Synthesis and in vitro antitumor activity of 1,3,4-thiadiazole derivatives based on benzisoselenazolone

Article abstract of DOI:10.1016/j.cclet.2012.04.005

A series of novel 1,3,4-thiadiazole derivatives based on benzisoselenazolone were synthesized and evaluated for their cytotoxicity in vitro against human liver cancer cell SSMC-7721, human breast cancer cell MCF-7 and human lung cancer cell A549 by CCK-8 assay. The results showed that compounds 7e, 7f, 7h, 7k, 7l and 7m displayed good cytotoxicity against MCF-7 cell lines. Compound 7l exhibited the most potent antitumor activities among the tested compounds.

Full text of DOI:10.1016/j.cclet.2012.04.005

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 817–819
www.elsevier.com/locate/cclet
Synthesis and in vitro antitumor activity of 1,3,4-thiadiazole
derivatives based on benzisoselenazolone
*
Jie Zhao, Bao Quan Chen , Yan Ping Shi, Yu Ming Liu, Hai Chuan Zhao, Ji Cheng
School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China
Received 15 February 2012
Available online 12 June 2012
Abstract
A series of novel 1,3,4-thiadiazole derivatives based on benzisoselenazolone were synthesized and evaluated for their
cytotoxicity in vitro against human liver cancer cell SSMC-7721, human breast cancer cell MCF-7 and human lung cancer cell
A549 by CCK-8 assay. The results showed that compounds 7e, 7f, 7h, 7k, 7l and 7m displayed good cytotoxicity against MCF-7 cell
lines. Compound 7l exhibited the most potent antitumor activities among the tested compounds.
# 2012 Bao Quan Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 1,3,4-Thiadiazole derivatives; Benzisoselenazolone; Synthesis; Antitumor activity
Selenium is closely related with human health as a trace element [1,2]. For many years the organoselenium
compounds were synthesized as potential pharmaceuticals, and have become hot spots in the studies of tumor
prevention and therapy [3,4]. Among them, Ebselen (Eb 1) is one of the most well-known mimic of glutathione
peroxidase(GSH-Px), which has been investigated as anti-inflammatory agents [5] and anticancer agents [6].
Moreover, the selenium in Eb is not bioavailable. This is probably the reason for its low toxicity (LD50: 6180 mg/kg,
rats). Study has demonstrated that the biological activity and low toxicity of Eb may be related to cyclic selenenamide
structure, but selenium is still the central element of biological activity [7]. This conclusion has a great guiding
significance for finding better selenium anticancer agents through structural transformation. Currently, a phase III
clinical trail for the antioxidant effect of Eb is being carried out in Japan.
It has been shown that 1,3,4-thiadiazole derivatives possess interesting biological properties such as anticancer [8],
antibacterial [9] and antifungal activity [10]. 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 the 1,3,4-thiadiazole nucleus will affect its biological activity,
which has drawn widespread attention [11,12]. We report herein the efficient synthesis of 1,3,4-thiadiazole derivatives
based on benzisoselenazolone and studies on their antitumor activities.
The synthetic route of these target compounds is outlined in Scheme 1. Eb 1 was prepared according to the literature
[13] in 84% yield.
* Corresponding author.
E-mail address: chenbaoquan6@yahoo.com.cn (B.Q. Chen).
1001-8417/$ – see front matter # 2012 Bao Quan Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.04.005

818
J. Zhao et al. / Chinese Chemical Letters 23 (2012) 817–819
O
N
N
N
N
N
a
+
RCl
SR
H2N
S
SH
H2N
S
2
Se
3a-m
1
b
Se + KBH4
K2Se2
4
O
N
Se
7a-m
COOH
NH2
COCl
SeCl
N
N
c, d
e
f
Se Se
SR
S
3a-m
COOH
COOH
6
5
Scheme 1. Reagents and conditions: (a) NaOH, H2O, MeOH, r.t., 10 h, yield: 73–88%; (b) H2O, NaOH, N2, r.t., 0.5 h; (c) NaNO2, HCl, 0 ꢀ 2 8C,
1 h; (d) K2Se2, 60–70 8C, 3 h, r.t., 2 h, yield: 83%; (e) SOCl2, reflux, 3 h, yield: 73%; (f) CH3CN, r.t., 2 h, yield: 40–52%.
Reaction of the commercially available 2-amino-5-mercapto-1,3,4-thiadiazole 2 with corresponding alkyl chloride
in the presence of NaOH in water and methanol at room temperature yielded the desired intermediates 3a–m in 73–
88% yields. Selenium was reduced by potassium borohydride under nitrogen atmosphere at room temperature to give
potassium diselenide 4. The diazonium salt of anthranilic acid was treated with compound 4 at 60–70 8C to produce
2,20-diselenodibenzoic acid 5 in 83% yield. Compound 5 was refluxed with thionyl chloride to furnish the key
intermediate 6 in 73% yield. Finally, the target compounds 7a–m were successfully obtained via the condensation of
intermediates 3a–m and 6 in acetonitrile at room temperature. The resulting products were purified by silica gel
column chromatography. The structures of target compounds are shown in Table 1 and characterized by IR, 1H NMR,
13C NMR, ESI-MS and elemental analysis (EA) [14].
The cytotoxicity of 13 compounds against human liver cancer cell SSMC-7721, human breast cancer cell MCF-7
and human lung cancer cell A549 was determined by CCK-8 assay [15] with Eb as the positive control and the results
expressed as IC50 are summarized in Table 1.
AsshowninTable1, allthecompounds7a–mshowedlowercytotoxicitythanEbinvitroagainstA549celllines,while
most of the tested compounds showed superior or comparable cytotoxicity to Eb against SSMC-7721 and MCF-7 cell
lines. Compounds 7e, 7f, 7h, 7k, 7l and 7m displayed good cytotoxicity against MCF-7 cell lines, and compound 7l
exhibited the most potent antitumor activities among the 13 compounds with IC50 values of 4.84, 1.12 and 4.53 mmol/L
against SSMC-7721, MCF-7 and A549 cell lines, respectively. The results also showed that electron-donating
Table 1
Structures and cytotoxic activity against three tumor cell lines of target compounds.
Compd.
R
IC50 (mmol/L)
SSMC-7721
MCF-7
A549
7a
–CH3
4.84
19.56
5.56
35.70
6.76
8.55
22.82
1.23
1.34
6.81
1.83
8.55
16.58
2.89
1.12
2.75
15.02
21.13
8.33
7b
7c
–C2H5
n-C3H7
7.45
7d
7e
i-C3H7
3.51
8.96
n-C4H9
4.75
18.23
25.85
21.90
23.71
23.74
22.11
5.85
7f
7g
i-C4H9
8.75
n-C5H11
29.68
40.28
30.00
8.75
7h
7i
n-C6H13
–CH2COOCH3
–CH2COOC2H5
C6H5CH2–
p-CH3–C6H4CH2–
p-NO2–C6H4CH2–
–
7j
7k
7l
24.18
4.84
4.53
7m
Ebselen
7.12
7.51
18.33
3.75
The IC50 of target compounds against three tumor cell lines was determined by CCK-8 assay.

J. Zhao et al. / Chinese Chemical Letters 23 (2012) 817–819
819
substituent of phenyl ring 7l enhanced antitumor activity compared with 7k and 7m against three tumor cell lines, while
the influence of other substituent group on antitumor activity did not show apparent regularity. The preliminary results
shown above are very encouraging, the further investigation is currently underway and the results will be reported later.
Acknowledgment
The work was supported by the National Natural Science Foundation of China (No. 20971097).
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[14] The data of selected compounds. 7a: yield 50.2%; pale yellow solid, mp > 300 8C; IR (KBr): 3045, 1663, 1471, 1329, 1066, 734, 674 cmꢁ1; 1H
NMR (400 MHz, DMSO-d6): d 8.09–8.11 (d, 1H, J = 8.1 Hz, ph-H), 7.98–8.00 (d, 1H, J = 6.8 Hz, ph-H), 7.75–7.79 (t, 1H, J = 7.7 Hz, ph-H),
7.51–7.55 (t, 1H, J = 7.5 Hz, ph-H), 2.75 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): d 165.43, 161.86, 157.98, 140.77, 134.37, 128.40,
127.90, 126.97, 126.82, 16.54; ESI-MS (m/z): 329.26[M+H]+; Anal. Calcd. for C10H7ON3S2Se: C 36.59, H 2.15, N 12.80; Found: C 36.47, H
2.11, N12.86. 7c: yield 52.0%; pale yellow solid, mp 201.9–203.8 8C: IR (KBr): 3026, 1659, 1458, 1312, 1048, 736, 674 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6): d 8.12–8.14 (d, 1H, J = 8.1 Hz, ph-H), 8.00–8.02 (d, 1H, J = 7.6 Hz, ph-H), 7.76–7.80 (t, 1H, J = 7.6 Hz, ph-H), 7.52–
7.56 (t, 1H, J = 7.4 Hz, ph-H), 3.23–3.26 (t, 2H, J = 7.3 Hz, SCH2), 1.65–1.82 (m, 2H, CH2), 0.97–1.06 (t, 3H, J = 7.3 Hz, CH3); 13C NMR
(100 MHz, DMSO-d6): d 165.69, 160.28, 158.46, 140.91, 134.41, 128.42, 127.29, 127.18, 126.96, 36.26, 22.90, 13.38; ESI-MS (m/z):
357.31[M+H]+; Anal. Calcd. for C12H11ON3S2Se: C 40.45, H 3.11, N 11.79; Found: C 40.31, H 3.15, N 11.82. 7g: yield 44.6%; pale yellow
1
solid, mp 185.2–186.5 8C; IR (KBr): 3056, 1621, 1469, 1327, 1051, 738, 674 cmꢁ1; H NMR (400 MHz, DMSO-d6): d 8.25–8.27 (d, 1H,
J = 8.2 Hz, ph-H), 7.97–7.99 (d, 1H, J = 7.4 Hz, ph-H), 7.72–7.76 (t, 1H, J = 7.7 Hz, ph-H), 7.49–7. 53 (t, 1H, J = 7.4 Hz, ph-H), 3.23–3.27 (t,
2H, J = 7.3 Hz, SCH2), 1.68–1.75 (m, 2H, CH2), 1.35–1.43 (m, 2H, CH2), 1.27–1.34 (m, 2H, CH2), 0.86–0.89 (t, J = 7.2 Hz, 3H, CH3); 13
C
NMR (100 MHz, DMSO-d6): d 165.73, 159.94, 158.73, 141.22, 134.04, 128.23, 127.80, 127.34, 126.93, 34.14, 30.62, 29.15, 22.09, 14.27; ESI-
MS (m/z, %): 385.37[M+H]+; Anal. Calcd. for C14H15ON3S2Se: C 43.75, H 3.93, N10.93; Found: C 43.61, H 3.95, N 10.99. 7i: yield 46.5%;
pale yellow solid, mp 192.2–193.7 8C; IR (KBr): 3044, 1664, 1744, 1471, 1322, 1157, 1055, 733, 672 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d
8.09–8.12 (d, 1H, J = 8.1 Hz, ph-H), 8.00–8.02 (d, 1H, J = 7.7 Hz, ph-H), 7.77–7.80 (t, 1H, J = 7.5 Hz, ph-H), 7.52–7. 57 (t, 1H, J = 7.5 Hz, ph-
H), 4.24 (s, 2H, CH2), 3.69 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): d 169.16, 165.65, 159.11, 158.85, 140.83, 134.51, 128.47, 127.23,
127.12, 126.88, 53.06, 35.40; ESI-MS (m/z): 387.30[M+H]+; Anal. Calcd. for C12H9O3N3S2Se: C 37.31, H 2.35, N10.88; Found: C 37.39, H
1
2.38, N 10.86. 7l: yield 40.3%; pale yellow solid, mp 231.9–232.7 8C; IR (KBr): 3020, 1667, 1471, 1316, 1049, 733, 672 cmꢁ1; H NMR
(DMSO-d6, 400 MHz): d 8.09–8.11 (d, 1H, J = 8.1 Hz, ph-H), 7.99–8.01 (d, 1H, J = 7.6 Hz, ph-H), 7.77–8.00 (t, 1H, J = 7.7 Hz, ph-H), 7.51–7.
56 (t, 1H, J = 7.5 Hz, ph-H), 7.32–7.34 (d, 2H, J = 8.0 Hz, ph-H), 7.14–7.16 (d, 2H, J = 7.9 Hz, ph-H), 4.49 (s, 2H, CH2), 2.28 (s, 3H, CH3); 13
C
NMR (100 MHz, DMSO-d6): d 165.58, 159.70, 158.62, 140.82, 137.33, 134.47, 134.01, 129.59(2C), 129.41(2C), 128.45, 127.20, 127.15,
126.87, 37.87, 21.18; ESI-MS (m/z): 419.38[M+H]+; Anal. Calcd. for C17H13ON3S2Se: C 48.80, H 3.13, N 10.04; Found: C 48.63, H 3.15, N
10.09.
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