Synthesis and antitumor-evaluation of 1,3,4-thiadiazole-containing benzisoselenazolone derivatives

Article abstract of DOI:10.1016/j.bmcl.2012.03.043

A series of novel 1,3,4-thiadiazole-containing benzisoselenazolone derivatives were prepared by the condensation of 2-chloroselenobenzoyl chloride and 2-amino-5-substituted-1,3,4-thiadiazole. Their in vitro antiproliferative activities were evaluated in SSMC-7721, MCF-7 and A-549 cells. The results suggest that, in different tumor cells, some compounds have good antiproliferative activity, certain selectivity and potential value of further research.

Full text of DOI:10.1016/j.bmcl.2012.03.043

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3191–3193
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antitumor-evaluation of 1,3,4-thiadiazole-containing
benzisoselenazolone derivatives
⇑
Zhenhua Luo, Baoquan Chen , Shuangyan He, Yanping Shi, Yuming Liu, Caiwen Li
Department of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China
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 1,3,4-thiadiazole-containing benzisoselenazolone derivatives were prepared by the
condensation of 2-chloroselenobenzoyl chloride and 2-amino-5-substituted-1,3,4-thiadiazole. Their
in vitro antiproliferative activities were evaluated in SSMC-7721, MCF-7 and A-549 cells. The results sug-
gest that, in different tumor cells, some compounds have good antiproliferative activity, certain selectiv-
ity and potential value of further research.
Received 29 December 2011
Revised 8 March 2012
Accepted 9 March 2012
Available online 21 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzisoselenazolone derivatives
1,3,4-Thiadiazole
Antitumor agents
Selenium is a trace element essential for maintaining normal
physiological function in human body. Selenium is tied with
human health and closely related with the prevention and inhibi-
tion of tumor.1 Thus, it has been dedicated to the design and trans-
formation of selenium compounds to find anticancer drugs from
selenium derivatives which have strong antitumor activity, low
toxicity and are suitable for clinical use.
Benzisoselenazolones (BESA) could mimic the features of
glutathione peroxidase (GSH-Px).2,3 Among them, ebselen[2-phe-
nyl-1,2-benziselenazol-3(2H)-one, Fig. 1] is one of the most
well-known analog of GSH-Px, with enhanced antioxidant capac-
ity,4,5 good anti-inflammatory effects6 and anticancer activity.7 In
addition, selenium in ebselen could not be absorbed by the body,
which confers the ebselen less toxic (LD50: 6180 mg/kg, rats).
Study has demonstrated that the biological activity and low toxic-
ity of ebselen may be related to cyclic selenenamide structure, but
selenium is still the central element of biological activity.8 This
conclusion has important guiding significance for seeking better
performance of selenium anticancer drugs through structural
transformation. Currently, a phase III clinical trail is being carried
out in Japan to test antioxidant effect of ebselen.
the thiadiazole nucleus will affect its biological activity, which
has drawn widespread attention.12
Based on the above ideas, in this Letter, using ebselen as a lead
compound, we optimized the reaction conditions, and carried out
the reaction by condensation of 2-chloroselenobenzoyl chloride
and 2-amino-5-substituted-1,3,4-thiadiazole, generated a series
of 1,3,4-thiadiazole-containing benzisoselenazolone derivatives
which increased the number of active groups in the molecule.
Meanwhile, the in vitro antiproliferative activities in various can-
cer cell lines were also evaluated.Benzisoselenazolone derivatives
were synthesized as shown in Scheme 1 with 38.8–53.5% yield.
The reaction of appropriate aromatic carboxylic acid with thiosem-
icarbazide afforded 2-amino-5-substituted-1,3,4-thiadiazole with
POCl3 as catalyst.13
Compound 1 was derived from selenium by potassium borohy-
dride reduction. Compound 3 was made by diazotization of anthra-
nilic acid (2). Compound 4 was made by the reaction of 1 and 3
under 60–70 °C for 3 h. Compound 4 was reacted with thionyl chlo-
ride to afford the compound 5 under refluxing condition for 3 h. The
condensation of
5 (1 equiv) and 2-amino-5-substituted-1,3,4-
thiadiazole (1 equiv) yielded the target compound 6 in the presence
of triethylamine(1.2 equiv) at room temperature in DMF, within
12 h. When preparing compounds (6a–6o), we keep the same reac-
tion conditions, simple operation, and mild conditions and it was
refined by the method of silica gel column separation (Table 1).
All synthesized compounds were structurally characterized by
IR, 1H NMR, ESI-MS techniques and elemental analysis. All
compounds reported herein were evaluated for in vitro antiprolif-
erative activities against SSMC-7721 (human liver cancer cell),
MCF-7 (human breast cancer cell) and A549 (human lung cancer
It has been shown that 1,3,4-thiadiazole derivatives possess
multiple biological activities including anticancer9 antibacterial10
and antifungal.11 Especially, the structure of ‘N-C-S’ in 1,3,4-
thiadiazole derivatives can work as the active center, chelate
certain metal ions in vivo, and show good tissue permeability.
Moreover, the introduction of different heterocyclic backbone to
⇑
Corresponding author. Tel.: +86 22 60214259; fax: +86 22 60214252.
E-mail address: chenbaoquan6@yahoo.com.cn (B. Chen).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.03.043

3192
Z. Luo et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3191–3193
Table 2
Calculated
benzisoselenazolone
O
N
IC50
values
for
synthetic
1,3,4-thiadiazole
derivatives
of
Se
No.
Compound
Calculated IC50 value (lM)
SSMC-7721
MCF-7
A-549
Figure 1. Chemical structure of ebselen.
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
20.46
42.91
40.16
24.39
27.40
68.22
19.41
17.80
16.61
14.33
16.45
7.15
4.02
61.51
4.43
19.45
59.36
43.32
36.81
19.90
18.69
3.92
10.02
3.44
31.15
29.21
37.79
15.02
2.48
21.12
10.11
10.36
12.67
39.12
18.60
14.75
13.42
3.12
5.93
3.24
11.44
16.13
17.91
3.75
a
Se + KBH4
K2Se2
1
COOH
9
COOH
N2+Cl-
b
c
10
11
12
13
14
15
16
NH2
6m
6n
6o
Ebselen
22.53
27.33
21.56
18.33
2
3
COCl
SeCl
e
d
Se Se
COOH
COOH
slightly decreased the antiproliferative activity compared with
ebselen. The introduction of electron-donating groups (6g–6l) en-
hanced antitumor activity compared with 6a, and most com-
pounds showed higher antiproliferative activity than that ebselen
did. In addition, multi-electron-donating substitution of phenyl
ring displays higher antiproliferative activity than single-elec-
tron-donating substitution of phenyl ring at C-2 position. For
example, 3,4,5-trimethoxyphenyl substituent (6l) showed the best
5
4
O
N
N
N
R
S
Se
6
antiproliferative activity (IC50 = 7.15 lM), that is much more effec-
Scheme 1. Reagents and conditions (a) H2O/NaOH, N2,0.5 h, 100%; (b) NaNO2/HCl/
H2O, 1 h, 0–2 °C, 1 h, 100%; (c) K2Se2, 60–70 °C, 3 h, 83.0%; (d) SOCl2, reflux, 3 h,
73.1%; (e) 2-amino-5-substituted-1,3,4-thiadiazole/(C2H5)3N, EtOAc, 8–12 h, rt,
38.8–53.5%.
tive than 4 or 2-methoxy-phenyl substituent. The activity was de-
creased while the introduction of electron-withdrawing groups.
Especially 4-bromophenyl substituent showed the lowest activity
(IC50 = 68.22
antiproliferative activity against MCF-7 cells (IC50 = 3.44
antiproliferative activity (IC50 = 4.02 M) of phenyl substituent
lM). The compound (6l) also showed the best
lM). The
l
Table 1
(6a) is better than ebselen. Except 6j and 6l, both electron-with-
drawing group and electron-donating group decreased the activity
compared with compound 6a against MCF-7 cells. 4-Fluorophenyl
substituent (6b) showed the minimum anticancer activity
Synthesis of 1,3,4-thiadiazole-containing benzisoselenazolone derivatives
Entry
6
Substrate R
Mp (°C)
Timea (h)
Yieldb (%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
Ph
4-F-Ph
2-Cl-Ph
4-Cl-Ph
2-Br-Ph
4-Br-Ph
2-CH3-Ph
3-CH3-Ph
4-CH3-Ph
2-OCH3-Ph
4-OCH3-Ph
3,4,5-(OCH3)3-Ph
2-NO2-Ph
3-NO2-Ph
3,5-(NO2)2-Ph
229.3–231.2
>300
250.2–252.2
225.0–227.0
>300
>300
>300
>300
>300
283.5–285.1
292.0–293.5
247.1–248.5
286.6–288.6
270.9–273.2
258.3–259.7
8
8
51.6
49.2
45.3
43.8
40.6
41.9
49.6
50.6
53.5
48.5
52.5
49.8
44.2
42.8
38.8
(IC50 = 61.51
stituent (6c) at C-2 showed significant antitumor activity
(IC50 = 4.43 M). This observation is poorly understood. Therefore,
lM), but, we were surprised that 2-chlorophenyl sub-
10
9
10
10
8
8
8
8
9
l
in MCF-7 cells, the influence of substituent group on antitumor
activity did not show apparent regularity. In A-549 cells, com-
pounds 6a showed the highest activity (IC50 = 2.48 lM). Other sub-
9
10
11
12
13
14
15
stituents all lowered the activity compared with 6a. But,
compounds (6j–6l) still have excellent anticancer activity. More-
over, compound 6j and 6l possess stronger activity than ebselen
did.
In summary, we have synthesized a series of novel 1,3,4-thiadi-
azole-containing benzisoselenazolone derivatives and evaluated
their in vitro antiproliferative activities against three different hu-
man tumor cell lines. Some of the compounds inhibited the prolif-
eration better than lead compound ebselen did, and the
performance of which has certain selectivity. In particular, the
compound 6l showed significant antiproliferative activities in
SSMC-7721, MCF-7 and A-549 cells, with IC50 values of 7.15, 3.44
8
10
10
12
a
Reaction time of 2-chloroselenobenzoyl chloride and 2-amino-5-substituted-
1,3,4-thiadiazole.
b
Isolated yield.
cell) cell lines using CCK-8 assay. The results are summarized in
Table 2 and are compared with the activity of ebselen.
and 3.24
l
M, respectively. The compound 6a was found to be the
As shown in Table 2, the majority of newly synthesized com-
pounds (6) exhibited antiproliferation against SSMC-7721 cells
with different degrees. Some compounds showed better activity
most potent compound in A-549 cells, with IC50 values 2.48
Similarly, the compound 6j also showed highly effective antiprolif-
lM.
erative activities in MCF-7 and A-549 cells, with IC50 values of 3.92
than ebselen did. All these compounds possess
a common
and 3.12 lM, respectively. A very interesting inhibition prolifera-
2-(1,3,4-thiadiazol-5-yl)-benzisoselenazolone nucleus in which
substituent group of phenyl ring at C-2 position on the 1,3,4-
thiadiazole plays important roles in the potency of biologically
active compounds. The phenyl substituent (6a) at C-2 position
tion against MCF-7 cells with compound 6c has been observed.
Therefore, the results laid a foundation for further improving the
potency and the selectivity of this series of compounds.

Z. Luo et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3191–3193
3193
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Supplementary data
Supplementary data associated with this article can be found, in
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