-
leum ether–ethyl acetate.
2
. Experimental
Reagents and solvents were commercially available. Solvents
were dried and purified prior to use using standard procedures.
Melting points were determined on SGW X-4 micro melting
point apparatus (Shanghai Precision & Scientific Instrument Co.,
Ltd., Shanghai, China) and are uncorrected. NMR spectra were
determined on a Bruker AV-400 NB spectrometer (Faellanden,
2.1. Synthesis of 2-(4-(bromomethyl)phenyl)ethanol (2)
To a cooled (0 8C) solution of carboxylic acid 1 (5.5 g, 24 mmol)
in dry tetrahydrofuran (THF, 100 mL) borane–dimethyl sulfide
complex (24 mL, 0.048 mol, 2 mol/L in THF) was added dropwise.
The reaction mixture was stirred at 0 8C for 1 h, and then at room
temperature for 10 h. Water (20 mL) was added slowly and
extracted with ethyl acetate (3ꢁ 100 mL). The combined organic
phase was successively washed with water and brine, dried over
anhydrous magnesium sulfate, and concentrated in vacuo. The
resulting residue was directly used without further purification in
the following step.
Switzerland) or Bruker AVANCE-500 spectrometer in CDCl
3
or
DMSO-d using TMS as internal standard, and coupling
6
constants (J) are in Hz. EI mass spectra were recorded on a
DSQ mass spectrometer. ESI mass spectra were recorded on an
Agilent 6460 Triple Quadrupole mass spectrometer (Agilent
Technologies, USA). HRMS spectra were recorded on LTQ
Orbitrap LC–MS (Thermo, Rockford, IL, USA). Elemental analyses

H. Chen et al. / Chinese Chemical Letters 27 (2016) 277–282
279
2
.2. Synthesis of 2-(4-(2-hydroxyethyl)benzyl)isoindoline-1,3-dione
2.5. Synthesis of (4-(2-(4-phenylpiperazin-1-yl)ethyl)phenyl)
methanamine (6)
(
3)
To a solution of compound 2 (4.7 g, 22 mmol) in CH
100 mL), phthalimide potassium salt (4.06 g, 22 mmol) and
3
CN
To a solution of 5 (5.0 g, 11.8 mmol) in ethanol hydrazine
hydrate (5.9 g, 118 mmol) was added. The reaction mixture was
stirred at room temperature for 16 h. The reaction mixture was
filtered through a Buchner funnel. After filtration the filtrate was
concentrated in vacuo to afforded 3 g crude product 6. The
resulting crude product was directly used without further
purification in the following step.
(
potassium carbonate (18.2 g, 132 mmol) were added, and the
reaction mixture was stirred at reflux for 16 h. After cooling to
ambient temperature, the reaction mixture was filtered through a
Buchner funnel. After filtration the filtrate was concentrated in
vacuo and the residue was purified by silica gel column
chromatography using ethyl acetate/petroleum ether (1/8, v/v)
as eluent to afford 4.72 g of compound 3 (70% from compound 1) as
2.6. General procedure for the preparation of arylpiperazine
+
a white solid. Mp 101–102 8C; MS (EI, m/z): 281 (M ), 236, 251
derivative hydrochloride salts 7–20
1
(
100%), 232, 204, 192, 178, 160; H NMR (400 MHz, CDCl
3
):
d
7.84
(dd, 2H, J = 5.5, 3.0 Hz), 7.70 (dd, 2H, J = 5.5, 3.0 Hz), 7.38 (d, 2H,
2 2
To a solution of 6 (100 mg, 3.39 mmol) in CH Cl (20 mL)
J = 8.0 Hz), 7.17 (d, 2H, J = 8.0 Hz), 4.82 (s, 2H), 3.82 (t, 2H,
was added the corresponding acid (1.2 equiv.), N,N-diisopro-
pylethylamine (DIPEA, 4 equiv.) and 2-(7-aza-1H-benzotriazole-
1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU,
1 equiv.). The reaction mixture was stirred at room temperature for
13
J = 6.5 Hz), 2.83 (t, 2H, J = 6.5 Hz), 1.44 (s, 1H); C NMR (101 MHz,
CDCl ): 168.5, 138.6, 135.0, 134.4, 132.6, 129.7, 129.3, 123.7, 64.0,
1.7, 39.3.
3
d
4
16 h. The reaction mixture was filtered through a Buchner funnel.
After filtration the filtrate was concentrated in vacuo and the
residue was purified by silica gel column chromatography using
ethyl acetate/petroleum ether (1/7, v/v) as eluent to afford the
corresponding products (7–20). To a solution of the above
corresponding products in ethyl acetate was added dropwise
2
.3. Synthesis of 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)phenyl)ethyl
4
-methylbenzenesulfonate (4)
To a solution of compound 3 (4.72 g, 16.8 mmol), triethyla-
mine (6.79 g, 67.2 mmol) and 4-dimethylaminopyridine (0.13 g,
.05 mmol) in dry dichloromethane (CH Cl , 80 mL) at 0 8C was
added dropwise a solution of 4-toluene sulfonyl chloride (4.79 g,
5.2 mmol) in CH Cl (20 mL). The reaction mixture was stirred
at 0 8C for 16 h. Water (20 mL) was added slowly and the
reaction mixture was extracted with CH Cl
4
mol/L HCl solution in ethyl acetate (50 mL), while maintaining
1
2
2
stirring for 0.5 h. Then the resulting solid was collected by filtration
to give corresponding hydrochloride salts as a white solid.
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)benzamide
dihydrochloride (7): White solid; Yield: 45%; Mp 152–153 8C (HCl
2
2
2
2
2
(2ꢁ 50 mL). The
+
1
salt); MS (ESI, m/z): 400.2 [M+1] ; H NMR (400 MHz, DMSO-d
1.51 (s, 1H), 8.68 (t, 1H, J = 6.0 Hz), 7.68–7.54 (m, 2H), 7.35–7.20
m, 7H), 7.14 (d, 1H, J = 8.3 Hz), 7.05 (t, 3H, J = 7.6 Hz), 6.77 (t, 1H,
J = 7.3 Hz), 4.46 (d, 2H, J = 6.0 Hz), 3.81 (d, 2H, J = 11.0 Hz), 3.64 (d,
6
): d
combined organic phase was successively washed with water
and brine, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography using ethyl acetate/petroleum ether
1
(
2
C
H, J = 11.0 Hz), 3.41–3.02 (m, 8H); Anal. Calcd. for
O.2HCl: C, 66.10; H, 6.61; N, 8.89. Found: C, 66.25; H,
(
1/10, v/v) as eluent to afford 6.9 g (95%) of compound 4 as a
+
26 29 3
H N
white solid. Mp 108–109 8C; MS (EI, m/z): 435 (M ), 363, 250
1
6.67; N, 8.78.
(
2
100%), 235, 204, 178, 148; H NMR (400 MHz, CDCl
H, J = 5.5, 3.0 Hz), 7.71 (dd, 2H, J = 5.5, 3.0 Hz), 7.66 (d, 2H,
J = 8.3 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.3 Hz), 7.05 (d,
H, J = 8.0 Hz), 4.81 (s, 2H), 4.16 (t, 2H, J = 7.0 Hz), 2.91 (t, 2H,
3
): d 7.84 (dd,
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)-2-methoxy-
benzamide hydrochloride dihydrochloride (8): White solid; Yield:
+
1
5
2%; Mp 168–169 8C (HCl salt); MS (ESI, m/z): 430.2 [M+1] ;
H
2
1
3
NMR (400 MHz, DMSO-d
6
): 11.58 (s, 1H), 8.66 (t, 1H, J = 6.0 Hz),
d
J = 7.0 Hz), 2.42 (s, 3H); C NMR (101 MHz, CDCl
1
1
3
):
45.1, 136.3, 135.5, 134.4, 133.4, 132.6, 130.2, 129.6, 129.2,
28.3, 123.8, 70.8, 41.6, 35.4, 22.0.
d 168.4,
7
7
4
2
d
.74 (dd, 1H, J = 7.6, 1.7 Hz), 7.52–7.41 (m, 1H), 7.35–7.20 (m, 6H),
.14 (d, 1H, J = 8.3 Hz), 7.03 (t, 3H, J = 7.6 Hz), 6.87 (t, 1H, J = 7.3 Hz),
.48 (d, 2H, J = 6.0 Hz), 3.89 (s, 3H), 3.82 (d, 2H, J = 11.0 Hz), 3.62 (d,
1
3
H, J = 11.0 Hz), 3.41–3.02 (m, 8H); C NMR (101 MHz, DMSO-d
6
):
2
.4. Synthesis of 2-(4-(2-(4-phenylpiperazin-1-yl)ethyl)benzyl)
165.3, 157.1, 149.6, 138.4, 135.6, 132.3, 130.5, 129.3, 128.7,
isoindoline-1,3-dione (5)
127.5, 123.4, 120.6, 120.2, 116.2, 112.2, 56.2, 56.0, 50.6, 45.6, 42.4,
0.3, 29.0; Anal. Calcd. for C27 .2HCl: C, 64.54; H, 6.62; N,
8.36. Found: C, 64.12; H, 6.67; N, 8.19.
4
31 3 2
H N O
3
To a solution of 4 (6.9 g, 15.9 mmol) in acetonitrile (CH CN,
5
0 mL) N-phenylpiperazine (3.09 g, 19.08 mmol) and potassium
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)-2-fluoroben-
zamide dihydrochloride (9): White solid; Yield: 46%; Mp 177–
carbonate (13.16 g, 95.4 mmol) were added. The reaction mixture
was stirred at reflux for 16 h. After cooling to ambient
temperature, the reaction mixture was filtered through a Buchner
funnel. After filtration the filtrate was concentrated in vacuo and
the residue was purified by silica gel column chromatography
using ethyl acetate/petroleum ether (1/8, v/v) as eluent to afford
+
1
178 8C (HCl salt); MS (ESI, m/z): 418.2 [M+1] ; H NMR (400 MHz,
DMSO-d ): 11.54 (s, 1H), 8.86 (t, 1H, J = 6.0 Hz), 7.64 (td, 1H,
6
d
J = 7.5, 1.5 Hz), 7.57–7.48 (m, 1H), 7.32–7.25 (m, 8H), 7.02 (d, 2H,
J = 8.0 Hz), 6.87 (t, 1H, J = 7.3 Hz), 4.45 (d, 2H, J = 6.0 Hz), 3.82 (d,
1
3
2H, J = 11.0 Hz), 3.62 (d, 2H, J = 11.0 Hz), 3.41–3.06 (m, 8H);
C
5
.0 g (74%) of compound 5 as a white solid. Mp 130–131 8C; HRMS
NMR (101 MHz, DMSO-d ): 163.9, 160.5, 158.0, 149.6, 138.0,
135.7, 132.5, 132.5, 130.2, 129.3, 128.7, 127.6, 124.6, 124.3, 124.1,
120.2, 116.3, 116.2, 56.2, 50.7, 45.6, 42.5, 29.0; Anal. Calcd. for
d
6
+
(
ESI): calcd for
C
27
H
27
N
3
O
2
,
426.2176 [M+1] , found,
+
1
4
26.2169 [M+1] ; H NMR (400 MHz, CDCl ): 7.84 (dd, 2H,
3
d
J = 5.5, 3.0 Hz), 7.70 (dd, 2H, J = 5.5, 3.0 Hz), 7.37 (d, 2H, J = 8.1 Hz),
C26H28FN O.2HCl: C, 63.67; H, 6.17; N, 8.57. Found: C, 63.36; H,
3
7
6
2
6
1
4
.28–7.24 (m, 2H), 7.18 (d, 2H, J = 8.1 Hz), 6.93 (d, 2H, J = 7.9 Hz),
.85 (t, 1H, J = 7.3 Hz), 4.82 (s, 2H), 3.22 (t, 4H, J = 5.0 Hz), 2.81 (dd,
H, J = 9.8, 6.3 Hz), 2.67 (t, 4H, J = 5.0 Hz), 2.62 (dd, 2H, J = 9.8,
6.41; N, 8.23.
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)cyclohexane-
carboxamide dihydrochloride (10): White solid; Yield: 40%; Mp
192–193 8C(HCl salt); MS (ESI, m/z): 406.2 [M+1] ; H NMR
(400 MHz, DMSO-d ): 11.36 (s, 1H), 8.21 (t, 1H, J = 6.0 Hz), 7.31–
7.16 (m, 7H), 7.02 (d, 2H, J = 8.0 Hz), 6.87 (t, 1H, J = 7.2 Hz), 4.22
1
3
+
1
.4 Hz); C NMR (101 MHz, CDCl
3
):
d
168.1, 151.4, 140.0, 134.3,
34.0, 132.3, 129.2, 129.1, 128.9, 123.4, 119.8, 116.2, 60.4, 53.3,
9.3, 41.4, 33.3.
d
6

2
80
H. Chen et al. / Chinese Chemical Letters 27 (2016) 277–282
(
3
d, 2H, J = 6.0 Hz), 3.82 (d, 2H, J = 10.6 Hz), 3.62 (d, 2H, J = 10.6 Hz),
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)-1H-indole-2-
carboxamide dihydrochloride (16): White solid; Yield: 57%; Mp
.41–3.02 (m, 8H), 2.24–2.07 (m, 1H), 1.70 (d, 4H, J = 11.2 Hz), 1.61
13
+
1
(
d
d, 1H, J = 10.1 Hz), 1.46–1.08 (m, 6H); C NMR (101 MHz, DMSO-
): 175.2, 149.6, 138.6, 135.5, 129.2, 128.7, 127.4, 120.2, 116.1,
6.2, 50.7, 45.6, 44.1, 41.62, 29.4, 29.0, 25.6, 25.4; Anal. Calcd. for
O.2HCl: C, 65.26; H, 7.79; N, 8.78. Found: C, 64.91; H,
163–164 8C (HCl salt); MS (ESI, m/z): 439.1 [M+1] ; H NMR
(400 MHz, DMSO-d ): 11.63 (s, 1H), 11.47 (s, 1H), 9.11 (t, 1H,
6
d
6
d
5
C
7
J = 6.0 Hz), 7.60 (d, 1H, J = 8.0 Hz), 7.43 (d, 1H, J = 8.0 Hz), 7.33 (d,
2H, J = 8.0 Hz), 7.30–6.97 (m, 9H), 6.87 (t, 1H, J = 7.2 Hz), 4.49 (d,
2H, J = 6.0 Hz), 3.81 (d, 2H, J = 10.8 Hz), 3.61 (d, 2H, J = 10.8 Hz),
26 33 3
H N
.60; N, 8.50.
1
3
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)cyclopentane-
6
3.36–3.02 (m, 8H); C NMR (101 MHz, DMSO-d ): d 161.2, 149.6,
carboxamide dihydrochloride (11): White solid; Yield: 44%; Mp
138.4, 136.6, 135.7, 131.8, 129.2, 128.7, 127.7, 127.2, 123.4, 121.6,
120.2, 119.8, 116.2, 112.4, 102.9, 56.2, 50.7, 45.6, 42.0, 29.0; Anal.
+
1
1
61–162 8C (HCl salt); MS (ESI, m/z): 392.2 [M+1] ; H NMR
(
400 MHz, DMSO-d ): 11.54 (s, 1H), 8.28 (t, 1H, J = 6.0 Hz), 7.37–
6
d
30 4
Calcd. for C28H N O.2HCl: C, 65.75; H, 6.31; N, 10.95. Found: C,
7
2
3
.16 (m, 6H), 7.02 (d, 2H, J = 8.0 Hz), 6.87 (t, 1H, J = 7.2 Hz), 4.23 (d,
65.59; H, 6.45; N, 10.69.
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)-5-fluoro-1H-
indole-2-carboxamid dihydrochloride (17): White solid; Yield:
47%; Mp 193–194 8C (HCl salt); MS (ESI, m/z): 457.1 [M+1] ;
NMR (500 MHz, DMSO-d ): 11.75 (s, 1H), 11.17 (s, 1H), 9.16 (t,
1H, J = 6.0 Hz), 7.50–7.21 (m, 9H), 7.07–6.94 (m, 3H), 6.86 (t, 1H,
J = 7.2 Hz), 4.48 (d, 2H, J = 6.0 Hz), 3.81 (d, 2H, J = 10.8 Hz), 3.61 (d,
2H, J = 10.8 Hz), 3.34–3.04 (m, 8H); C NMR (126 MHz, DMSO-d
H, J = 6.0 Hz), 3.82 (d, 2H, J = 10.6 Hz), 3.62 (d, 2H, J = 10.6 Hz),
13
.42–3.00 (m, 8H), 2.78–2.54 (m, 1H), 1.78–1.50 (m, 8H); C NMR
): 175.1, 149.4, 138.4, 135.3, 129.0, 128.5,
27.3, 120.0, 115.9, 56.0, 50.4, 45.3, 44.2, 41.6, 29.9, 28.8, 25.5;
O.2HCl: C, 64.65; H, 7.60; N, 9.05. Found:
C, 64.58; H, 7.74; N, 8.85.
+
1
(101 MHz, DMSO-d
6
d
H
1
6
d
Anal. Calcd. for C25
H
33
N
3
1
3
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)cyclopropane-
carboxamide dihydrochloride (12): White solid; Yield: 39%; Mp
6
):
d
160.9, 158.2, 156.3, 149.7, 138.3, 135.7, 133.4, 133.3, 129.3,
+
1
1
72–173 8C (HCl salt); MS (ESI, m/z): 364.2 [M+1] ; H NMR
128.8, 127.7, 127.3, 127.2, 120.2, 116.1, 113.7, 113.6, 112.3, 112.0,
105.9, 105.7, 102.9, 56.3, 50.7, 45.6, 42.0, 29.1; Anal. Calcd. for
(500 MHz, DMSO-d ): 11.03 (s, 1H), 8.58 (t, 1H, J = 6.0 Hz), 7.36–
6
d
7
2
3
.15 (m, 6H), 7.02 (d, 2H, J = 8.0 Hz), 6.87 (t, 1H, J = 7.2 Hz), 4.25 (d,
28 4
C H29FN O.2HCl: C, 63.52; H, 5.90; N, 10.58. Found: C, 63.87; H,
H, J = 6.0 Hz), 3.84 (d, 2H, J = 10.6 Hz), 3.63 (d, 2H, J = 10.6 Hz),
5.99; N, 10.47.
13
.44–2.98 (m, 8H), 1.72–1.35 (m, 1H), 0.78–0.54 (m, 4H); C NMR
): 172.8, 149.8, 138.6, 135.7, 129.4, 128.9,
27.9, 120.3, 116.2, 56.3, 50.8, 45.7, 42.1, 29.2, 13.8, 6.5; Anal.
O.2HCl: C, 63.30; H, 7.16; N, 9.63. Found: C,
2.97; H, 6.39; N, 9.57.
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)-1-naphtha-
mide dihydrochloride (13): White solid; Yield: 59%; Mp 191–
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)benzofuran-2-
carboxamide (18): White solid; Yield: 56%; Mp 166–167 8C; MS
(126 MHz, DMSO-d
6
d
+
1
1
6
(ESI, m/z): 440.1 [M+1] ; H NMR (400 MHz, DMSO-d ): d 9.21 (t,
Calcd. for C23
6
H
29
N
3
1H, J = 6.0 Hz), 7.77 (d, 1H, J = 7.8 Hz), 7.65 (d, 1H, J = 8.3 Hz), 7.56
(s, 1H), 7.46 (t, 1H, J = 7.8 Hz), 7.33 (t, 1H, J = 7.5 Hz), 7.26–7.17 (m,
6H), 6.91 (d, 2H, J = 8.0 Hz), 6.76 (t, 1H, J = 7.2 Hz), 4.45 (d, 2H,
1
3
J = 6.0 Hz), 3.12 (br s, 4H), 2.88–2.51 (m, 8H); C NMR (101 MHz,
DMSO-d ): 158.6, 154.8, 151.6, 149.7, 139.5, 137.3, 129.4, 129.1,
127.9, 127.7, 127.3, 124.2, 123.3, 119.2, 115.8, 112.3, 110.1, 110.0,
60.2, 53.2, 48.7, 42.5, 32.9; Anal. Calcd. for C28 : C, 76.51; H,
6.65; N, 9.56. Found: C, 76.48; H, 6.74; N, 9.47.
+
1
1
92 8C (HCl salt); MS (ESI, m/z): 450.2 [M+1] ; H NMR (400 MHz,
DMSO-d ): 11.56 (s, 1H), 9.09 (t, 1H, J = 6.0 Hz), 8.23–8.18 (m,
H), 8.02 (d, 1H, J = 8.2 Hz), 8.00–7.96 (m, 1H), 7.65 (d, 1H,
J = 6.5 Hz), 7.59–7.51 (m, 3H), 7.39 (d, 2H, J = 8.0 Hz), 7.32–7.21 (m,
H), 7.02 (d, 2H, J = 8.0 Hz), 6.87 (t, 1H, J = 7.2 Hz), 4.53 (d, 2H,
J = 6.0 Hz), 3.82 (d, 2H, J = 10.9 Hz), 3.63 (d, 2H, J = 10.9 Hz), 3.51–
6
d
6
d
1
29 3 2
H N O
4
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)benzo[b]thio-
phene-2-carboxamide dihydrochloride (19): White solid; Yield:
13
+ 1
3
1
1
.01 (m, 8H); C NMR (101 MHz, DMSO-d
6
):
d
169.3, 150.2, 138.9,
34%; Mp 176–177 8C (HCl salt); MS (ESI, m/z): 456.2 [M+1] ; H
NMR (400 MHz, DMSO-d ): 11.51 (s, 1H), 9.42 (t, 1H, J = 6.0 Hz),
36.3, 135.3, 133.9, 130.6, 129.9, 129.4, 129.0, 128.3, 127.4, 126.9,
26.0, 125.9, 125.7, 120.8, 116.8, 56.8, 51.3, 46.2, 43.0, 29.6; Anal.
6
d
8.20 (s, 1H), 8.08–7.88 (m, 2H), 7.51–7.38 (m, 2H), 7.34 (d, 2H,
J = 8.0 Hz), 7.30–7.20 (m, 4H), 7.02 (d, 2H, J = 8.0 Hz), 6.87 (t, 1H,
J = 7.2 Hz), 4.47 (d, 2H, J = 6.0 Hz), 3.82 (d, 2H, J = 10.8 Hz), 3.62
Calcd. for C30
8.59; H, 6.42; N, 7.89.
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)-2-naphtha-
mide dihydrochloride (14): White solid; Yield: 37%; Mp 188–
31 3
H N O.2HCl: C, 68.96; H, 6.37; N, 8.04. Found: C,
6
1
3
(d, 2H, J = 10.8 Hz), 3.41–3.05 (m, 8H);
C NMR (101 MHz,
DMSO-d ): 162.0, 150.0, 140.7, 140.4, 139.7, 138.4, 136.3,
6
d
+
1
1
89 8C (HCl salt); MS (ESI, m/z): 450.2 [M+1] ; H NMR (400 MHz,
DMSO-d ): 11.42 (s, 1H), 9.24 (t, 1H, J = 6.0 Hz), 8.52 (s, 1H), 8.13–
.88 (m, 4H), 7.72–7.50 (m, 2H), 7.35 (d, 2H, J = 8.0 Hz), 7.30–7.09
m, 4H), 7.01 (d, 2H, J = 8.0 Hz), 6.86 (t, 1H, J = 7.2 Hz), 4.52 (d, 2H,
J = 6.0 Hz), 3.82 (d, 2H, J = 10.9 Hz), 3.62 (d, 2H, J = 10.9 Hz), 3.48–
129.7, 129.2, 128.3, 126.7, 125.7, 125.5, 125.4, 123.3, 120.6,
116.6, 56.6, 51.1, 46.0, 43.0, 40.7, 40.5, 40.3, 29.4; Anal. Calcd. for
6
d
7
(
28 29 3
C H N OS.2HCl: C, 63.63; H, 5.91; N, 7.95. Found: C, 63.40; H,
6.06; N, 7.65.
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)benzo[b]thio-
phene-3-carboxamide dihydrochloride (20): White solid; Yield:
13
2
1
1
6
.93 (m, 8H); C NMR (101 MHz, DMSO-d ): d 165.9, 149.2, 138.0,
35.2, 133.8, 131.9, 131.4, 128.8, 128.5, 128.3, 127.6, 127.4, 127.3,
27.2, 126.4, 123.9, 119.7, 115.7, 55.8, 50.3, 45.1, 42.2, 28.6; Anal.
+
1
27%; Mp 179–180 8C (HCl salt); MS (ESI, m/z): 456.1 [M+1] ;
H
NMR (400 MHz, DMSO-d ): 11.39 (s, 1H), 9.08 (t, 1H, J = 6.0 Hz),
6
d
Calcd. for C30
8.62; H, 6.43; N, 7.93.
N-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)-4-fluoro-1-
naphthamide dihydrochloride (15): White solid; Yield: 50%; Mp
H
31
N
3
O.2HCl: C, 68.96; H, 6.37; N, 8.04. Found: C,
8.53–8.38 (m, 2H), 8.04 (d, 1H, J = 7.7 Hz), 7.49–7.20 (m, 8H), 7.01
(d, 2H, J = 8.0 Hz), 6.86 (t, 1H, J = 7.2 Hz), 4.48 (d, 2H, J = 6.0 Hz),
3.82 (d, 2H, J = 10.8 Hz), 3.62 (d, 2H, J = 10.8 Hz), 3.44–3.04 (m, 8H);
C NMR (101 MHz, DMSO-d ): d 162.6, 149.0, 138.9, 137.8, 136.8,
6
135.0, 130.3, 128.6, 128.1, 127.1, 124.3, 124.3, 124.0, 122.2, 119.5,
115.5, 55.6, 50.1, 44.9, 41.5, 39.7, 39.5, 39.3, 28.4; Anal. Calcd. for
6
1
3
+
1
2
02–203 8C (HCl salt); MS (ESI, m/z): 468.1 [M+1] ; H NMR
(
400 MHz, DMSO-d ): 11.45 (s, 1H), 9.11 (t, 1H, J = 6.0 Hz), 8.39–
6
d
8
7
2
3
1
1
5
6
.20 (m, 1H), 8.11 (dd, 1H, J = 6.4, 3.2 Hz), 7.76–7.58 (m, 3H), 7.48–
.15 (m, 7H), 7.02 (d, 2H, J = 8.0 Hz), 6.87 (t, 1H, J = 7.2 Hz), 4.52 (d,
H, J = 6.0 Hz), 3.82 (d, 2H, J = 10.9 Hz), 3.63 (d, 2H, J = 10.9 Hz),
28 29 3
C H N OS.2HCl: C, 63.63; H, 5.91; N, 7.95. Found: C, 63.27; H,
6.00; N, 7.87.
13
.46–3.00 (m, 8H); C NMR (101 MHz, DMSO-d
6
):
d
167.9, 160.0,
2.7. General procedure for the preparation of arylpiperazine
57.5, 149.7, 138.2, 135.7, 131.7, 131.1, 129.2, 128.8, 128.0, 127.7,
27.1, 126.1, 126.0, 125.7, 123.1, 122.9, 120.1, 116.1, 109.0, 108.8,
derivative hydrochloride salts 21–23
6.2, 50.7, 45.5, 42.5, 29.0; Anal. Calcd. for C30
H
30
N
4
O.2HCl: C,
To a solution of 6 (100 mg, 3.39 mmol) in toluene (20 mL) was
added the corresponding acid anhydride (1.5 equiv.). The reaction
6.66; H, 5.97; N, 7.77. Found: C, 66.40; H, 6.23; N, 7.53.

H. Chen et al. / Chinese Chemical Letters 27 (2016) 277–282
281
mixture was stirred at reflux for 16 h. After cooling to ambient
temperature, the reaction mixture was filtered through a
Buchner funnel. After filtration the filtrate was concentrated
in vacuo and the residue was purified by silica gel column
chromatography using ethyl acetate/petroleum ether (1/7, v/v)
as eluent to afford the corresponding products (21–23). To a
solution of above corresponding products in ethyl acetate was
added dropwise 4 mol/L HCl solution in ethyl acetate (50 mL),
while maintaining stirring for 0.5 h. Then the resulting solid was
collected by filtration to give corresponding hydrochloride salts
as a white solid.
performed. Cell growth inhibition was calculated according to
the following equation:
ꢀ
ꢁ
OD of treated cells
OD of control cells
Growth inhibition ¼ 1ꢂ
ꢁ100%
The half maximal inhibitory concentrations (IC50
) were
obtained from liner regression analysis of the concentration–
response curves plotted for each tested compound.
2
-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)-5-fluoroisoin-
3. Results and discussion
doline-1,3-dione dihydrochloride (21): White solid; Yield: 38%;
+
1
Mp 201–202 8C (HCl salt); MS (ESI, m/z): 444.1 [M+1] ; H NMR
400 MHz, DMSO-d ): 11.30 (s, 1H), 7.96 (dd, 1H, J = 8.2, 4.5 Hz),
.78 (dd, 1H, J = 7.4, 2.2 Hz), 7.73–7.63 (m, 1H), 7.29 (d, 3H,
J = 8.3 Hz), 7.25 (d, 3H, J = 8.3 Hz), 7.01 (d, 2H, J = 8.0 Hz), 6.86 (t,
H, J = 7.2 Hz), 4.75 (s, 2H), 3.81 (d, 2H, J = 9.8 Hz), 3.61 (d, 2H,
J = 9.8 Hz), 3.42–2.96 (m, 8H); Anal. Calcd. for C27 O.2HCl: C,
2.79; H, 5.46; N, 8.14. Found: C, 63.03; H, 5.59; N, 7.91.
-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)-5-chloroisoin-
doline-1,3-dione dihydrochloride (22): White solid; Yield: 45%;
3.1. Chemistry
(
7
6
d
As depicted in Scheme 1, a series of novel arylpiperazine
derivatives were synthesized starting from the commercially
available 2-(4-(bromomethyl)phenyl)acetic acid 1. First, com-
pound 1 was reduced to alcohol 2 in the presence of a borane–
methyl sulfide complex (2 mol/L in tetrahydrofuran) at 0 8C for 1 h,
and then at room temperature for 10 h. The intermediate 2 was
directly used without further purification. The nucleophilic
substitution reaction of compound 2 with phthalimide potassium
1
H
26FN
3
6
2
+
1
Mp 204–205 8C (HCl salt); MS (ESI, m/z): 460.1 [M+1] ; H NMR
400 MHz, DMSO-d ): 11.32 (s, 1H), 7.90 (dd, 1H, J = 8.0, 4.6 Hz),
.80–7.65 (m, 2H), 7.30 (d, 3H, J = 8.0 Hz), 7.26 (d, 3H, J = 8.0 Hz),
(
6
d
2 3
salt in the presence of potassium carbonate (K CO ) gave
7
7
2
compound 3 (70% yield from compound 1) after 16 h at reflux.
Compound 3 was treated with 4-toluene-sulfonyl chloride in the
presence of triethylamine and a catalytic amount of 4-dimethy-
laminopyridine at 0 8C for 16 h to generate compound 4 (95%
yield). The reaction of compound 4 with N-Phenylpiperazine in the
.03 (d, 2H, J = 8.1 Hz), 6.78 (t, 1H, J = 7.2 Hz), 4.76 (s, 2H), 3.82 (d,
H, J = 9.8 Hz), 3.63 (d, 2H, J = 9.8 Hz), 3.46–2.94 (m, 8H); Anal.
Calcd. for C27
0.74; H, 5.38; N, 7.91.
-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)-5,6-dichloroi-
soindoline-1,3-dione (23): White solid; Yield: 40%; Mp 103–
3 2
H26ClN O .2HCl: C, 60.85; H, 5.30; N, 7.89. Found: C,
6
2
2 3
presence of K CO at reflux for 16 h gave arylpiperazine derivative
5, and then the deprotection of the phthaloyl group gave amine
compound 6. The intermediate 6 was directly used without further
purification. Finally, the condensation of compound 6 and various
acids (in the presence of DIPEA and HATU) or acid anhydrides gave
arylpiperazine derivatives 7–23 (27%–59% yield; Scheme 1). The
structures of the compounds (as their HCl salts) were confirmed
+
1
1
04 8C; MS (ESI, m/z): 494.1 [M+1] ; H NMR (400 MHz, DMSO-d
6
):
d
8.19 (s, 2H), 7.42–7.09 (m, 6H), 6.91 (d, 2H, J = 8.0 Hz), 6.76 (t, 1H,
J = 7.2 Hz), 4.73 (s, 2H), 3.29 (br s, 4H), 3.11 (br s, 4H), 2.74 (t, 2H,
13
J = 7.2 Hz), 2.56 (t, 2H, J = 7.2 Hz); C NMR (101 MHz, DMSO-d
6
d
):
65.6, 150.7, 139.5, 137.1, 133.5, 131.3, 128.6, 127.1, 125.1, 118.4,
15.0, 59.2, 52.3, 47.8, 40.7, 32.0; Anal. Calcd. for C27 : C,
5.59; H, 5.10; N, 8.50; Found: C, 65.45; H, 5.12; N, 8.46.
1
1
6
1
13
H
25Cl
2
N
3
O
2
using H NMR, C NMR, MS and elemental analyses (C, H, and N).
3.2. Evaluation of the bioactivity
2.8. Biological activity
The synthesized target compounds 7–23 were evaluated for
2
.8.1. Cell culture
their in vitro cytotoxic activities against the three human prostate
cancer cell lines (PC-3, LNCaP, and DU145), and compared with
their effects on human prostate epithelial cell line WPMY-1 by
CCK-8 assay [19–23]. The results are summarized in Table 1. As
shown in Table 1, some compounds exhibited strong cytotoxic
activities against the tested cancer cell lines, and even exhibited
much better activity than naftopidil. For example, the compounds
8–10, 13 and 16–20 exhibited strong cytotoxic activities against
PC-3 and WPMY-1 cells were cultured in Dulbecco’s
modification Eagle’s medium (DMEM, Invitrogen, Carlsbad, CA,
USA) supplemented with 10% fetal bovine serum (FBS, Hyclone,
Logan, UT, USA), 100 U/mL penicillin and 0.1 mg/mL streptomy-
cin (Invitrogen). DU145 cells were cultured in RPMI1640 media
supplemented with 10% fetal bovine serum (FBS, Hyclone),
1
00 U/mL penicillin and 0.1 mg/mL streptomycin (Invitrogen).
LNCaP cells were cultured in F12 media supplemented with 10%
fetal bovine serum (FBS, Hyclone), 100 U/mL penicillin and
the tested cancer cell lines (IC50 < 10 mmol/L), and these
compounds exhibited weak cytotoxic effects on human epithelial
prostate normal cells WPMY-1. In addition, compounds 10 and 20
showed potent activity against tested cancer cells.
0
.1 mg/mL streptomycin (Invitrogen). The cells were incubated
at 37 8C in a humidified atmosphere with 5% CO
2
.
The SAR analysis revealed the following: (1) Compared to
2
.8.2. Assessment of antitumor activity by CCK-8 assay
Cell proliferation was measured with the Cell Counting Kit-8
CCK-8) assay kit (Dojindo Corp., Kumamoto, Japan). Cells were
compound 7, compound 13 (IC50 = 2.31 and 6.73 mmol/L, respec-
tively) exhibited potent cytotoxic activities against LNCaP and
DU145 cells. These results suggest that the introduction of a large
hydrophobic group was beneficial for anti-cancer activity.
Moreover, compound 13 exhibited weak cytotoxic effects on
human epithelial prostate normal cells WPMY-1. (2) Compound 8
exhibited strong cytotoxic activities against PC-3 cells compared
with compound 9, however, these activities decreased significantly
in DU145 cells. (3) Compound 10 exhibited a more effective
cytotoxic activity than compounds 11 and 12 against tested cancer
cells. These results suggest that the introduction of a large group
was beneficial for anti-cancer activity. In addition, compound 10
(
harvested during logarithmic growth phase and seeded in 96-
5
well plates at a density of 1 ꢁ 10 cells/mL, and cultured at 37 8C
2
in a humidified incubator (5% CO ) for 24 h, followed by
exposure to various concentrations of compounds tested for
4 h. Subsequently 10 L of CCK-8 (Dojindo) was added to each
2
m
well, the cells were then incubated for an additional 1 h at 37 8C
to convert WST-8 into formazan. Cell growth inhibition was
determined by measuring the absorbance (Abs) at
using a microplate reader. Three independent experiments were
l = 450 nm

2
82
H. Chen et al. / Chinese Chemical Letters 27 (2016) 277–282
Table 1
guideline for further research on arylpiperazine derivatives as
novel anti-prostate cancer agents. Further research involving other
classes of arylpiperazine derivatives is in progress.
In vitro cytotoxicity of compounds 7–23.
a
Compd.
IC50
PC-3
>50
(mmol/L)
b
b
b
b
LNCaP
DU145
WPMY-1
Acknowledgments
5
7
8
>50
>50
>50
2.23 ꢀ 0.29
>50
33.42 ꢀ 0.67
1.05 ꢀ 0.27
13.26 ꢀ 0.48
>50
>50
43.06
The project was supported by the Technological Innovation
Project of Colleges and Universities in Guangdong Province (No.
cx2d1127), the China Postdoctoral Science Foundation (Nos.
ꢀ
0.39
9
>50
13.44 ꢀ 0.54
6.23 ꢀ 0.24
33.21 ꢀ 0.68
25.26 ꢀ 0.60
2.31 ꢀ 0.05
4.06 ꢀ 0.07
1.23 ꢀ 0.09
44.62 ꢀ 1.02
26.06 ꢀ 1.13
6.73 ꢀ 0.30
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
1.18 ꢀ 0.08
47.69 ꢀ 1.67
32.60 ꢀ 0.14
2013M542165, 2013M531837), the National Science Foundation
of Guangdong Province (No. S2013040014088) and the Guangzhou
Postdoctoral Scientific Research Foundation (Nos. Q130, Q074).
>50
>50
>50
>50
>50
>50
33.30 ꢀ 0.49
>50
References
5.50 ꢀ 0.34
>50
27.60 ꢀ 0.04
>50
5.50 ꢀ 0.32
29.57 ꢀ 0.43
17.79 ꢀ 0.20
14.30 ꢀ 0.56
2.42 ꢀ 0.30
5.17 ꢀ 0.17
8.21 ꢀ 0.60
[
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activity for PC-3 cells than did the -naphtholyl group for PC-3
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7
a
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m
m
ly). Moreover, these compounds exhibited weak cytotoxic effects
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[
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4
. Conclusion
This paper has reported the synthesis and biological evaluation
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(IC50 < 2 mmol/L). These positive results could serve as a valuable