Design and synthesis of sulfonamide-1,2,3-triazole derivatives bearing a dithiocarbamate moiety as antiproliferative agents

Article abstract of DOI:10.3184/174751917X15027935057950

A series of nine novel 1-(4′-sulfamoylphenyl)-1,2,3-triazole derivatives bearing a 4-dithiocarbamylmethyl moiety were designed using the molecular hybridisation approach and synthesised by alkyne/azide click chemistry. Most of the synthesised compounds ex

Full text of DOI:10.3184/174751917X15027935057950

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 SEPTEMBER, 523–525
RESEARCH PAPER 523
Design and synthesis of sulfonamide-1,2,3-triazole derivatives bearing a
dithiocarbamate moiety as antiproliferative agents
a,b,c,d
a,b,c,d
a,b,c,d
a,b,c,d
a,b,c,d
Dong-Jun Fu
, Ying-Chao Liu
, Xu-Xu Yin
, Jia-Jia Yang
, Ji Zhang
, Chao-Dong Xiong
,
a,b,c,d
a,b,c,d
a,b,c,d
a,b,c,d
Zhu-Song Cao
, Wei Wei
and Yan-Bing Zhang
*
a
New Drug Research and Development Center, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P.R. China
Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, P.R. China
Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education, Zhengzhou 450001, P.R. China
Key Laboratory of Henan Province for Drug Quality and Evaluation, Zhengzhou 450001, P.R. China
b
c
d
A series of nine novel 1-(4′-sulfamoylphenyl)-1,2,3-triazole derivatives bearing a 4-dithiocarbamylmethyl moiety were designed using
the molecular hybridisation approach and synthesised by alkyne/azide click chemistry. Most of the synthesised compounds exhibited
moderate to good antiproliferative activity against oesophagus, gastric and prostate cancer cell lines, but a compound containing a
4
-(t-butoxycarbonyl)piperazinylthiocarbonyl moiety showed the highest activity. Against a prostate cancer cell line, it had an IC value
50
of 2.4 μM, about 10-fold more active than 5-flurouracil. This work shows that novel sulfonamide-1,2,3-triazole derivatives bearing a
dithiocarbamate moiety linked to a 4-substituted piperazine are promising lead compounds for the development of antitumour agents.
Keywords: antiproliferative activity, sulfonamide-1,2,3-triazole, dithiocarbamate
Sulfonamide drugs display a host of biological properties, for
example, as anticancer agents, antibacterials and animalarials.
Examples of anticancer drugs are the anthraquinone-sulfonamide
molecular platform to generate a new hybrid architecture with the
aim of exploring the impact of such modification on their anticancer
activity (Fig. 2).
1–4
derivative 1, which displays potent antiproliferative activity against
5
Results and discussion
MOLT-3 cells with an IC value of 2.18 µM, and the anthranilic
50
acid sulfonamide derivative 2, which has led to inhibitors of human
As shown in Fig. 2, a molecular hybridisation strategy based on the
structures of bioactive compounds 1–4 produced a scaffold that
has three parts: (1) a 1,2,3-triazole as a central backbone; (2) an
attachment to the 1,2,3-triazole at position 1 of a 4-sulfamoylphenyl
group; and (3) an attachment to the 1,2,3-triazole at position 4 of
a piperazinyldithiocarbamylmethyl moiety. From there, it was
envisaged that optimisation of bioactivity could be investigated by
introduction of substituents at the 4 position of the piperazin-1-yl
group.
MetAP2 with human microvascular endothelial cell (HMVEC)
6
proliferation inhibitory activity (Fig. 1).
1,2,3-Triazole and dithiocarbamate are privileged scaffolds in
antitumour drug discovery. Recently, our group has designed many
antiproliferative agents bearing a 1,2,3-triazole or a dithiocarbamate
7–11
moiety. For example, 1,2,3-triazole derivative 3 inhibited the
proliferation of SK-N-SH cancer cells by inducing apoptosis and
7
arresting the cell cycle at the G1 phase, and dithiocarbamate–
chalcone derivative 4 exhibited excellent growth inhibition against
The synthetic route to this series of compounds 8a–i is shown
in Scheme 1. Commercially available 4-aminosulfanilamide 5
was treated with sodium nitrite/sulfuric acid and sodium azide
to yield aryl azide 6. Reaction of 6 with various alkynes 7 in a
SK-N-SH with an IC value of 2.03 µM by inducing apoptosis and
5
0
1
0
arresting the cell cycle at the G0/G1 phase (Fig. 1).
The above interesting findings and our continuous quest to
synthesise novel antiproliferative analogues
the molecular hybridisation of biologically active sulfonamide,
,2,3-triazole and dithiocarbamate to integrate them in one
12–14
led us to carry out
click reaction in the presence of CuSO and sodium ascorbate at
4
room temperature yielded target compounds 8a–i. The structures
of the synthesised compounds were characterised using spectral
1
O
O
H
HO
O
N
H
O
S
N
O
S
Cl
O
N
O
Br
H
Cl
1
2
O
O
O
O
O
S
N
S
O
N
H
N
N
N
N
O
N
3
4
Fig. 1 Reported antiproliferative agents.
*
Correspondent. E-mail: zhangyb@zzu.edu.cn

524 JOURNAL OF CHEMICAL RESEARCH 2017
HO
O
H
O
S
N
O
Br
Cl
R
Molecular
Hybridisation
N
O
N
N
N
O
N
O
S
S
H N
S
2
O
N
H
N
N
N
N
O
O
O
S
N
S
O
N
O
Fig. 2 Illustration of the design strategy for target compounds.
CuSO .5H O,
ascorbic acid
NaNO , NaN3
4
2
2
S
NH2
N3
+
S
o
O
S
2 4
H SO (aq) , 0 C
O
O
N
S
THF-H O, rt.
2
N
S
NH
2
N
S
S
H N
H N
N
N
N
N
O
2
2
R
O
O
R
5
6
7
8a-8i
Scheme 1
Table 1 Antiproliferative activity against gastric (MGC-803), oesophagus
EC-109) and prostate (PC-3) cancer cell lines of the synthesised
,2,3-triazole derivatives 8a–i (Scheme 1)
antiproliferative activity. When a piperidine group was attached
to the dithiocarbamate moiety, compound 8b displayed weak
inhibitory activity against all cancer cell lines. Replacing the
1-(4-fluorophenyl)piperazine scaffold of compound 8c (15.9
µM) with 1-phenylpiperazine (8e, 12.4 µM) led to a small
increment of activity against PC-3 cancer cells, whereas,
changing the 1-(4-(t-butyl)benzyl)piperazine (8f, 37.3 µM) to
a 1-benzylpiperazine (8a, 13.4 µM) or a 1-ethylpiperazine (8d,
22.1 µM) led to an improvement of activity against PC-3 cells.
Compound 8i with a 1-(piperazin-1-yl)ethan-1-one group exhibited
no inhibitory activity, but sulfonamide-1,2,3-triazole derivative 8g
had good selectivity between PC-3 cells and other cells (MGC-803,
EC-109).
(
1
a
R
IC (μM)
Compound
50
MGC-803
>100
>100
>100
>100
EC-109
>100
>100
>100
>100
PC-3
8
8
8
8
8
8
8
8
8
a
b
c
d
e
f
g
h
i
PhCH2
13.4 ± 0.3
38.3 ± 9.5
15.9 ± 0.4
22.1 ± 10.3
12.4 ± 0.2
NR = CH2
4F-C6H
4
Et
Ph
45.78 ± 4.49 >100
t
4-Bu -C H -CH 9.00 ± 0.01
27.21 ± 2.95 37.3 ± 4.5
6
4
2
t
Bu -OCO
50.42 ± 2.49 35.97 ± 7.77 2.4 ± 0.4
>100
>100
11.7 ± 1.5
Ph CH
96.71 ± 4.80 26.1 ± 2.5
>100
12.1 ± 1.5
2
MeCO
–
>100
29.3 ± 1.9
Experimental
b
5
-Fu
a
All reagents and solvents were purchased from Zhengzhou Research
Biotechnology Co., Ltd. Thin-layer chromatography was carried out on
glass plates coated with silica gel and visualised by UV light (254 nm).
Melting points were determined on a Beijing Keyi XT4A apparatus and
are uncorrected. NMR spectra were obtained on a Bruker DPX 400 MHz
Antiproliferative activity was assayed by exposure for 48 h to the tested substances and
expressed as the concentration required to inhibit tumour cell proliferation by 50% (IC ).
5
0
The data are presented as the means with standard deviation from the dose–response
curves of three independent experiments. The values in bold represent the potent inhibitory
activity results.
b
1
13
5
-Fu = 5-fluorouracil
spectrometer ( H NMR at 400 MHz, C NMR at 100 MHz) in CDCl or
3
DMSO-d using TMS as an internal standard. Chemical shifts (δ) are given
6
in ppm and coupling constants (J) are given in Hz. Mass spectra (MS) were
recorded on a Bruker 3000 mass spectrometer by electrospray ionisation
methods, and all spectral data corroborated the assumed
structures.
All the synthesised sulfonamide-1,2,3-triazole derivatives
bearing a dithiocarbamate moiety 8a–i were evaluated for their
cytotoxic activity in vitro against three cancer cell lines, MGC-803
(
ESI).
Synthesis of 4-azidobenzenesulfonamide (6)
4-Aminobenzenesulfonamide 5 (3 g) and NaNO (1.8 g) were added to 4 N
2
(human gastric cancer cell line), EC-109 (human esophageal cancer
H SO (100 mL). The mixture was stirred at 0 °C for 0.5 h. Then NaN (1.7
2
4
3
cell line) and PC-3 (human prostate cancer cell line), using the MTT
assay method and compared with the well-known anticancer drug
g) was added to the mixture and the system was stirred at room temperature
for 1 h. On completion, the reaction mixture was concentrated under
vacuum, the residue was dissolved in EtOAc (30 mL) and washed with
water and brine, and then dried over anhydrous Na SO and concentrated
under vacuum to afford compound 6, which was used in the next reaction
without further purification.
15
5-fluorouracil. The antiproliferative activity results are shown
in Table 1. All compounds exhibited moderate antiproliferative
activity against at least one of the three selected cancer cell lines.
Among them, compound 8g showed the highest antiproliferative
activity with an IC value of 2.35 µM, some tenfold better than
2
4
Synthesis of sulfonamide-1,2,3-triazole derivatives (8a–i); general
50
5-fluorouracil, against PC-3 cells (Table 1).
procedure
Based on the structure–activity relationships, the nature of
Compound 6 (1.05 mmol), an alkyne (7; R = various) (1 mmol),
the piperazine substituents has a remarkable effect on their
CuSO ·5H O (0.2 mmol) and sodium ascorbate (0.1 mmol) were dissolved
4
2

JOURNAL OF CHEMICAL RESEARCH 2017 525
in 50% THF/H O (10 mL) and stirred at room temperature. The reaction
δ 193.6, 143.8, 143.8, 142.1, 138.5, 128.6, 127.6, 127.5, 127.0, 122.1, 120.3,
2
+
was monitored by TLC until the reaction was finished. On completion, the
reaction mixture was concentrated under vacuum, the residue was dissolved
in EtOAc and washed with water and brine, and then dried over anhydrous
74.1, 50.9, 31.2. HRMS (ESI) calcd for C H N O S [M + H] : 565.1516;
27
29
6
2 3
found: 565.1514.
(1- (4-Sulfamoylphenyl) -1H-1,2,3-triazol-4-yl) methyl-4-
acetylpiperazine-1-carbodithioate (8i): Yellow solid; yield 33%; m.p.
MgSO and concentrated under vacuum to afford compounds 8a–i, which
4
1
were purified by column chromatography (petroleum ether: EtOAc = 8:1).
163–164 °C; H NMR (400 MHz, DMSO-d ): δ 8.87 (s, 1H), 8.12 (d,
6
(
1- (4-Sulfamoylphenyl) -1H-1,2,3-triazol-4-yl) methyl-4-
J = 8.7 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.52 (s, 2H), 4.72 (s, 2H), 4.22
13
benzylpiperazine-1-carbodithioate (8a): Yellow solid; yield 56%; m.p.
(s, 2H), 3.98 (s, 2H), 3.75–3.48 (m, 4H), 2.03 (s, 3H); C NMR (100 MHz,
1
1
(
4
73–175 °C; H NMR (400 MHz, DMSO-d ): δ 8.86 (s, 1H), 8.16–8.08
CDCl ): δ 199.4, 173.9, 149.1, 149.0, 143.7, 132.7, 127.4, 125.5, 49.7, 36.4,
6
3
+
m, 2H), 8.04–7.95 (m, 2H), 7.53 (s, 2H), 7.38–7.24 (m, 5H), 4.69 (s, 2H),
.25 (s, 2H), 3.91 (s, 2H), 3.52 (s, 2H), 2.46 (s, 4H); C NMR (100 MHz,
26.4. HRMS (ESI) calcd for C H N O S [M + H] : 441.0835; found:
16
21
6
3 3
13
441.0837.
DMSO-d ): δ 193.6, 143.8, 143.8, 138.5, 137.5, 128.9, 128.2, 127.5, 127.1,
6
Antiproliferative activity assays
1
22.1, 120.3, 61.2, 51.9, 31.3. HRMS (ESI) calcd for C H N O S [M +
21 25 6 2 3
+
Antiproliferative activity assays were carried out using the reported
H] : 489.1192; found: 489.1201.
1-(4-Sulfamoylphenyl)-1H-1,2,3-triazol-4-yl)methylpiperidine-1-
16
methods.
(
1
carbodithioate (8b): White solid; yield 34%; m.p. 152–153 °C; H NMR
Acknowledgements
(
400 MHz, DMSO-d ): δ 8.86 (s, 1H), 8.14–8.10 (d, J= 8.8 Hz, 2H), 8.01 (d,
6
J = 8.8 Hz, 2H), 7.53 (s, 2H), 4.68 (s, 2H), 4.23 (s, 2H), 3.89 (s, 2H), 1.65 (d,
J = 4.9 Hz, 2H), 1.59 (d, J = 4.7 Hz, 4H); C NMR (100 MHz, DMSO-d ): δ
1
Dong-Jun Fu and Ying-Chao Liu contributed equally to this work.
This work was supported by the National Natural Sciences
Foundations of China (No. 81673322, 81273393, 81430085,
21372206, and 81172937) and Ph.D. Educational Award from
Ministry of Education (No. 20134101130001). This work was
also supported by the excellent doctoral dissertations fund of
Zhengzhou University, and the graduate student innovation
project of Zhengzhou University.
13
6
92.3, 143.9, 143.8, 138.5, 127.5, 122.1, 120.3, 31.3, 25.8, 25.2, 23.5. HRMS
+
(
ESI) calcd for C H N O S [M + H] : 398.0776; found: 398.0779.
15 20 5 2 3
(
1- (4-Sulfamoylphenyl)-1H-1,2,3-triazol-4-yl)methyl-4- (4-
fluorophenyl)piperazine-1-carbodithioate (8c): Yellow solid; yield 45%;
1
m.p. 194–196 °C; H NMR (400 MHz, DMSO-d ): δ 8.88 (s, 1H), 8.12 (d, J
6
=
8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.53 (s, 2H), 7.08 (t, J = 8.9 Hz, 2H),
7
.02–6.92 (m, 2H), 4.73 (s, 2H), 4.38 (s, 2H), 4.06 (s, 2H), 3.29–3.18 (m,
13
4
H); C NMR (100 MHz, DMSO-d ): δ 193.9, 146.9, 143.8, 138.5, 127.5,
6
Electronic Supplementary Information
122.2, 120.3, 117.5, 117.4, 115.5, 115.3, 48.5, 31.2, 29.5. HRMS (ESI) calcd
The ESI is available through: http://ingentaconnect.com/content/
stl/jcr/2017/00000041/00000009
+
for C H FN O S [M + H] : 493.0943; found: 493.0950.
20
22
6
2 33
(
1- (4-Sulfamoylphenyl) -1H-1,2,3-triazol-4-yl) methyl-4-
ethylpiperazine-1-carbodithioate (8d): Yellow solid; yield 20%; m.p.
1
Received 27 June 2017; accepted 21 July 2017
Paper 1704853
https://doi.org/10.3184/174751917X15027935057950
Published online: 22 August 2017
1
92–193 °C; H NMR (400 MHz, CDCl ): δ 8.16 (s, 1H), 7.96 (d,
3
J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 4.70 (s, 2H), 4.26 (d, J = 22.4 Hz,
2
H), 3.87 (s, 5H), 2.46 (s, 4H), 2.38 (q, J = 7.2 Hz, 2H), 1.02 (t, J = 7.2 Hz,
13
3
H); C NMR (100 MHz, CDCl ): δ 210.0, 194.2, 144.6, 141.4, 138.4,
3
127.2, 120.1, 119.4, 51.0, 50.8, 30.3, 28.7, 10.9. HRMS (ESI) calcd for
+
References
C H N O S [M + H] : 427.1036; found: 427.1044.
16
23
6
2 3
1
2
3
4
5
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(
1- (4-Sulfamoylphenyl) -1H-1,2,3-triazol-4-yl) methyl-4-
phenylpiperazine-1-carbodithioate (8e): White solid; yield 73%; m.p.
1
2
19–220 °C; H NMR (400 MHz, DMSO-d ): δ 8.87 (s, 1H), 8.12 (d,
6
J = 8.2 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 7.53 (s, 2H), 7.24 (t, J = 7.6 Hz,
2
H), 6.95 (d, J = 8.3 Hz, 2H), 6.81 (t, J = 7.2 Hz, 1H), 4.73 (s, 2H), 4.38 (s,
13
2
H), 4.07 (s, 2H), 3.32–3.27 (m, 4H); C NMR (100 MHz, DMSO-d ): δ
6
193.8, 150.0, 143.8, 138.5, 129.0, 127.5, 122.1, 120.3, 119.3, 115.4, 47.5, 31.2.
+
HRMS (ESI) calcd for C H N O S [M + H] : 475.1047; found: 475.1045.
20
23
6
2 3
(1-(4-Sulfamoylphenyl)-1H-1,2,3-triazol-4-yl)methyl-4-(4-(tert- butyl)
2015, 103, 446.
benzyl)piperazine-1-carbodithioate (8f): White solid; yield 78%; m.p.
6
M. Kawai, N.Y. BaMaung, S.D. Fidanze, S.A. Erickson, J.S. Tedrow, W.J.
Sanders, A. Vasudevan, C. Park, C. Hutchins, K.M. Comess, D. Kalvin, J.
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Zhang, Molecules, 2016, 21, 653.
1
1
8
98–199 °C; H NMR (400 MHz, DMSO-d ): δ 8.86 (s, 1H), 8.12 (d, J =
6
.6 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.53 (s, 2H), 7.35 (d, J = 8.1 Hz, 2H),
7
.23 (d, J = 8.1 Hz, 2H), 4.69 (s, 2H), 4.25 (s, 2H), 3.90 (s, 2H), 3.48 (s, 2H),
13
7
8
9
2
.45 (s, 4H), 1.27 (s, 9H); C NMR (100 MHz, DMSO-d ): δ 193.6, 149.4,
6
143.8, 143.8, 138.5, 134.5, 128.7, 127.5, 125.0, 122.1, 120.3, 60.9, 51.9, 34.2,
+
31.3, 31.2. HRMS (ESI) calcd for C H N O S [M + H] : 545.1824; found:
25 33 6 2 3
545.1827.
D.J. Fu, J. Song, R.H. Zhao, Y.C. Liu, Y.B. Zhang and H.M. Liu, J. Chem. Res.,
2016, 40, 674.
t-Butyl-4-((((1-(4-sulfamoylphenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)
carbonothioyl)piperazine-1-carboxylate (8g): Yellow solid; yield 81%;
10 D.J. Fu, S.Y. Zhang, Y.C. Liu, L. Zhang, J.J. Liu, J. Song, R.H. Zhao, F. Li, H.H.
1
Sun, H.M. Liu and Y.B. Zhang, Bioorg. Med. Chem. Lett., 2016, 26, 3918.
m.p. 188–190 °C; H NMR (400 MHz, DMSO-d ): δ 8.86 (s, 1H), 8.12 (d,
6
11
D.J. Fu, L. Zhang, J. Song, R.W. Mao, R.H. Zhao, Y.C. Liu, Y.H. Hou, J.H. Li,
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J = 8.7 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.52 (s, 2H), 4.71 (s, 2H), 4.24
13
(
s, 2H), 3.94 (s, 2H), 3.65–3.41 (m, 4H), 1.41 (s, 9H); C NMR (100 MHz,
DMSO-d ): δ 193.8, 150.0, 143.8, 138.5, 129.0, 127.5, 122.1, 120.3, 119.3,
6
12 S.Y. Zhang, D.J. Fu, H.H. Sun, X.X. Yue, Y.C. Liu, Y.B. Zhang and H.M. Liu,
Chem. Heterocycl. Compd, 2016, 52, 374.
+
1
15.4, 47.5, 31.2. HRMS (ESI) calcd for C H N O S [M + H] : 499.1255;
19
27
6
4 3
found: 499.1256.
13 D.J. Fu, S.Y. Zhang, Y.C. Liu, J. Song, R.H. Zhao, R.W. Mao, H.M. Liu and Y.B.
Zhang, J. Chem. Res., 2016, 40, 624.
(
1- (4-Sulfamoylphenyl) -1H-1,2,3-triazol-4-yl) methyl-4-
14
D.J. Fu, S.Y. Zhang, J. Song, Y.C. Liu, L. Zhang, R.H. Zhao, X.L. Zi, H.M. Liu
benzhydrylpiperazine-1-carbodithioate (8h): White solid; yield 57%; m.p.
and Y.B. Zhang, J. Chem. Res., 2016, 40, 620.
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Sakthivel and P.S. Mohan, Mol. Divers., 2017, 21, 37.
1
2
8
19–220 °C; H NMR (400 MHz, DMSO-d ) δ 8.84 (s, 1H), 8.11 (d, J =
6
.7 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.53 (s, 2H), 7.44 (d, J = 7.5 Hz, 4H),
7.31 (t, J = 7.6 Hz, 4H), 7.20 (t, J = 7.3 Hz, 2H), 4.67 (s, 2H), 4.39 (s, 1H),
13
4.26 (s, 2H), 3.94 (s, 2H), 2.41 (s, 4H); C NMR (100 MHz, DMSO-d ):
6