Synthesis, biological evaluation and SAR of naftopidil-based arylpiperazine derivatives

Article abstract of DOI:10.1016/j.bmcl.2018.03.070

For the development of potential anti-prostate cancer agents, 24 kinds of novel naftopidil-based arylpiperazine derivatives have been synthesized and characterized by spectroscopic methods. Their antitumor activities were evaluated against several classic

Full text of DOI:10.1016/j.bmcl.2018.03.070

Accepted Manuscript
Synthesis, Biological Evaluation and SAR of Naftopidil-based Arylpiperazine
Derivatives
Hong Chen, Cai-Lu Wang, Tao Sun, Zhan Zhou, Jiang-Xiu Niu, Xiu-Mei Tian,
Mu Yuan
PII:
S0960-894X(18)30273-7
https://doi.org/10.1016/j.bmcl.2018.03.070
BMCL 25724
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
14 January 2018
16 March 2018
24 March 2018
Please cite this article as: Chen, H., Wang, C-L., Sun, T., Zhou, Z., Niu, J-X., Tian, X-M., Yuan, M., Synthesis,
Biological Evaluation and SAR of Naftopidil-based Arylpiperazine Derivatives, Bioorganic & Medicinal Chemistry
Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.03.070
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Synthesis, Biological Evaluation and SAR of Naftopidil-based
Arylpiperazine Derivatives
a,†
a,†
a
a
a
Hong Chen , Cai-Lu Wang , Tao Sun , Zhan Zhou , Jiang-Xiu Niu ,
Xiu-Mei Tian , Mu Yuan c,
b
a
College of Food and Drug, Luoyang Normal University, Luoyang, Henan 471934, China
b
School of Basic Medical Sciences，Guangzhou Medical University, Guangzhou, Guangdong
5
11436, China
c
Pharmaceutical Research Center, Guangzhou Medical University, Guangzhou, Guangdong
11436 , China
5
ABSTRACT
For the development of potential anti-prostate cancer agents, 24 kinds of novel
naftopidil-based arylpiperazine derivatives have been synthesized and characterized
by spectroscopic methods. Their antitumor activities were evaluated against several
classical prostate cancer cell lines including PC-3, LNCaP, and DU145. Among all
the compounds, 9, 13, 17, 21 and 27 showed strong cytotoxic activities against
DU145 cells (IC50 <1 μM). Further testing confirmed that compound 17 inhibited the
growth of DU145 cells by inducing cell cycle arrest at G0/G1 phase. Besides,
antagonistic activities of compounds (9, 13, 17, 21 and 27) towards a
and α1D) were further evaluated using dual-luciferase reporter assays, and the
compounds 13 and 17 exhibited better a -ARs subtype selectivity. The
1
-ARs (α1A, α1B,
1
structure–activity relationship (SAR) of these developed arylpiperazine derivatives
was rationally discussed. Taken together, these results suggested that further
development of such compounds may be of great interest.
Keywords: Synthesis; Derivatives; Prostate cancer; CCK-8; Structure-activity
relationship
Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous solid cancer
1
in men in the U.S. and it is the second most lethal cancer. The development and
progression of prostate cancer is directly related to the nuclear steroidal androgen
2
–5
receptor (AR), which regulates the binding of androgens like testosterone (T) and
its active metabolite dihydrotestosterone (DHT). Testosterone is the principal
6
androgen in the blood, while DHT is the most potent androgen in the cells. In order
to induce their biological effects, androgens have to bind to the AR: the

Corresponding author. Tel./fax: +86 020 37103509 (X.-M. Tian).
E-mail address: chenwexpo@163.com (X.-M. Tian); mryuanmu838@sina.com (M. Yuan).
These authors contributed equally to this work.
†
1

7
hormone-receptor complex binds DNA and modulates gene expression. Upon
androgen stimulation, the proliferation of prostate cells is increased and a malignant
7
tumour can develop.
Current therapies (radical prostatectomy, chemotherapy, local radiotherapy, or
hormonotherapy) are successful in treating localized disease (androgen-dependent
8
prostate cancer). However, for non-organ-confined disease, especially metastatic
prostate cancer (androgen-independent prostate cancer), upon the onset of it no
9
–12
significantly effective therapies exist,
and androgen ablation therapy has been the
1
3
major therapeutic modality for advanced prostate cancer. Consequently, novel
anti-cancer drugs are needed to stop the progression of prostate cancer at later stages.
Naftopidil (Fig. 1) is an α
1
--adrenoceptor blocker, which belongs to the phenyl
piperazine derivatives, and used for treating lower urinary tract symptoms (LUTS)
1
4
associated with benign prostatic hyperplasia (BPH). The studies demonstrated that
naftopidil inhibited cell proliferation, and caused cell cycle arrest in LNCaP and PC-3
1
5
cells. Moreover, naftopidil decreases PCa tumor growth by altering tumor–stroma
interactions, and the antiproliferative effect of it is not related to androgen sensitivity
1
6
of the cells or the a
1
-AR subtype expression in PCa cells. In addition, other studies
1
7–19
have displayed that arylpiperazine derivatives have anti-proliferative properties.
Inspired by these, we sought to apply such strategy to developing targeted
arylpiperazine derivatives for the treatment of prostate cancer. Recently, we have
reported a series of arylpiperazine derivatives as anticancer drugs for site-directed
chemotherapy of prostate cancer. Indeed, these new hybrids showed moderate to
2
0–22
significant cytotoxic activity in prostate cancer cell lines.
As part of our group’s
continuing efforts to study the arylpiperazine derivatives and the core framework of
naftopidil, herein we report the synthesis of a series of new naftopidil-based
arylpiperazine derivatives (Scheme 1), and the anticancer activities of the products
were evaluated against three prostate cancer cell lines (PC-3, LNCaP and DU145).
Furthermore, antagonistic activities of representative compounds towards
a
1
-adrenergic receptors (a -ARs) were further evaluated by dual-luciferase reporter
1
assays. A simple SAR study was also explored to facilitate the further development of
the arylpiperazine derivatives. As expected, some synthesized compounds exhibited
significant cytotoxic activities against the LNCaP and DU145 cells, and showed better
1
a -ARs subtype selectivity.
Fig. 1. Structures of naftopidil
2

Scheme 1 illustrates the synthesis of arylpiperazine derivatives 5–28 via a
four-step reaction using 2-(4-(bromomethyl)phenyl)acetic acid 1 as starting material.
The first step involved a reduction reaction between 1 and borane–methyl sulfide
complex (2 M in tetrahydrofuran) to synthesize 2, and the obtained crudes were directly
used in the next step without further purification. After the nucleophilic substitution
reaction was carried out between compound 2 and 5,6,7,8-tetrahydronaphthalen-2-ol
o
using CH
3
CN as solvent in the presence of potassium carbonate at 85 C for 16 h, and
compound 3 was obtained (70% yield from 1). Subsequently, compound 4 (95% yield)
was obtained by reacting 3 with 4-toluene-sulfonyl chloride using CH Cl as solvent in
the presence of triethylamine and a catalytic amount of 4-dimethylaminopyridine at
°C for 16 h. Finally, compound 4 were treated with various arylpiperazines or
phenylpiperidines (1.2 eq) in the presence of K CO (6 eq) to obtain derivatives 5–28
in moderate to good yields. (60–82%). All synthesized products (HCl salts) have been
2
2
0
2
3
+
1
13
confirmed based on their expected m/z of [M+1] , H-NMR, C-NMR spectra and
elemental analyses (C, H, and N).
OH
(i)
OH
(ii)
O
OH
Br
Br
O
2
3
1
O
O
(iv), (vi)
(iii)
Ar
.xHCl
N
N
OTs
4
5-26
(
v), (vi)
R
O
.
xHCl
N
27-28
N
5, Ar =
6, Ar =
7, Ar =
8, Ar =
9, Ar =
O
NC
O
O
F
O
10, Ar =
11, Ar =
16, Ar =
12, Ar =
13, Ar =
O
F
14, Ar =
F
Cl
15, Ar =
20, Ar =
25, Ar =
17, Ar =
22, Ar =
F
18, Ar =
23, Ar =
19, Ar =
24, Ar =
Cl
Cl
Cl
Cl
Cl 21, Ar =
26, Ar =
Br
Cl
F3C
28, R = OH
CF3
27, R = H
Scheme 1. Reagents and conditions are as follows: (i) BH
3
.S(CH
3
)
2
, anhydrous THF, 11 h; (ii)
o
5
,6,7,8-tetrahydronaphthalen-2-ol, K
2
CO
3
, CH
3
CN, 85 C, 16 h; (iii) TsCl, Et
3
N and
3

o
4
-dimethylaminopyridine (catalytic amount), Cl
2
CH
2
, 0 C, 16 h; (iv) arylpiperazines, K
2
CO
3
,
o
o
CH
h
3
CN, 85 C, 16 h; (v) phenylpiperidines, K
2
CO
3
, CH
3
CN, 85 C, 16 h; (vi) HCl, AcOEt, rt, 0.5
All the target compounds were screened for in vitro cytotoxicity against a panel of
three human prostate cancer cell lines including PC-3, LNCaP, and DU145 in
comparison to their effects in normal non-cancer human prostate epithelial WPMY-1
2
3–25
26
cell line using the CCK-8 assay.
Naftopidil and finasteride were taken as
reference compounds and the results are reported in terms of IC50 values. The results
are summarized in Table 1.
Table 1 In vitro cytotoxicity of compounds 5–28
a
Compd.
IC50 (μM)
b
b
b
b
PC-3
>50
LNCaP
DU145
>50
WPMY-1
>50
5
6
7
8
9
6.53 ± 0.26
2.92 ± 0.19
32.85 ± 0.42
>50
29.22 ± 0.18
25.49 ± 0.18
>50
11.15 ± 0.46
>50
49.21
>50
25.10 ± 0.51
0.83 ± 0.13
29.69 ± 0.27
2.24 ± 0.08
>50
>50
56.83 ± 0.12
31.97 ± 0.21
>50
>50
>50
1
0
1.99 ± 0.15
3.62 ± 0.10
27.98 ± 0.08
46.16 ± 0.15
8.02 ± 0.10
>50
>50
11
28.07 ± 0.39
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
>50
>50
>50
76.47± 0.57
2.84 ± 0.10
>50
0.93 ± 0.19
28.09 ± 0.80
25.05 ± 0.81
>50
29.14 ± 0.60
47.03 ± 1.20
>50
27.27 ± 0.16
57.32 ± 0.61
>50
7.57 ± 0.16
48.18 ± 1.27
4.40 ± 0.15
4.68 ± 0.06
>50
0.90 ± 0.20
>50
>50
>50
31.29 ± 0.15
>50
>50
>50
>50
>50
46.72 ± 0.20
>50
17.33 ± 0.64
3.06 ± 0.23
7.81 ± 0.06
>50
0.86 ± 0.20
23.11 ± 0.67
>50
>50
>50
>50
>50
>50
21.07 ± 0.49
>50
>50
>50
6.09 ± 0.15
>50
>50
>50
>50
>50
10.49 ± 0.08
>50
3.94 ± 0.21
3.03 ± 0.14
22.36 ± 0.61
14.53
0.95 ± 0.10
3.38 ± 0.11
34.58 ± 0.31
13.53
>50
31.74 ± 0.49
>50
naftopidil
42.10 ± 0.79
17.83
finasteride
a
–
IC50 values are taken as means ± standard deviation from three experiments.
4

b
PC-3, androgen-insensitive human prostate cancer cell line; LNCaP,
androgen-sensitive human prostate cancer cell line; DU145, androgen-insensitive
human prostate cancer cell line; WPMY-1, normal non-cancer human prostate
epithelial cell line.
As shown in Table 1, the tested compounds exhibited strong activities against
LNCaP and DU145 cells, and displayed excellent selective activity for LNCaP and
DU145 cells over PC-3 cells. For example, all the compounds exhibited moderate to
weak cytotoxic activities against PC-3 cells except 14. For LNCaP cells, thirteen
compounds possessed higher activities than naftopidil and finasteride (IC50 <10 μM),
and the majority of compounds displayed low cytotoxic character toward normal
human prostate epithelial cell (WPMY-1) with >50 μM of IC50. In addition, seven
compounds are more potent than naftopidil and finasteride against DU145 cells.
Among these compounds, compounds 9, 13, 17, 21 and 27 exhibited the most potent
activity against DU145 cells with IC50 values of 0.83, 0.93, 0.90, 0.86 and 0.95 μM,
which were 41-, 37-, 38-, 40- and 36-fold more active than naftopidil (Fig. 2),
respectively, and exhibited low cytotoxic character toward normal human prostate
epithelial cell (WPMY-1) with >50 μM of IC50
.
Taking compound 5 as a lead, the SAR investigation was mainly focused on the
variation of phenyl group at the 4-position of piperazine ring with other aryl group
and the substitute’s type and position on the phenyl group as a required group for
antitumor activity. Firstly, in replacing the phenyl group at the 4-position of
piperazine ring with pyridinyl group, the resultant compound 6 displayed improved
cytotoxic activity against the tested cancer cells. However, compound 6 exhibited
cytotoxic activities against WPMY-1 cells. The position of the substituent on the
phenyl interestingly affected the cytotoxic activities. Amongst the compounds
containing a methyl substituent, the order of the cytotoxic activities of compounds 7
(
2-CH
3
), 8 (4-CH
3
), and 9 (3-CH
3
) against DU145 cells could be placed as following:
9
> 8 > 7. Also, compounds 19, 20 and 21 had the similar results. In addition,
compounds 7, 8 and 9 exhibited moderate to weak cytotoxic activities against PC-3,
LNCaP, and DU145 cells except 14 against DU145 cells, and exhibited low cytotoxic
character toward normal human prostate epithelial cell (WPMY-1) with >50 μM of
IC50. However, the compounds with electron-donating groups on the phenyl group
showed another rule, for instance, the cytotoxic activities of compounds 11 (2-OCH
3 (4-OCH ), and 14 (3-OCH ) against DU145 cells could be placed as following: 13
IC50 = 0.93 μM) > 11 (IC50 = 2.24 μM) > 14 (IC50 = 28.09 μM). But for LNCaP cells,
3
),
1
3
3
(
the order of activity was obviously different, such as compounds 11 (IC50 = 3.62 μM)
and 14 (IC50 = 8.02 μM) exhibited a more effective cytotoxic activity than compound
1
3 (IC50 = 46.16 μM). Moreover, compound 14 (IC50 = 2.84 μM) exhibited strong
activities against PC-3 cells. The similar results were also found in compounds 16
(
2-F, IC50 = 7.57 μM) vs. 17 (4-F), 19 (2-Cl, IC50 = 4.68 μM) vs. 20 (4-Cl), as well as
5

2
5 (2-CF3, IC50 = 6.09 μM) vs. 26 (4-CF ) for LNCaP cells. However, those
3
compounds exhibited moderate to weak cytotoxic activities against PC-3 cells. In
addition, compounds with difluoro-substituents on the phenyl showed higher
effectiveness than those with monofluoro-substituent. For example, the cytotoxic
activity of compound 18 (2,4-F2, IC50 = 4.40 μM ) exhibited a more effective
cytotoxic activity than compounds 16 and 17 against LNCaP cells. Moreover,
compound 18 also exhibited excellent selective activity for LNCaP cells over other
tested cancer cells, and displayed low cytotoxic character toward normal human
prostate epithelial cell (WPMY-1) with >50 μM of IC50. Compound 23 (2-CH
IC50 = 7.81 μM) exhibited higher cytotoxic activity than compounds 7 (2-CH ) and 21
3-Cl) against LNCaP cells, exhibited excellent selective activity for LNCaP cells
over PC-3 and DU145 cells. Piperidine compounds 27 and 28 exhibited strong
cytotoxic activities against LNCaP and DU145 cells. Especially, compound 27 (IC50
.95 μM) exhibited potent cytotoxic activity against DU145 cells. Moreover,
compound 27 exhibited low cytotoxic character toward normal human prostate
epithelial cell (WPMY-1) with >50 μM of IC50
3
, 5-Cl,
3
(
=
0
.
PC-3 and DU145 cells are androgen insensitive cell lines, however, PC-3 cells are
insensitive to derivatives. The literatures have reported that DU145 (p53 mutant)
carries a missense mutation on both alleles of the p53 gene, while PC-3 (p53 null) has
2
7
only one p53 allele with frame-shift mutation. In DU145 cells, KAI1, p53 and c-Jun
were significantly activated by drugs. However, in PC-3 cells, only KAI1 and c-Jun
2
8
genes were activated and the expression of the p53 gene was undetectable. p53 is
one of the most commonly mutated genes in human cancer and loss of wild-type
function through mutation or deletion can have profound effects on how cells respond
2
9
to cell stress. So, it is possible that the expression of p53 gene is a crucial
determinant of derivatives sensitivity in prostate cancer DU145 cells.
6

Fig. 2. Arylpiperazine derivatives 9, 13, 17, 21 and 27 inhibited cell viability (percent relative to
control) in prostate cell lines PC-3 and DU145. The all cells were exposed to escalating
concentrations of arylpiperazine derivatives respectively for 24 h, and the cell viability was
detected by CCK-8 assay.
To examine the mechanism by which 13 and 17 inhibits cell proliferation, we
evaluated the effect of 13 and 17 on cell cycle progression. DU145 cells were not only
treated with DMSO (0.1%) alone as controls but were also treated with 13 (8 µM) and
1
1
7 (6 µM) for 24 h and then stained with propidium iodide (PI). The effects of 13 and
7 on the cell cycle distribution of DU145 were evaluated by flow cytometry.
Representative flow histograms are shown in Fig. 3. Compound 17 with
electron-withdrawing group have significantly increased the number of DU145 cells
in the G0/G1 phase compared with vehicle treated controls. However, compound 13
with electron-donating groups have no significant differences compared with CTL.
We hypothesized that 13 has other mechanism in inhibiting cancer cell proliferation.
7

Fig. 3. Cell cycle analysis of DU145 cells treated with 13 (8 µM) and 17 (6 µM) for
2
4 h through flow cytometry.
To further investigate whether or not the antiproliferative effect of 13 and 17 on
DU145 cells, apoptosis is conducted with flow cytometry stained with Annexin-V/PI.
DU145 cells were treated with 13 (8 µM), 17 (6 µM) and CTL (0.1% DMSO) for 24 h.
The results are showed in Fig. 4. No significant differences were seen between 13, 17
and CTL. The results suggested that the compounds 13 and 17 had no effect on
DU145 cell survival. Therefore, the mechanism of 13 and 17 in inhabiting cancer
cells growth are not involved with the apoptosis.
Fig. 4. Externalization of phosphatidylserine in DU145 treated with 13 (8 µM) and 17
8

(
6 µM) for 24 h was detected through Annexin V/PI double staining assay. The cell
population in the lower right quadrant represents early apoptotic cells, whereas the
population in the upper right quadrant represents late apoptotic cells or dead cells.
Prostate cancer and benign prostatic hyperplasia are common diseases in elderly
males, and the studies have shown that androgen receptor-mediated androgen affects
the incidence of the benign prostatic hyperplasia and prostate cancer. Moreover,
previous studies have shown arylpiperazine derivatives may act as potential α1a and/or
30
α1a- + α1d-selective ligands for the treatment of benign prostatic hyperplasia (BPH).
So, we also further evaluated antagonistic activities of 9, 13, 17, 21 and 27 towards
3
0,31
a
1
-ARs (Table 2) using dual-luciferase reporter assays
to identify a
1
-AR
subselective antagonist candidates to treat BPH from arylpiperazine derivatives with
3
0
potent anticancer activities. As previously reported in the literature, in the a
pockets, the key amino residues around the binding pocket of the three subtypes (α1a
1b, and α1d) were differentiated. The conformations of Ile193 in a1a and Val193 in a1b
1
-ARs’s
,
α
were entirely different, and the different conformations of the same amino residues at
the same region of the three subtypes can induce change in the active pocket
conformation. The above results indicated that there was different conformation in
the same binding ligand, and the different conformations of the same amino residues
in the three subtypes can also induce change. In a1a, Ile193 was closer to the binding
pocket, exhibited hydrogen bonding interaction with the ligand. So, as shown in Table
2
, compared to arylpiperazine derivatives with the isoindoline-1,3-dione moiety (11
3
0
(
4-OCH
3
) and 14 (4-F)), compound 13 (4-OCH ) with the tetrahydronaphthalenyl
3
moiety exhibited better a1A subtype selectivity over a1b (a1b/a1a ratio = 16.1), and it is
possible to promote intermolecular hydrogen bonding with Ile193 amino residue in
a1a-AR model. However, compound 17 (4-F) with electron-withdrawing group is
possible to interact with other amino residues or by charge–charge intramolecular
interactions to match the pocket of a1d-AR, and exhibited better a1d subtype selectivity
(
a1b/a1d ratio = 10.9). The results provide valuable information for further finding
more new potential drugs in clinic in treating BPH.
Table 2 Antagonistic activities (IC50) on α
1
-ARs (α1a, α1b, and α1d) of compounds 9,
1
3, 17, 21 and 27
a
IC50 (nM)
Selectivity ratio
Compd.
α
1a
α
1b
α
1d
α1b/α1a
α1b/α1d
9
502.12
57.58
583.21
972.31
1124.56
998.17
826.47
736.47
102.85
287.18
1.2
16.7
1.0
0.8
0.7
1.3
10.9
3.5
1
1
2
3
7
1
1073.85
1212.48
9

2
7
567.63
555
672.65
634
452.84
55.2
1.2
1.1
1.5
naftopidil
11.48
a
IC50 values are taken as means from three experiments.
This paper has reported the synthesis of a novel class of arylpiperazine derivatives
containing 5,6,7,8-tetrahydronaphthalenyl moiety and their antitumor activities
against several classical prostate cancer cell lines including PC-3, LNCaP, and
DU145, as well as antagonistic activities of the test compounds towards a -ARs. The
1
results showed that some compounds are more potent than positive drugs naftopidil
and finasteride against LNCaP and DU145 cells. Especially, compounds 9, 13, 17, 21
and 27 demonstrated a relatively strong cytotoxicities against DU145 cells (IC50 <1
μM), and compound 17 inhibited the growth of DU145 cells by inducing cell cycle
arrest at G0/G1 phase. Moreover, compounds 13 (a1B/a1A ratio = 16.7) and 17 (a1B/a1D
ratio = 10.9) exhibited better a -ARs subtype selectivity. The SARs were discussed
1
based on the obtained experimental data. Taken together, these results suggested that
such type of compounds could serve as the promising candidates for the treatment of
prostate cancer and benign prostatic hyperplasia. Further research involving other
novel class of arylpiperazine derivatives is in progress.
Acknowledgment
The work was supported by the Natural Science Foundation of China (No.
8
1
1401462), Henan Province Science and Technology Attack Plan Foundation (No.
62102310477), the Key Scientific Research Project of Higher Education of Henan
Province (Nos. 16A350008, 17A150039 and 17B350001) and National Scientific
Research Foundation of Luoyang Normal University (No. 2015-PYJJ-005). We also
thank Dr. W. Yi for helpful instruction.
Supplementary data
Supplementary data associated with this article can be found, in the online version,
at…
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