Cytotoxicity and DNA binding property of triphenylethylene-coumarin hybrids with two amino side chains

Article abstract of DOI:10.1016/j.bmcl.2013.12.084

Novel triphenylethylene-coumarin hybrids containing two amino side chains were designed and synthesized. Some of these 3,4-diphenyl coumarins, 7b-c (the double chains at 4-position on 3-,4-phenyl, respectively), and 13b-f (the double chains at 4-position on 3-phenyl and 7-position, respectively), showed a broad-spectrum and good anti-proliferative activity against five tumor cells and low cytotoxicity in osteoblast. UV-vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that compounds 7b (R = piperidinyl), 7e (R = NEt₂), and 7f (R = 4-methylpiperazinyl) had significant interactions with Ct-DNA by the intercalative mode of binding. Structure activity relationships (SARs) analysis suggested that the location of the two amino alkyl chains would play an important role both in the compounds against tumor cells proliferation and their interactions with DNA.

Full text of DOI:10.1016/j.bmcl.2013.12.084

Bioorganic & Medicinal Chemistry Letters 24 (2014) 900–904
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Cytotoxicity and DNA binding property of triphenylethylene–
coumarin hybrids with two amino side chains
⇑
⇑
Lian Zhao, Yuchao Yao, Shuai Li, Mengjiao Lv, Hua Chen , Xiaoliu Li
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel triphenylethylene–coumarin hybrids containing two amino side chains were designed and synthe-
sized. Some of these 3,4-diphenyl coumarins, 7b–c (the double chains at 4-position on 3-,4-phenyl,
respectively), and 13b–f (the double chains at 4-position on 3-phenyl and 7-position, respectively),
showed a broad-spectrum and good anti-proliferative activity against five tumor cells and low cytotox-
icity in osteoblast. UV–vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denatur-
ation exhibited that compounds 7b (R = piperidinyl), 7e (R = NEt2), and 7f (R = 4-methylpiperazinyl) had
significant interactions with Ct-DNA by the intercalative mode of binding. Structure activity relationships
(SARs) analysis suggested that the location of the two amino alkyl chains would play an important role
both in the compounds against tumor cells proliferation and their interactions with DNA.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 4 September 2013
Revised 18 December 2013
Accepted 19 December 2013
Available online 27 December 2013
Keywords:
Coumarin
Triphenylethylene
Anti-tumor activity
DNA binding property
Basic side chain
Coumarins are a wide group of naturally occurring compounds
and have a variety of biological activities such as anti-cancer, anti-
HIV, antimicrobial, and anti-inflammatory.1 They represent a sig-
nificant source of inspiration for the new drugs discovery.2 As
the anti-tumor agents, they can act on the cancer formation by
interfering with the cellular proliferation.1a,b,3 They can block cell
cycle,4 induce cell apoptosis,5 modulate estrogen receptor (ER),6
or inhibit the DNA-associated enzymes, such as topoisomerase or
gryase.7 Due to their potential applications in cancer therapy,
extensive studies have been carried out on the design and synthe-
sis of coumarin derivatives with improved anticancer activity.8
Among them, coupling coumarin with different bioactive mole-
cules is one of the effective ways. Adopting this approach, chal-
cone- pyrazole-, and stilbene-commarin hybrids (compounds A,
B, C in Fig. 1)2,8a,c have exhibited significant anti-tumor activities.
Recently,9 we have also found that triphenylethylene-coumarin
hybrids (compound D in Fig. 1) containing indispensable two ami-
no (except morpholinyl) side chains showed a broad-spectrum and
excellent anti-tumor activity possibly by acting on DNA via the
intercalative mode. The positions of the side chains were randomly
chosen and the amount of them had important impact on both
their anti-tumor activity and DNA binding property. So far only
the 3,4-diphenyl coumarin SP500263, a structural resemblance to
the triphenylethylene–coumarin hybrids, was studied as the new
selective estrogen receptor (SERM).6 In order to shed more light
on the structure–activity relationships (SARs) and demonstrate
how the positions of the two side chains affect their anti-proliferative
activity, we herein report the design and synthesis of the novel
triphenylethylene–coumarin hybrids with two amino side chains
at different positions based on our previous helpful results.9 The
interactions of the compounds with Ct-DNA were also tested by
UV–vis, fluorescence, and circular dichroism (CD) spectroscopies
and thermal denaturation experiment.
Since the compounds containing three amino side chains at
4-position on 3-,4-phenyl and 7-position, respectively, had been
explored to exhibit weak anti-tumor activity but strong DNA
CH3
O
O
O
CH3
O
N
N
O
O
CH3
O
O
H3C
CH3
B
A
R
H3C
CH3
O
O
N
N
R=
O
N
O
O
C
O
R
H3CO
D
⇑
Corresponding authors. Tel./fax: +86 312 5971116.
E-mail addresses: hua-todd@163.com (H. Chen), lixl@hbu.cn (X. Li).
Figure 1. The hybrid derivatives of coumarin.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.084

L. Zhao et al. / Bioorg. Med. Chem. Lett. 24 (2014) 900–904
901
OMe
O
OMe
COOH
OH
(a)
(d)
(b)
OAc
+
OH
OMe
3
2
1
O
O
4
R
OMe
OH
O
O
(c)
OH
OH
O
(e)
R
O
O
O
6
O
O
7a-f
5
R=
N
N
N
N
N
N
O
N
a
b
c
d
e
f
Scheme 1. Synthesis of compounds 7a–f. Reagents and conditions: (a) POCl3, ZnCl2, 65 °C, 2.5 h, 45%; (b) 4-hydroxyphenylacetic acid, Ac2O, K2CO3, 130 °C, 5 h, 50%; (c) 3 N
HCl, ethanol, reflux, 2 h, 85%; (d) BBr3, CH2Cl2, ice bath, 1 h, 80%; (e) ClCH2CH2R, dry acetone, K2CO3, KI, 65 °C, 8 h, 21–73%.
Table 1
COOH
O
OH
OH
Cytotoxicity of compounds against the cancer cell lines
OAc
(a)
(b)
+
Compds
IC50 (lM)
OH
10
HO
9
Hela
A549
K562
MCF-7
8
O
11
O
AcO
7a
>100a
>100
>100
>100
7b
7c
7d
7e
4.36 0.46
8.25 0.94
>100
45.24 6.62
60.52 8.65
>100
5.08 0.56
4.70 0.44
8.49 0.75
9.58 1.72
3.68 0.39
10.82 1.01
7.28 0.84
8.79 1.17
>100
46.31 5.01
55.61 7.34
>100
5.21 0.62
7.35 0.58
9.13 0.82
8.97 0.98
4.70 0.73
9.21 1.22
5.44 0.51
7.54 1.99
99.56 9.48
56.25 12.49
53.25 9.40
>100
4.90 0.22
5.46 0.88
7.19 1.01
2.73 0.55
3.23 0.38
8.00 0.71
4.29 0.30
16.65 1.22
71.59 12.48
50.13 4.70
78.33 26.40
>100
6.53 0.59
6.63 0.54
6.99 0.42
5.95 0.60
3.47 0.51
7.93 0.67
OH
(d)
O
(c)
R
7f
O
13a-f
O
O
12
O
R
HO
N
O
13a
13b
13c
13d
13e
13f
Cisplatin
R=
N
O
N
N
N
N
N
a
b
c
d
e
f
Scheme 2. Synthesis of compounds 13a–13f. Reagents and conditions: (a) POCl3,
ZnCl2, 65 °C, 3 h, 30%; (b) 4-hydroxyphenylacetic acid, Ac2O, K2CO3, 135 °C, 5 h,
67%; (c) 3 N HCl, ethanol, reflux, 2 h, 96%; (d) ClCH2CH2R, dry acetone, K2CO3, KI,
65 °C, 8 h, 22–71%.
a
No activity.
carcinoma), A549 (human lung cancer), K562 (chronic myeloid leu-
kemia), and MCF-7 (human breast cancer). Cisplatin was used as
positive controls. As shown in Table 1, compounds 13b–f and
7b–c exhibited significant anti-proliferative activity against four
cancer cells at IC50 of near 10 lM, and better than the positive con-
trol except 7c against MCF-7. It seemed that these compounds
binding property,9 except for the reported two positions in com-
pound D (Fig. 1), the corresponding other two positions of the
chains were chosen for this study (compound 7 in Scheme 1 and
13 in Scheme 2).
Synthesis of the 3,4-diphenyl coumarins (7a–f) containing two
amino alkyl chains at 4-position on 3-,4-phenyl, respectively, was
achieved according to the previous procedures6,9 as outlined in
Scheme 1. Briefly, commercially available 2-hydroxybenzoic acid
(1) reacted with anisole (2) to yield the benzophenone (3) under
Fries reaction condition. The treatment of 3 with 4-hydroxyphenyl
acetic acid mainly gave the acylated 3,4-diaryl coumarin derivative
(4) via Perkin reaction route. The deprotection of acetyl group was
performed in 3 N HCl to achieve 5, and then methyl group was re-
moved in BBr3 solution to obtain 6. The SN2 nucleophilic substitu-
tions of 6 with a variety of 2-chloroethanamine provided the final
products (7a–f). Following the same procedures, the target prod-
ucts (13a–f) containing two amino alkyl chains at 4-position on
3-phenyl and 7-position, respectively, were synthesized by using
1,2-benzenediol and benzoic acid as the starting materials
(Scheme 2).
exhibited a broad-spectrum anti-proliferative activity. Compounds
Table 2
Cytotoxicity of compounds 7b–c and 13b–c towards osteoblasta
Compds
% Cell cytotoxicity
20 40
1
lM
10
lM
l
M
l
M
100 lM
7b
7c
À3.2 2.2b 1.6 2.1*
10.6 0.9* 22.3 0.6* 40.3 0.2***
0.1 2.4*
À6.5 3.1
À2.5 2.8
À0.6 3.1
À7.2 2.9
À0.5 2.9
8.4 1.1
20.4 1.5* 39.5 0.4**
18.6 0.5* 33.4 0.7**
16.4 0.7* 32.8 0.6*
13b
13c
13d
13e
13f
3.7 1.1
4.9 1.3*
À5.6 2.4* 5.2 0.8**
À0.2 3.4
4.3 1.7
13.8 1.5
31.5 0.3*
À1.5 1.2* 3.7 1.4
15.8 0.9* 31.7 0.6**
14.6 0.8* 31.6 0.4**
À2.4 2.2* 0.6 1.9
3.2 0.8*
a
Primary cultured osteoblasts (separated from newborn mice skull) were treated
with active coumarin compounds at varying concentrations for 48 h and induced
cell death was measured with MTT assay.
The structures of all the newly compounds were determined by
NMR, MS, and elemental analysis. Both analytical and spectral data
of compounds are in agreement with the proposed structures.
Compounds 7a–f and 13a–f were subjected to anti-proliferative
tests against the following cancer cell lines, Hela (cervical
b
The data presented are means SEM and six replicates were performed.
*
p < 0.05.
p < 0.01.
**
***
p < 0.001 with respect to the untreated cells.

902
L. Zhao et al. / Bioorg. Med. Chem. Lett. 24 (2014) 900–904
Table 3
7e–f showed weak anti-tumor activities and 7d showed no
activity. Compounds 7a and 13a (R = morpholinyl) didn’t express
anti-proliferative activity, which was similar with the previous
observation5 that the weaker basic amino group on the side chain,
for example the morpholinyl, demonstrated a detrimental effect on
the anti-proliferative activity. It should be mentioned that com-
pounds 6 and 12 without the amino side chains also showed no
anti-proliferative effects on K562 and MCF-7 (not listed), which
further reflected the importance of the two amino side chains.10
Compounds 13d–f were more active than 7d–f implied that the
farther location of the two side chains was favor to the anti-tumor
activities of such compounds. In addition, the anti-proliferative
activities of compounds 7b–c were more superior to those of 7d–
f suggested that the basic amino group had certain effects on their
activity when the two side chains were close to each other.
The active compounds 7b–c and 13b–f were further evaluated
for possible cytotoxicity in normal cell, for example, osteoblast (Ta-
ble 2). It could be found that all the tested compounds did not sig-
nificantly affect the growth of osteoblasts, suggesting that these
molecules had selectivity for inducing growth inhibition of tumor
cells. The results suggested that these coumarins might be suitable
as potential drug candidate for cancer chemotherapy.
Photometric properties of the coumarin derivatives 7b, 7e, 7f, 13b, 13e, and 13f with
Ct-DNA investigated by UV–vis spectra and binding constants (K) by fluorescence
spectra
Compds
Hypsochromic shift (nm)
Hyperchromicitya (%)
Kb (MÀ1
)
7b
7e
7f
13b
13e
13f
2.5 (324.5À322)
4.5 (318À313.5)
5.0 (323À318)
0.5 (335À334.5)
0.5 (334.5À334)
1.0 (339À338)
16
17
17
6
8
8
1.2 Â 104
1.0 Â 104
1.4 Â 104
7.0 Â 103
6.0 Â 103
5.2 Â 103
a
Obtained at kmax
.
shown in Figure 2 and Table 3, the absorption intensities of com-
pounds 7b, 7e, and 7f enhanced with increased Ct-DNA concentra-
tions in high hyperchromities of 16%, 16% and 17%, respectively,
while the intensities of compounds 13b, 13e, and 13f increased
in middle hyperchromities of 6%, 8% and 8%, respectively. The max-
imum absorption (kmax) of the tested coumarin derivatives 7b, 7e,
and 7f showed obviously blue shift (2.5–5.0 nm) and 13b, 13e, and
13f had little hypsochromic shift (0.5–1.0 nm) in the presence of
increasing concentration of Ct-DNA. These results demonstrated
that the 3,4-diphenyl coumarin derivatives 7b, 7e, and 7f contain-
ing two amino alkyl chains at 4-position on 3-, 4-phenyl, respec-
tively, had stronger binding capacity with DNA than 13b, 13e,
and 13f containing the two chains at 4-position on 3-phenyl and
7-position, respectively. This suggested that the closer the distance
of the two side chains was, the stronger the DNA binding
In order to evaluate the interactions with DNA, UV–vis, fluores-
cence, and CD spectroscopies and DNA thermal denaturation
experiment were used to ascertain the DNA binding properties of
compounds 7b, 7e, 7f, 13b, 13e, and 13f with calf thymus (Ct) DNA.
The DNA binding properties of compounds 7b, 7e, 7f, 13b, 13e,
and 13f with Ct-DNA were investigated by UV–vis spectra in phos-
phate buffer (10 mM, pH 7.4) containing 50 mM NaCl at 25 °C. As
1500
1000
500
0
1500
1000
500
0
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350 400 450 500 550 600
Wavelength/nm
350 400 450 500 550 600
Wavelength/nm
330 360 390 420
Wavelength/nm
330 360 390 420
Wavelength/nm
7e
7b
7b
7e
1000
500
0
4000
3000
2000
1000
0
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0.20
0.16
0.12
0.08
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0.02
0.00
ꢀꢁꢃꢅꢂ
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Concentration of Ct-DNA
Concentration of Ct-DNA
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350 400 450 500 550 600
Wavelength/nm
350 400 450 500 550 600
Wavelength/nm
330
360
390
420
330 360 390 420
Wavelenth/nm
Wavelength/nm
13b
7f
7f
13b
3000
2000
1000
0
3000
2000
1000
0
0.18
0.15
0.12
0.09
0.06
0.03
0.00
0.18
0.15
0.12
0.09
0.06
0.03
0.00
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Wavelength/nm
13e
350 400 450 500 550 600
Wavelength/nm
330 360 390 420
Wavelength/nm
330 360 390 420
Wavelength/nm
13e
13f
13f
Figure 3. Fluorescence spectral changes of 7b (kex = 324.5 nm), 7e (kex = 318 nm),
7f (kex = 323 nm), 13b (kex = 335 nm), 13e (kex = 334.5 nm), and 13f (kex = 339 nm)
Figure 2. UV–vis spectral changes of compounds 7b, 7e, 7f, 13b, 13e, and 13f at the
at the concentration of 5.0 Â 10À5 M upon addition of Ct-DNA (0–200
lM) in
concentration of 1.0 Â 10À5 M upon addition of Ct-DNA (0 –200
l
M) in phosphate
phosphate buffer (10 mM, pH 7.4) containing 50 mM NaCl and 2% DMSO at 25 °C.
Both excitation and emission slit widths were 10.0 nm. Inset: Stern–Volmer plots
for the observed fluorescence enhancement upon addition of Ct-DNA to the
coumarin derivatives.
buffer (10 mM, pH 7.4) containing 50 mM NaCl and 2% DMSO at 25 °C. Inset: the
fitting plots for 7b, 7e, 7f, 13b, 13e, and 13f with Ct-DNA obtained at the maximum
absorption.

L. Zhao et al. / Bioorg. Med. Chem. Lett. 24 (2014) 900–904
903
properties of such compounds had. Additional, the observed spec-
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Ct-DNA
Ct-DNA + 7b
Ct-DNA + 7e
Ct-DNA + 7f
Ct-DNA + 13b
Ct-DNA + 13e
Ct-DNA + 13f
tral changes (significant blue shift and hypsochromism) in com-
pounds 7b, 7e, and 7f implied that they would insert into the
base pairs of DNA as DNA-intercalating agents,11 while 13b, 13e,
and 13f (little blue shift and middle hypsochromism) possibly
acted in a same binding mode with DNA.12
The fluorescence properties were performed to investigate the
interactions between compounds 7b, 7e, 7f, 13b, 13e, and 13f
and Ct-DNA in phosphate buffer (10 mM, pH 7.4) containing
50 mM NaCl at 25 °C. As shown in Figure 3, all compounds showed
similar binding properties with Ct-DNA around 455 nm in the fluo-
rescence spectra. Upon addition of DNA, fluorescence intensities
increased markedly, possibly due to the coplanar modulation of
the conformation of 3- and 4-phenyl groups induced by Ct-
DNA.13 The maximum emission bands were blue shifted which im-
plied that these compounds entered Ct-DNA-stacking region with
lower polarity than the buffer solution,14 and intercalated into
the bases of the Ct-DNA.13a The observed fluorescence intensities
were quantified by plotting F/F0 as a function of Ct-DNA concentra-
tions, where F0 and F are the fluorescence intensity without and
with Ct-DNA, respectively. Stern–Volmer analysis gave deep in-
sight into the binding efficiency of fluorescence enhancement of
the coumarins with increasing concentrations of Ct-DNA.13a The
55 60 65 70 75 80 85
o
Temperature ( C)
Figure 5. DNA melting curves for Ct-DNA (5.0 Â 10À5 M) in the absence and
presence of 7b, 7e, 7f, 13b, 13e, and 13f with concentration of 5.0 Â 10À6 M in
phosphate buffer (1 mM, pH 7.4) containing 5 mM NaCl and 2% DMSO at 25 °C.
Table 4
Average Tm and
and 13f
DTm for Ct-DNA in the absence and presence of 7b, 7e, 7f, 13b, 13e,
Compds
Tm (°C)
D
Tm (°C)
Ct-DNA
7b
7e
67.0
70.0
71.5
71.0
68.2
68.8
69.2
0
3.0
4.5
4.0
1.2
1.7
2.2
7f
13b
13e
13f
calculated binding efficiency (Table 3) were 1.2 Â 104 MÀ1
,
1.0 Â 104 MÀ1, and 1.4 Â 104 MÀ1 for compounds 7b, 7e, and 7f,
and 7.0 Â 103 MÀ1, 6.0 Â 103 MÀ1, and 5.2 Â 103 MÀ1 for com-
pounds 13b, 13e, and 13f (Fig. 3, inset), respectively.15 The
Stern–Volmer plots indicate that the fluorescence of compounds
7b, 7e, and 7f possessing two amino side chains at 4-position on
3-, 4-phenyl, respectively, is higher sensitive to the Ct-DNA con-
centrations than those of 13b, 13e, and 13f. These results are con-
sistent with the observations by UV, that is, the closer distance of
the two side chains is of benefit to improving the DNA binding
capacity of these coumarins.
triphenylethylene–coumarin hybrid derivatives (350–500 nm),
which indicated that 7b, 7e, 7f, 13b, 13e, and 13f intercalated
DNA with a vertical orientation in the intercalation pocket.18
It is well known that the temperature at which a half of a DNA
sample melts is known as the melting temperature (Tm). A change
of Tm may be observed if a molecule binds with DNA.19 Thus the
thermal behavior of DNA in the presence of the triphenylethy-
lene–coumarin hybrid derivatives provides useful information on
the conformational changes and the strength of the DNA-
compound complexes. The melting curves of Ct-DNA in the ab-
sence and presence of 7b, 7e, 7f, 13b, 13e, and 13f are illustrated
in Figure 5 and Table 4, respectively. The Tm value for the free
Ct-DNA was 67.0 °C. Upon addition of 7b, 7e, and 7f, obvious
changes in the DNA melting temperature were observed. The Tm
values increased to 70.0, 71.5 and 71.0 °C, respectively, and the
CD is a useful technique to investigate the conformational
changes in DNA morphology during small molecules-DNA interac-
tions. As shown in Figure 4, the CD spectrum of free Ct-DNA
showed a negative band at 246 nm due to the polynucleotide helic-
ity, and a positive band at 277 nm due to the base staking, which
indicated that the Ct-DNA existed in the right-band B form.16 Upon
addition of all the tested compounds, the intensity of the positive
band at 277 nm increased obviously, while the intensity of the neg-
ative band at 246 nm decreased (without significant wavelength
change). This observation implied that these compounds could
intercalate DNA and induce a B to A conformational change on
Ct-DNA.17 The order of the intensity change of 7b, 7e, and 7f
(strong intercalation) >13b, 13e, and 13f (poor intercalation),
which was in agreement with the UV–vis analysis. Additional, very
weak positive induced circular dichroisms (ICD) signals were
observed in the region of the characteristic absorption of these
levels of the increased melting temperature (DTm) induced by
DNA-compound interactions were 3.0, 4.5 and 4.0 °C, respectively.
Compounds 13b, 13e, and 13f possessed lower DNA melting tem-
perature than 7b, 7e, and 7f, and the
DTm values were 1.2, 1.7, and
2.0 °C, respectively. These results further illuminated that com-
pounds 7b, 7e, and 7f with various amino alkyl chains at 4-position
on 3-,4-phenyl, respectively, exhibited strong affinities with Ct-
DNA, consistent with the results from the fluorescence data.
Considering all the above results, we could conclude that the
novel triphenylethylene-coumarin hybrid derivatives with two
amino side chains possessed the intercalative mode of binding
properties with DNA, such as 7b, 7e, 7f, 13b, 13e, and 13f. When
the two chains locate at 4-position on 3-,4-phenyl, respectively,
like 7b, 7e, and 7f, the intercalative binding is more efficient pos-
sibly due to the different noncovalent force between the chains
and DNA grooves.20 The similar binding constants of 7b, 7e, and
7f indicated that the basic amino group (except morpholinyl) had
little effects on their interactions with DNA, although they affected
their anti-tumor activities. These compounds possessed potential
application as novel DNA staining agent. Furthermore, it should
be noticed that the anti-tumor activity of such coumarins did not
tie in very closely with the observed DNA binding, for example
7e, 7f and 13e, 13f. That is, compounds 7e and 7f with low
8
6
4
2
Ct-DNA
Ct-DNA + 7b
Ct-DNA + 7e
Ct-DNA + 7f
Ct-DNA + 13b
Ct-DNA + 13e
Ct-DNA + 13f
0
-2
1.0
0.5
0.0
-4
-6
-0.5
-1.0
360
400
440
480
Wavelength/nm
-8
240
280
320
360
Wavelength/nm
Figure 4. CD spectra of Ct-DNA (5.0 Â 10À5 M) in the absence and presence of 7b,
7e, 7f, 13b, 13e, and 13f (2.0 Â 10À5 M) in phosphate buffer (10 mM, pH 7.4)
containing 50 mM NaCl and 2% DMSO at 25 °C.

904
L. Zhao et al. / Bioorg. Med. Chem. Lett. 24 (2014) 900–904
Rasal, V. P.; Patel, H.; Mutha, S. S.; Mohite, A. A. Eur. J. Med. Chem. 2010, 45,
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Q. J. Med. Chem. 2010, 53, 8252; (f) Farag, N. A. H.; El-Tayeb, W. Eur. J. Med.
Chem. 2010, 45, 317.
anti-tumor activities intercalate into DNA more strongly than com-
pounds 13e and 13f with good anti-proliferative effects. It was dif-
ficult to exactly explain this discrepancy. In the absence of any
other evidence, we hypothesized that the possibility can not be ex-
cluded that these compounds may be targeting one or more other
bio-macromolecular,21 such as DNA topoisomerase or ER (estrogen
receptor). These additional binding forces might also contribute to
the compounds’ anti-proliferative efficacy.22 Therefore, DNA might
be one of the potential targets but not the only one or not the most
pivotal target for such triphenylethylene–coumarin hybrids as
anti-tumor drug candidates. This and other possible targets remain
to be explored in subsequent studies.
In summary, a series of novel triphenylethylene–coumarin hy-
brids possessing two amino side chains were designed and synthe-
sized based on the triphenylethylene template. Compounds 13b–f
and 7b–c showed a broad-spectrum and excellent anti-tumor
activity and low cytotoxicity in osteoblast, which suggested that
they might be suitable as potential drug candidate for cancer che-
motherapy. The structure–activity relationships (SARs) suggested
that the positions of the two amino alkyl chains had profound ef-
fects on their anti-proliferative activities and DNA binding
properties.
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This work was supported by the 973 Program (2010CB534913)
and the National Natural Science Foundation of China (NSFC)
(20902016).
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Supplementary data
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Supplementary data (experimental procedures and character-
ization data for compounds 7a–f and 13a–f) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.bmcl.2013.12.084.
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