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

Article abstract of DOI:10.1016/j.bmcl.2013.10.062

A series of novel 1,3-selenazole-containing 1,3,4-thiadiazole derivatives bearing Schiff base moieties were synthesized and evaluated for their in vitro antiproliferative activities against human breast cancer cell MCF-7 and mouse lymphocyte leukemia cell

Full text of DOI:10.1016/j.bmcl.2013.10.062

Bioorganic & Medicinal Chemistry Letters 23 (2013) 6577–6579
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antitumor-evaluation of 1,3-selenazole-containing
1,3,4-thiadiazole derivatives
Hai-Chuan Zhao, Yan-Ping Shi, Yu-Ming Liu, Cai-Wen Li, Li-Na Xuan, Peng Wang, Kai Zhang,
⇑
Bao-Quan Chen
Department of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, PR 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-selenazole-containing 1,3,4-thiadiazole derivatives bearing Schiff base moieties
were synthesized and evaluated for their in vitro antiproliferative activities against human breast cancer
cell MCF-7 and mouse lymphocyte leukemia cell L1210 by CCK-8 assay. The majority of the compounds
showed better activity against MCF-7 cell, compared with lead compound PCS. In particular, compound
Received 9 September 2013
Revised 21 October 2013
Accepted 29 October 2013
Available online 6 November 2013
6c was the most potent compound with IC50 value of 4.02 lM.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Selenazole
1,3,4-Thiadiazole derivatives
Schiff base
Antitumor agents
Selenium is closely related with human health as a trace
element.1,2 Recently, reports of selenium-containing heterocyclic
compounds have gradually increased because of their pharmaceuti-
cal applications, and have become hot spots in the studies of tumor
prevention and therapy.3–5 Among them, functionalized 1,3-sele-
nazole moieties are present in many pharmacologically active
substances.6–8 The prominent examples are selenazofurin(2-b-ribo-
furanosyl-1,3-selenazole-4-carboxamide) and 2-phenyl-4-car-
boxyl-1,3-selenazole (PCS, Fig. 1) which possess potent antiviral
and antitumor activities.9,10 Moreover, complexes prepared by
PCS and transition metals showed good antitumor activity.11,12
This result has a great guiding significance for finding better
selenium-containing anticancer agents through structural
transformation.
Based on the above ideas, we optimized the reaction conditions,
and carried out the reaction by condensation of 2-phenyl-4-[(2-
amino-1,3,4-thiadiazol-5-ylthio)methyl]-1,3-selenazole
and
substituted aromatic aldehyde, generated a series of novel 1,3-sele-
nazole-containing 1,3,4-thiadiazole derivatives bearing Schiff base
moieties which increased the number of active groups in the mole-
cule. Meanwhile, their in vitro antiproliferative activities were also
evaluated. These target compounds were synthesized as shown in
Scheme 1 with 38.2–72.1% yield. PCS was prepared according to
the literature10 in 45.6% yield.
CONH2
Se
N
HO
1,3,4-Thiadiazole derivatives bearing Schiff base moieties have
been reported to display a wide range of biological properties, such
as anticancer,13 antibacterial,14 antidepressant,15 antidiabetic16
and antifungal activities.17 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. The
introduction of different heterocyclic backbone to the thiadiazole
nucleus affects its biological activity, and thus has drawn wide-
spread attention.18–20
COOH
O
N
OH OH
Selenazofurin
Se
PCS
N
N
N
R
N
S
S
Se
Target compound 6
Figure l. Structures of selenazofurin, the lead compound PCS and target compound.
⇑
Corresponding author. Tel.: +86 22 60214259; fax: +86 22 60214252.
E-mail address: chenbaoquan6@126.com (B.-Q. Chen).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.10.062

6578
H.-C. Zhao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6577–6579
a
NaHSe
+
B(OC2H5)3
+
H2
Se
+
NaBH4
+
C2H5OH
b
1
Se
C
CH2Cl
N
c
CN
NH2
Se
4
3
2
N
N
N
S
S
NH2
d
e
Se
6a: R=Ph
5
6b:
6c:
6d:
6e:
6f:
R=4-F-Ph
R=4-Cl-Ph
R=4-Br-Ph
N
N
R=2-OH-Ph
R=4-OH-Ph
R=2,4-(OH)2-Ph
R
6g:
N
S
N
S
6h: R=3-OCH3-4-OH-Ph
6i: R=4-CH3-Ph
6j: R=4-N(CH3)2-Ph
6k: R=4-NO2-Ph
Se
6a-k
Scheme 1. Synthesis of the target compounds 6a–6k. Reagents and conditions: (a) N2, rt, 0.5 h; (b) NaHSe, 80 °C, 6 h; (c) ClCH2COCH2Cl/acetone, rt, 4 h; (d) 2-amino-5-
mercapto-1,3,4-thiadiazole/KOH/PEG-400/acetone, reflux, 4 h; (e) substituted aromatic aldehyde/BTEAC/CH(OCH3)3, reflux, 5 h.
Compound 1 was derived from selenium by sodium borohydride
reduction in the presence of ethanol under nitrogen atmosphere.
The reaction of benzonitrile(2) with sodium hydrogen selenide(1)
yielded selenobenzamide 3, which was reacted with 1,3-dichloro-
acetone in acetone to produce compound 4 at room temperature
for 4 h. Compound 5 was made by the reaction of 4 and 2-amino-
5-mercapto-1,3,4-thiadiazole using PEG-400 as catalyst under
reflux condition for 3 h. Finally, the condensation of 5 (1 equiv)
and corresponding substituted aromatic aldehyde (1 equiv) in the
presence of trimethyl orthoformate (1.2 equiv) using benzyl trieth-
ylammonium chloride (BTEAC, 10 mol %) as catalyst yielded the
target compound 6 under reflux condition (see Supplementary
data). All the synthesized compounds (6a–6k) were purified by
recrystalization using appropriate solvent. The structures of target
compounds were characterized by IR, 1H NMR, ESI-MS techniques
and elemental analysis (see Supplementary data).
assay. Inhibition of cell proliferation by these active compounds at
various concentrations were measured, and their IC50 (the concen-
tration that causes a 50% cell proliferation inhibition) values were
calculated and summarized in Table 1. PCS was used as a positive
control.
As shown in Table 1, all the newly synthesized compounds (6a–
6k) exhibited antiproliferation against MCF-7 cells with different
degrees, and most of the compounds showed better activity than
PCS. The substituent group of phenyl ring on the 1,3,4-thiadiazole
Schiff base plays important roles in the potency of biologically ac-
tive compounds. The phenyl substituent (6a) decreased the antipro-
liferative activity compared with PCS. Except 6k, the introduction of
electron-withdrawing groups (6b–6d) enhanced antitumor activity
compared with 6a, and these compounds showed higher antiprolif-
erative activity than PCS. Especially, 4-chlorophenyl substituent
(6c) showed significant antitumor activity (IC50 = 4.02 lM), while
The CCK-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-
(2,4-disulfophenyl)-2H-tetrazolium monosodium salt] cell prolif-
eration assay was used to evaluate the antiproliferative activity
of the synthesized compounds against MCF-7 (human breast
cancer cell) and L1210 (mouse lymphocyte leukemia cell) cell lines
(see Supplementary data), which was used as a substitute for MTT
4-nitrophenyl substituent (6k) displayed the lowest activity. Except
6f and 6j, the introduction of electron-donating groups (6e, 6g–6i)
exhibited enhanced antitumor activity compared with 6a, and these
compounds showed higher antiproliferative activity than PCS. It is
worth noticing that compounds 6g and 6i exhibited fairly good anti-
proliferative activities with IC50 values of 8.51 and 7.55
tively. But, 4-dimethyaminophenyl substituent (6j) showed the
minimum anticancer activity (IC50 = 80.26 M), This result is poorly
lM, respec-
l
understood. Therefore, in MCF-7 cells, the influence of substituent
group on antitumor activity did not show apparent regularity. In
L1210 cells, compounds 6a–6e and 6i exhibited a moderate increase
in antiproliferative activity compared with PCS, while compounds
6f, 6h, 6j and 6k did not display noticeable cytotoxicity. Apparently,
this class of compounds were only weak inhibitors of L1210 cells.
In conclusion, we have designed and synthesized a series of no-
vel 1,3-selenazole-containing 1,3,4-thiadiazole derivatives bearing
Schiff base moieties and evaluated their in vitro antiproliferative
activities against two different cancer cell lines. Some of the com-
pounds inhibited the proliferation better than positive control PCS
did, and their performance has certain selectivity. In particular,
compound 6c showed the most potent antiproliferative activity
against MCF-7 cells. The preliminary results shown above against
MCF-7 cell are very encouraging. Therefore, this study has pro-
vided meaningful information for further improving the potency
and the selectivity of this class of compounds.
Table 1
Antiproliferative activities of compounds 6a–6k against MCF-7 and L1210 cell lines
a
Compound
IC50
(l
M)
L1210
MCF-7
6a
6b
6c
6d
6e
6f
6g
6h
6i
46.51
56.92
50.01
46.46
38.73
>100
62.18
>100
58.56
>100
>100
60.11
25.60
10.23
4.02
14.77
15.23
31.10
8.51
14.97
7.55
80.26
49.10
16.56
6j
6k
PCS
a
The concentration that causes a 50% cell proliferation inhibition.

H.-C. Zhao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6577–6579
6579
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We are grateful to the National Natural Science Foundation of
China (20971097) for financial support.
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.10.062.
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