Synthesis and antiproliferative evaluation of novel 1,2,4-triazole derivatives incorporating benzisoselenazolone scaffold

Article abstract of DOI:10.1016/j.bmcl.2016.01.017

A series of novel 1,2,4-triazole derivatives incorporating benzisoselenazolone scaffold were designed, synthesized and evaluated for their in vitro antiproliferative activities against human cancer cell lines SMMC-7721, Hela, A549, and normal cell lines L

Full text of DOI:10.1016/j.bmcl.2016.01.017

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiproliferative evaluation of novel 1,2,4-triazole
derivatives incorporating benzisoselenazolone scaffold
Bao-Lin Li, Bo Li, Rui-Lian Zhang, Ji-Jun Zhao, Xue-Feng Wang, Yu-Ming Liu, Yan-Ping Shi, Jin-Biao Liu,
⇑
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 1,2,4-triazole derivatives incorporating benzisoselenazolone scaffold were designed,
synthesized and evaluated for their in vitro antiproliferative activities against human cancer cell lines
SMMC-7721, Hela, A549, and normal cell lines L929 by CCK-8 assay. The preliminary bioassay results
demonstrated that most of the tested compounds 3a–3n exhibited antiproliferation with different
degrees, and some compounds showed better effects than positive controls ethaselen and 5-fluorouracil
(5-FU) against various cancer cell lines. Among these compounds, compounds 3b and 3c displayed highly
Received 20 October 2015
Revised 29 December 2015
Accepted 8 January 2016
Available online xxxx
Keywords:
effective biological activities against SMMC-7721cells with IC50 values of 6.02 and 6.01 lM, respectively.
1,2,4-Triazole derivatives
Benzisoselenazolone
Ebselen
Compound 3n showed significant antiproliferative activities against Hela cells with IC50 value of 3.94
Compound 3n exhibited the best inhibitory effect against A549 cells with IC50 value 9.14
l
l
M.
M.
Furthermore, most of the tested compounds showed weak cytotoxic effect against the normal cell lines
L929. The pharmacological results suggest that the substituent groups are vital for improving the potency
and selectivity of this class of compounds.
Ethaselen
Antiproliferative activity
Ó 2016 Published by Elsevier Ltd.
Cancer is considered to be second most common cause of
deaths after cardiovascular diseases in the world. Despite signifi-
cant progress has been achieved in anticancer therapy, the man-
agement of malignancies in humans still constitutes one of the
most intractable worldwide health problems.1 Therefore, it is
important to identify effective drugs and new targets for the treat-
ment of cancer. Thioredoxin (Trx), thioredoxin reductase (TrxR)
and nicotinamide adenine dinucleotide phosphate (NADPH) com-
prise a thioredoxin system that is involved in many aspects of
tumor physiology such as proliferation, apoptosis and metastasis,
and has become a novel attractive target for development of new
cancer therapeutics.2–7 Recently, reports of selenium-containing
heterocyclic compounds have gradually increased because of their
pharmaceutical applications, and have become hot spots in the
studies of tumor prevention and therapy.8–10 Among them, func-
tionalized benzisoselenazolone moieties are present in many phar-
macologically active substances. The prominent examples are
ebselen [2-phenyl-1,2-benziso-selenazol-3(2H)-one, Fig. 1] and
reductase (TrxR), ethaselen has been reported to exhibit broad
spectrum of antitumor effects with slight toxicity, and has now
entered Phase I clinical trails in China.4–6
1,2,4-Triazole is
a versatile lead molecule for designing
potential bioactive agent, and its derivatives are associated with
many types of biological properties, including antioxidant,15,16
antimicrobial,17,18 anti-inflammatory,19,20 antifungal,21,22 anticon-
vulsant,23,24 and anti-thymidine phosphorylase effects.25 In partic-
ular, compounds bearing 1,2,4-triazole moieties have enhanced
considerable attention for the past few decades due to their
anticancer value.26–33
In view of these facts, we report herein the synthesis of 1,2,4-
triazole derivatives incorporating benzisoselenazolone scaffold
with ebselen as a lead compound. Meanwhile, their in vitro
antiproliferative activities were evaluated against three types of
human cancer cell lines, including human liver cancer cell
(SMMC-7721), human cervix adenocarcinoma cell (Hela), human
lung cancer cell (A549), and mouse fibroblast cell (L929) with the
ultimate aim of developing novel potent antitumor agents.
In this study, fourteen 1,2,4-triazole derivatives incorporating
benzisoselenazolone scaffold 3a–3n were synthesized and
reported for the first time.
ethaselen
[1,2-(bis-1,2-benzisoselenazol-3(2H)-one)ethane,
Fig. 1], which possess potent antioxidant, anti-inflammatory, anti-
cancer and cholinesterase inhibitory activities.4,11–14 Particularly,
as
a novel organoselenium compound targeting thioredoxin
As depicted in Scheme 1, the reaction of commercially available
3-amino-5-mercapto-1,2,4-triazole 1 with appropriate alkyl halide
in the presence of NaOH or K2CO3 in water and ethanol under
⇑
Corresponding author. Tel.: +86 22 60214259; fax: +86 22 60214252.
E-mail address: chenbaoquan66@126.com (B.-Q. Chen).
http://dx.doi.org/10.1016/j.bmcl.2016.01.017
0960-894X/Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Li, B.-L.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.01.017

2
B.-L. Li et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 1
O
O
N
In vitro antiproliferative activities of compounds 3a–3n against various cell lines
Se
N
Se
(CH2)2 N
a
Compound
IC50 (lM)
Se
SMMC-7721
Hela
A549
L929
O
Ethaselen
Ebselen
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
10.01
6.02
6.01
14.14
30.44
34.64
32.91
34.91
30.28
35.94
>50
>50
40.89
6.13
42.62
34.76
3.94
15.86
17.21
39.61
45.52
36.64
12.49
37.77
21.14
20.31
>50
36.37
42.05
9.72
12.37
>50
35.16
31.80
37.09
30.43
33.40
33.52
39.27
>50
O
N
HN
N
16.77
35.02
31.41
22.42
32.01
46.08
33.85
36.23
9.04
>50
8.91
10.68
5.62
SR
N
Se
Target compound 3
Figure 1. Structures of ebselen, ethaselen and target compounds.
>50
39.50
15.63
>50
>50
7.43
reflux condition yielded the desired intermediates 2a–2n in 68–
76% yields. The preparation of 2-chloroselenobenzoyl chloride
was carried out by reported literature method.4,14 Finally, the tar-
get compounds 3a–3n were successfully obtained via the conden-
sation of intermediates 2a–2n and 2-chloroselenobenzoyl chloride
in dry acetonitrile at room temperature. All newly synthesized
compounds 3a–3n were purified by silica gel column chromatog-
raphy and their structures were characterized by IR, 1H NMR, High
Resolution-Electrospray Ionization-Mass Spectrometer (HR-ESI-
MS) and elemental analysis (see Supplementary data).
9.14
3.26
8.13
Ethaselenb
5-FUb
>50
2.98
a
The concentration that causes a 50% cell proliferation inhibition.
Used as positive control.
b
potency than ethaselen and 5-fluorouracil. Especially noteworthy
is compound 3n, showed significant antiproliferative activities
The antiproliferative activities of the newly synthesized com-
pounds 3a–3n were tested against the human cancer cell lines
SMMC-7721, Hela, A549, and normal cell lines L929 using CCK-8
[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disul-
fophenyl)-2H-tetrazolium monosodium salt] assay (see Supple-
mentary data). Inhibition of cell proliferation by these active
compounds at various concentrations were measured, and their
IC50 (the concentration that causes a 50% cell proliferation inhibi-
tion) values were calculated and summarized in Table 1. Ethaselen
and 5-fluorouracil (5-FU) were used as positive controls.
As shown in Table 1, all compounds 3a–3n showed weaker
antiproliferative activities than positive control 5-fluorouracil
against SMMC-7721 cells, and the majority of them displayed
lower antitumor activities than ethaselen. It was interesting to
note that the shorter alkyl chains substituted derivatives, including
3a, 3b and 3c exhibited better activities than the longer alkyl
chains substituted derivatives, including 3d, 3e, 3f and 3g. Espe-
cially, ethyl and n-propyl substituted derivatives 3b and 3c, dis-
played highly effective biological activities with IC50 values of
with IC50 value of 3.94 lM. These results indicated that the influ-
ence of the sort and position of substituents on antitumor activity
against Hela cells is complex and unexplained at present. In A549
cells, most of the compounds 3a–3n exhibited antiproliferation
with different degrees, and compound 3n bearing 4-nitro sub-
stituent at the phenyl ring, exhibited the best inhibitory effect with
IC50 value of 9.14 lM. But all compounds showed lower antiprolif-
erative effects than positive controls ethaselen and 5-fluorouracil.
In L929 cells, most of the compounds 3a–3n exhibited weak cyto-
toxic activity, and all compounds showed highly lower cytotoxic
effect than 5-fluorouracil. Therefore, it is necessary that the further
investigation is carried out through structural transformation for
improving the potency and selectivity of this class of compounds.
In summary, a series of novel 1,2,4-triazole derivatives incorpo-
rating benzisoselenazolone scaffold were designed, synthesized
and evaluated for their in vitro antiproliferative activities human
cancer cell lines SMMC-7721, Hela, A549, and normal cell lines
L929 by CCK-8 assay. Some of the compounds inhibited the prolif-
eration better than positive controls ethaselen and 5-fluorouracil.
In particular, compounds 3b and 3c displayed highly effective bio-
logical activities against SMMC-7721 cells with IC50 values of 6.02
6.02 and 6.01 lM, respectively, and the activity was superior to
ethaselen. In addition, a similar effect was observed for compound
3n possessing 4-nitro substituent at the phenyl ring, with IC50
value of 8.91 lM. But, the electronic effects of substituents at the
phenyl ring on antitumor activity did not show apparent regular-
ity. In Hela cells, most of the tested compounds 3a–3n showed
weaker antiproliferative activities than positive controls ethaselen
and 5-fluorouracil. But, compounds 3k and 3n possessing 2-methyl
and 4-nitro substituents at the phenyl ring, displayed much better
and 6.01
antiproliferative activities against Hela cells with IC50 value of
3.94 M. Compound 3n exhibited the best inhibitory effect against
A549 cells with IC50 value 9.14 M. Furthermore, most of the
tested compounds showed weak cytotoxic effect against the nor-
mal cell lines L929. Therefore, the results will be significant in
the development of potent antitumor agents.
lM, respectively. Compound 3n showed significant
l
l
O
HN
N
HN
N
HN N
b
a
N
Se
SR
N
H2N
SH
H2N
SR
N
N
2a-2n
3a-3n
1
R= C2H5- (3a); n-C3H7- (3b); i-C3H7- (3c); n-C4H9- (3d); i-C4H9- (3e); n-C5H11- (3f); n-C6H13
(3g); C6H5CH2- (3h); 4-F-C6H4CH2- (3i); 4-Cl-C6H4CH2- (3j); 2-CH3-C6H4CH2- (3k);
3l
-
3-CH3-C6H4CH2- ( ); 4-CH -C H CH - (3m); 4-NO -C H CH - (
3n
)
3
6
4
2
2
6
4
2
Scheme 1. Synthesis of the target compounds 3a–3n. Reagents and conditions: (a) alkyl halide/NaOH or K2CO3/H2O/ethanol, reflux, 1–2h; (b) 2-chloroselenobenzoyl
chloride/CH3CN, rt, 6–10 h.
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Please cite this article in press as: Li, B.-L.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.01.017