Synthesis and bioactivity evaluation of 2,3-diaryl acrylonitrile derivatives as potential anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2016.11.025

Thirty novel derivatives of 2,3-diaryl acrylonitrile were synthesized and evaluated for biological activity. Preliminary investigations of antitumor activity in vitro showed that most of the synthesized compounds have significant antiproliferative effects

Full text of DOI:10.1016/j.bmcl.2016.11.025

Accepted Manuscript
Synthesis and bioactivity evaluation of 2,3-diaryl acrylonitrile derivatives as
potential anticancer agents
Jun Ma, Jiajun Li, Yu-Shun Tian
PII:
S0960-894X(16)31167-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.11.025
BMCL 24420
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
20 August 2016
9 October 2016
11 November 2016
Please cite this article as: Ma, J., Li, J., Tian, Y-S., Synthesis and bioactivity evaluation of 2,3-diaryl acrylonitrile
derivatives as potential anticancer agents, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/
1
0.1016/j.bmcl.2016.11.025
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Graphical Abstract
Thirty novel derivatives of 2,3-diaryl acrylonitrile were synthesized using TMSCN and TBAF, and evaluated for biological
activity. Preliminary investigations of antitumor activity in vitro showed that most of the synthesized compounds have
significant antiproliferative effects on human cancer cell lines, such as BEL-7402, HeLa, and HCT116 with IC50 values in the
range of 0.13–60.23 μM without significant toxic effects on the non-cancerous human liver cell line L-02. In particular,
compounds 4d and 4p were found to be the most potent against HeLa (4.20 μM) and HCT116 cells (0.13 μM), respectively,
with superior or similar in vitro efficacy to that of the broad-spectrum anticancer drug taxol.
Synthesis and bioactivity evaluation of 2,3-
diaryl acrylonitrile derivatives as potential
anticancer agents
Leave this area blank for abstract info.
Jun Ma, Jiajun Li, Yu-Shun Tian*
1

Bioorganic & Medicinal Chemistry Letters
Synthesis and bioactivity evaluation of 2,3-diaryl acrylonitrile derivatives as
potential anticancer agents
Jun Ma, Jiajun Li, Yu-Shun Tian*
Yanbian University, College of Pharmacy, Yanji City, Jinlin Province 133002, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Thirty novel derivatives of 2,3-diaryl acrylonitrile were synthesized and evaluated for biological
activity. Preliminary investigations of antitumor activity in vitro showed that most of the
synthesized compounds have significant antiproliferative effects on human cancer cell lines,
such as BEL-7402, HeLa, and HCT116 with IC50 values in the range of 0.13–60.23 μM without
significant toxic effects on the non-cancerous human liver cell line L-02. In particular,
compounds 4d and 4p were found to be the most potent against HeLa (4.20 μM) and HCT116
cells (0.13 μM), respectively, with superior or similar in vitro efficacy to that of the broad-
spectrum anticancer drug taxol.
Keywords:
2
,3-Diaryl acrylonitrile
Cyano group
Antitumor activity
Selective inhibition
Migration
1
necessary to obtain
a more stable structure. (Z)-3,5,4'-
Cancer is a common disease that poses a serious threat to
human health. Hundreds of thousands of people die of cancer
trimethoxystilbene, an O-methylated form of resveratrol (Fig. 1)
1
has been shown to have a significantly stronger antiproliferative
9
every year. Despite the availability of a variety of anticancer
agents, such as cisplatin, no currently available agents can
entirely eradicate cancer cells without also having toxic effects
on patients’ noncancerous, healthy tissues. Therefore, the
development of new anticancer agents that enable more selective
treatment strategies is very important.
effect on Caco-2 colon cancer cells than resveratrol. Treatment
with 0.3 μM (Z)-3,5,4'-trimethoxystilbene resulted in an 80%
reduction in Caco-2 cell growth compared with treatment with
the trans-3,5,4'-trimethoxystilbene, indicating a 100-fold stronger
9
antiproliferative effect.
Resveratrol, (E)-3,5,4'-trihydroxystilbene (Fig. 1), a polyphe-
nolic stilbene that is naturally present in medicinal plants, grape
skins, and red wine has been extensively investigated as an anti-
2,3
aging, anti-inflammatory and cardioprotective agent. Data from
a large number of studies have shown that resveratrol has potent
anticancer effects. These effects are evidenced by the in vitro and
in vivo inhibitory effects of resveratrol on the growth of a number
of tumor cell lines including those derived from colorectal, liver,
4
breast, pancreatic, and prostate tumors. Resveratrol has also
been demonstrated to sensitize resistant tumor cell lines to a
variety of chemotherapeutic agents, such as thalidomide or
Fig. 1. The molecular structures of resveratrol and (Z)-3,5,4'-
trimethoxystilbene.
5
6
bortezomib. Jang, et al reported that resveratrol inhibits the
initiation, promotion, and development of cancer, suggesting that
resveratrol is a natural chemopreventive agent. In addition to this
effect, resveratrol has been reported to have other diverse effects
on signaling pathways, such as the activation of pro-apoptotic
mechanisms and induction of cell-cycle arrest. However,
resveratrol is unstable and easily oxidized owing to the presence
of three phenolic hydroxyl groups. Thus, methylation, or other
chemical modification of these three hydroxyl groups is
A cyano, or nitrile, group consists of a carbon and nitrogen
atom joined by a triple bond. This structure confers a high level
of polarity and electron-withdrawing properties, with a volume
10
that is substantially smaller than that of a methyl group. These
characteristics enable a cyano group to bind with the key amino
acid residues of the active site of various enzymes by forming
hydrogen bonds. Introducing a cyano group to small molecule
drugs can alter the physical and chemical properties of the
7
8
1,11
agent, resulting in enhanced interactions between the drug and
the target protein, improved efficacy as an antiproliferative
1
12
Corresponding author: Tel.: +864332436028
agent, and increased metabolic stability of the compound in vivo
Fax: +864332435026
E-mail address: tyshhanguo@hanmail.net (Y.-S. Tian)
Present address: 977Gongyuan Road, Yanji, Jilin province, P.R. China.
13
owing to inhibition of metabolic enzymes. Cyano-containing
drugs applied in the clinic include the dipeptidyl peptidase IV
2

1
4
inhibitor saxagliptin, the phosphodiesterase-3 inhibitor, heart
level of antiproliferative activity than that of DDP in three
different cancer cell lines and 16 compounds had selective toxic
effects on cancer cells, with fewer toxic effects on the non-
cancerous human liver cell line L-02. Against HCT116 and BEL-
1
5
failure inhibitory drug milrinone, and the calcium channel
antagonist verapamil, which are indicated for a variety of
different clinical conditions.
1
0
7
402 cell lines, the inhibitory activity of approximately half of
Nitrile substitution enables the generation of a 2,3-diaryl
acrylonitrile agent that is amenable to further structural
modifications for medicinal chemistry purposes. On the basis of
these results, we were interested in designing and synthesizing a
number of novel compounds bearing resveratrol and cyano
moieties (Scheme 1).
compounds 4a–4z and 5a–5d was >50% of the antiproliferative
effects. However, only six of these compounds such as 4d and 4p
had >50% inhibitory potency against HeLa cells. Importantly, the
activity of 4d and 4p against HeLa cells was superior to that of
taxol (IC50=12.95 μM); the IC50 values were 4.2 and 7.77 μM,
respectively. Interestingly, except compounds 4j, 5c and 5d, the
other 27 compounds had less than 50% antiproliferative activity
against the human normal cell line L-02 (Table S1). In general,
para-dimethyl amino derivatives were selectively active against
cancer cells, and the methyl and methoxy derivatives were vital
for conferring selective antiproliferative effects. Several of these
derivatives had IC50 values suggesting an excellent level of
1
6
selectivity, such as para-N(CH
μM), para-CH (4n) against BEL-7402 (0.59 μM), para-CH
4o) against BEL-7402 (0.35 μM), and para-OCH CH
3
)
2
(4m) against HCT116 (0.59
CH
(4p)
3
2
3
(
2
3
against HCT116 (0.13 μM). Several of these agents obtained a
selectivity index (SI) >50, indicating that the agents are
considered the good candidate drugs (Table 1 and 2). In
particular, compound 4p demonstrated an SI value >769 in
HCT116 cells relative to L-02 cells, suggesting that 4p has
potential as a treatment for colon cancer, with a low risk of
cytotoxic effects on liver cells. However, when 2,3-diaryl
acrylonitrile derivatives are conjugated with carbon chains of
more than two carbon atoms for methyl derivatives (data not
shown) and more than three carbon atoms for methoxy
derivatives (4r-4u), this resulted in a loss of antiproliferative
activity. The meta-alkoxyl (4v, 4w and 4z), ortho-alkoxyl (4u
and 4z), and ortho-alkyl (4y) substituents showed very low
inhibitory activities, which were far worse than those of the
corresponding para structures of the compound. Although
compounds of the para-methyl group (4n) and the para-methoxy
group (4p) had very strong in vitro antitumor activity, the level of
activity of these compounds decreased substantially with the
introduction of more than one methyl group or one methoxy
group, with the exception of methyl or methoxy group in the para
position (4y and 4z). This difference might be the result of a
steric effect. In general, halogen-containing activities of para-
position (4c, 4d and 4e) and ortho-position (4f, 4g and 4h)
substituted halogen-containing compounds were stronger than
those of meta-substituted (4k and 4l) compounds. Most of the
derivatives of halogen substituents of the benzene ring (4c–4h, 4j)
or B ring (Scheme 1) were modified to aromatic heterocycles
(5a–5d), and had potent antitumor effects, with fewer toxic
effects on L-02 cells, although the SI values of these compounds
were not as high as those of several of the halogen substituents.
These results indicate that several of the synthesized series of
2,3-diaryl acrylonitrile derivatives have more specific
antiproliferative effects on cancer cell lines, with fewer toxic
effects on a L-02 human normal cell line compared with
resveratrol. Several compounds with strong activity and SI values
indicating a promising level of selectivity for cancer cells,
relative to the L-02 cell line, are listed in Table 2. To further
confirm whether these have any antibacterial activity, we have
investigated the antibacterial effects of these compounds against
several Gram-positive (Staphylococcus aureus RN4220 and
Streptococcus mutans 3289) and Gram-negative (Escherichia
coli KCTC1924 and Pseudomonas aeruginosa 2742) strains of
bacteria. The detailed processes are described in supplementary
data. The results indicated that none of these derivatives have any
notable activity against either Gram-positive or Gram-negative
bacteria, even at 64 µg/mL.
Scheme 1. Reagents and conditions: (I): (CH
reflux, 4 h; LiAlH4, THF, 0°C-rt, 4-6 h; CH Cl
CH
aldehydes, 4-6 h.
3
)
2
SO
4
, (CH
3
)
2
CO, K
2
CO
(II):
ONa, aromatic
3
,
2
2
, PBr
3
, 0°C-rt, 3-6 h
;
3
CN, TMSCN, TBAF, reflux, 4-6 h; (III): CH
3
OH, CH
3
In this research, we synthesized a series of novel derivatives of
,3-diaryl acrylonitrile using a unusual method that avoids the
2
use of sodium cyanide or potassium cyanide, which are both
17
highly toxic. Briefly, TMSCN (trimethylsilyl cyanide) and
TBAF (tetrabutylammonium fluoride) were used in the process of
synthesizing
3
from
2
(Scheme 1), which is more
environmentally friendly, and safer than the use of sodium or
potassium cyanide. The concise synthetic route used to
synthesize the title compounds is outlined in Scheme 1. The
detailed synthetic method and information on the structural and
physiochemical characteristics of the compounds can be found in
the supplementary material. Owing to the existence of a cyano-
steric effect, the final structure was fixed to the cis-isomer,
confirmed by NOE (nuclear overhauser effect) (supplementary
data). The trans-isomer structure of resveratrol is more stable and
18,19
has more useful properties than the cis-isomer,
therefore,
trans-resveratrol was used as the reference compound. The
synthesis of trans-resveratrol is presented in supplementary
material. All compounds were evaluated for their in vitro
antitumor activities against a panel of human tumor cell lines and
normal human liver cells (L-02) using an MTT (methylthiazolyl
diphenyl-tetrazolium bromide) assay, with taxol and cisplatin
(DDP) as the reference agents. The panel consisted of human
colorectal cancer (HCT116), human cervical cancer (HeLa) and
human liver cancer (BEL-7402) cells. The antiproliferative
potency of the various 2,3-diaryl acrylonitrile derivatives against
these four human cell lines is shown in Fig. 2. On the basis of
data from a preliminary MTT assay, the IC50 values of a range of
2,3-diaryl acrylonitrile derivatives against the four cell lines were
further investigated. The substituent structures, cytotoxicity (IC50
and selectivity index are listed in Table 1 and, for more detailed
inhibition rates, see Table S1.
)
As shown in Fig. 2, 100 μM of resveratrol had a significant
antiproliferative effect on HCT116, BEL-7402 and L-02 cells.
These data indicate that resveratrol has limited tumor selectivity
and that this agent might be more toxic to L-02 non-cancerous
normal cells. To explore the structure-activity relationships (SAR)
resulting in more potent and selective antiproliferative effects, we
substituted various groups on the benzene ring with a variety of
different moieties, such as halogens, methyl groups, methoxy
groups, and amines. The most of tested compounds had a higher
3

Fig. 2. Antiproliferative potency (%) of 4a–4z and 5a–5d against three human cancer cell lines (HCT116, BEL-7402, and HeLa) and human non-cancerous liver
cells (L-02) at 100 μM. Resveratrol abrreviated as res.
Table 1. Cytotoxic effects in vitro of 4a–4z and 5a–5d on HCT116, BEL-7402, HeLa and L-02 cells, including selectivity index values relative to effects on L-
0
2 cells.
a
b
IC50 (μM)
SI
SI
Agent
R
HCT116
>100
>100
43.31±0.64
11.37±1.85
21.82±2.68
12.21±0.83
8.64±1.05
8.44±1.52
>100
HeLa
BEL-7402
>100
>100
8.04±1.89
>100
27.61±4.07
72.59±1.08
28.47±6.47
>100
L-02
>100
>100
HCT116
BEL7402
4
4
4
4
4
a
b
c
H
4-F
>100
>100
15.87±0.68
4.20±0.23
>100
4-Cl
4-Br
4-CF3
2-F
2-Cl
2-Br
>100
>2.31
>8.79
>4.58
>8.19
>11.57
>11.84
>12.43
d
e
>100
>100
>3.62
>1.38
>3.51
4
f
>100
28.20±1.74
>100
>100
>100
>100
4
4
g
h
4
i
j
2-CF
3-F
3
>100
>100
>100
61.30±9.22
>100
>100
95.98±0.65
>100
4
37.96±3.49
>100
>2.63
>1.63
4
k
3-Br
>100
4
l
3-CF
3
>100
>100
>100
>100
4
m
4-N(CH
3
)
2
0.59±0.29
2.00±0.08
1.30±0.22
0.13±0.06
14.15±2.32
>100
>100
1.74±0.38
0.59±0.12
0.35±0.08
0.66±0.12
41.98±5.36
>100
>100
>169.49
>50
>76.92
>769.23
>7.06
>57.47
>169.49
>285.71
>151.52
>2.38
4
n
o
p
q
4-CH
4-CH CH
4-OCH
3
>100
>100
>100
>100
4
2
3
4
4
2
CH
3
7.77±0.43
>100
>100
>100
>100
>100
4-O(CH
4-O(CH
2
)
2
)
2
CH
CH
3
3
4
4
4
r
s
t
3
4-OCH
4-OBn
2-O(CH CH
3-OCH
3-OCH CH
2-Cl, 6-F
2
CH(CH
3
)
2
>100
>100
>100
>100
>100
>100
>100
>100
4
4
u
v
2
)
2
3
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
3
4
w
2
3
3
4
x
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
4
y
2,4,6-CH
3,4,5-OCH
X=S
3
4
z
5
5
a
b
31.61±4.38
3.31±0.02
20.45±1.81
5.15±1.78
62.61±3.75
>100
111.59±16.39
>100
56.04±6.74
120.27±24.01
36.66±6.56
75.72±12.65
26.43±8.62
80.47±7.44
139.03±6.10
>100
>100
>3.16
>30.21
3.59
14.66
1.57
>2.73
>1.32
2.78
0.94
0.71
X=O
5
5
c
Naphthalene-1-yl
Pyridine-2-yl
73.58±10.09
75.53±3.15
98.60±21.11
d
Res
Taxol
DDP
<0.1
>200
12.95±0.47
<0.1
>200
>100
>200
>1000
>1000
>200
IC50 is the concentration of compound that inhibit 50% of the cell growth.
a
SI : selectivity index IC50 (L02) / IC50 (HCT116)
b
SI : selectivity index IC50 (L02) / IC50 (BEL-7402)
Taxol and DDP were used as the positive reference drugs.
4

Table 2. Selectivity index values of compounds relative to effects on L-02
had excellent anti-proliferative effects, which were significantly
greater than those of taxol (Table 1 and 2). To determine whether
the suppression of cancer cell growth using 4d or 4p was a result
of inhibition of cell cycle progression, a cellular proliferation
assay involving propidium iodide staining was used to quantify
the percentages of HeLa cells at different stages of the cell cycle.
Percentages of cells at each stage were quantified using flow
cytometric analysis. The extent of cell cycle inhibition in cells
treated with taxol, resveratrol or vehicle (control) were
determined under the same conditions (Fig. 4). The detailed
experimental method can be found in the supplementary material.
As shown in Fig. 4, compounds 4d and 4p effectively inhibited
HeLa cellular proliferation, resulting in accumulation of cells at
cells.
Compd
IC50(L02)/ IC50 (HCT116)
>8.79
IC50(L02)/IC50 (HeLa)
IC50(L02)/IC50(BEL7402)
-
4
d
>23.81
4
m
>169.49
>50
>76.92
>769.23
1.57
-
-
-
>57.47
>169.49
>285.71
>151.52
0.71
4
n
o
p
4
4
>12.87
0.82
>7.72
Res
Taxol
>1000
>1000
-: not suitable for calculation.
the G
/M phase increased from 7.12% under control conditions to
9.87% and 51.63% in the presence of 4d or 4p, respectively, an
effect very similar to that of the reference drug taxol. A decrease
in the percentage of cells in the G /G phase was observed from
1.71% under control conditions to 0.7% in the presence of 4d or
p, respectively. Under control conditions, the cellular
2
/M stage of the cell cycle. The percentage of cells in the
G
2
6
0
1
6
4
population in the S-phase of the cell cycle was 31.26%, which
was changed to 30.13% and 47.64% by 4d and 4p, respectively.
These distributions were quite different from those observed in
the resveratrol treatment group. Compared with the control
group, the percentage of cells in the G
by treatment with resveratrol, but the percentage of cells in the S-
phase and G /M phases were both decreased by resveratrol. From
these results, the mechanisms of inhibition of HeLa cell
proliferation by compound 4d and 4p appear similar to those of
the anticancer agent taxol, but both have a notably different effect
compared with that of resveratrol. Hence, 4d and 4p induced a
0 1
/G phase was increased
Fig. 3. Compound 4d inhibits the migration of HeLa cells. HeLa cells
were treated with either 4d (1 μM), taxol (1 μM), resveratrol (50 μM), or
2
0
.1% DMSO (vehicle).
Proliferation of tumor cells is closely related to tumor-cell
20
migration. We investigated compound 4d, which has the most
potent antiproliferative effects on HeLa cells, as verified using an
MTT assay (Table 1). The effects of compound 4d on HeLa cell
migration were investigated using a wound-scratch assay.
Closure of the wound, under control conditions, could typically
be observed after 24 hours (Fig. 3). Treatment with 50 μM
resveratrol resulted in complete healing after 24 hours of
treatment. Compared with these results, when treated with
compound 4d (1 μM) no wound healing was observed after 24
hours, and a similar finding was observed with use of taxol in
this assay.
2
marked arrest of the cell cycle at the G /M phase and subsequent
cell death. Then, in order to determine whether cancer cell
apoptosis affects cell proliferation as well as cell cycle
progression, the apoptosis assay was carried out (Fig. S1). The
results shows that when treatment with taxol, the early apoptotic
cells were increased slightly, but there were no any changes by
4d and 4p compared with the control group. The results indicated
that apoptosis does not play an important role in the inhibition of
HeLa cell proliferation by the both compounds, maybe cell cycle
22
progression and apoptosis are two separable functions in this
conditions.
The cell-cycle involves a series of events, resulting in cell
division, duplication, and proliferation. Compounds 4d and 4p
Fig. 4. Cell-cycle analysis using flow cytometry in HeLa cells. (A, B, C) Treatment with 4d, 4p and taxol at 0.1 μM for 24 h. (D) Treatment with resveratrol at
5
0 μM for 24 h. (E) Treated with 0.1% DMSO for 24 h as vehicle.
In summary, a novel series of 2,3-diaryl acrylonitrile
derivatives were designed and synthesized using a safer, and
the HCT116 cell line relative to that observed in L-02 cells
is >769, which suggests that this agent has potential as a
treatment for colon cancer, with a low risk of hepatotoxic adverse
effects. In this research, the antiproliferative effects of 4d and 4p
on HeLa cells were stronger than taxol. Further investigation
revealed that the anti-proliferative effects of 4d and 4p are a
21
more effective method than those widely used elsewhere,
which typically involve the use of highly toxic agents such as
17
sodium cyanide or potassium cyanide. Preliminary SAR
analyses indicated the requirement of a cyano-group and
modification of the R group on the benzene ring or modification
of the B ring to an aromatic heterocyclic form of the parent 2,3-
diaryl acrylonitrile to achieve satisfactory, selective antitumor
activity (Scheme 1, B). The selective inhibitory activity of 4p on
2
result of cell-cycle arrest at the G /M phase (Fig. 4) and
antitumor activity of 4d was also shown through suppression of
HeLa cell migration (Fig. 3). Further investigations are required
to identify the cell cycle proteins that are modulated, and thus the
5

mechanism of action of 4d and 4p. The potential effects of these
agents include promoting the accumulation of cell cycle
activation related cyclins such as cyclins A, E, and D, or the
inhibition or downregulation of cyclin-dependent kinase
inhibitors such as p21 and p27. These data suggest that the 2,3-
diaryl acrylonitrile structure can be used as a lead structure for
further optimization to find more specific, potent and safe
antitumor agents.
7. Kotha, A; Sekharam, M.; Cilenti, L.; Siddiquee, K.; Khaled, A.; Zervos, A.
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Supplementary data
(synthetic
procedures,
structural
3
086.
characterization and biological experiments) associated with this
article can be found in the online version at supplementary
data.csv.
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99.
6

Highlights





Thirty of 2,3-diaryl acrylonitrile derivatives were
synthesized by an unusual method.
Most of the derivatives showed selective inhibitory
activity in human cancer cells.
The anti-proliferative effects of 4d and 4p on HeLa cells
were stronger than taxol.
The antitumor effects of 4d and 4p are a result of cell-
2
cycle arrest at G /M phase.
The antitumor activity of 4d was also through
suppression of HeLa cell migration.
8

Table 1. Cytotoxic effects in vitro of 4a–4z and 5a–5d on HCT116,
BEL-7402, HeLa and L-02 cells, including selectivity index values
relative to effects on L-02 cells.
IC50 is the
a
b
IC50 (μM)
SI
SI
concentrati
on of
Agent
4a
R
H
HCT116
>100
HeLa
BEL-7402
>100
L-02
>100
HCT116
BEL7402
compound
that inhibit
>100
4
4
4
b
4-F
>100
>100
>100
>100
5
0% of the
c
4-Cl
4-Br
4-CF3
2-F
43.31±0.64
11.37±1.85
21.82±2.68
12.21±0.83
8.64±1.05
8.44±1.52
>100
15.87±0.68
4.20±0.23
>100
8.04±1.89
>100
>100
>2.31
>8.79
>4.58
>8.19
>11.57
>11.84
>12.43
cell
d
>100
growth.
a
4e
4f
27.61±4.07
72.59±1.08
28.47±6.47
>100
>100
>3.62
>1.38
>3.51
SI :
selectivity
index IC50
>100
>100
4g
2-Cl
2-Br
28.20±1.74
>100
>100
(
L02) / IC50
4
h
>100
(
HCT116)
b
4
i
2-CF
3-F
3
>100
>100
>100
SI :
4
j
37.96±3.49
>100
>100
61.30±9.22
>100
95.98±0.65
>100
>2.63
>1.63
selectivity
index IC50
4
k
3-Br
>100
(
L02) / IC50
4l
4m
3-CF
3
>100
>100
>100
>100
(BEL-7402)
4-N(CH3)2
0.59±0.29
2.00±0.08
1.30±0.22
0.13±0.06
14.15±2.32
>100
>100
1.74±0.38
0.59±0.12
0.35±0.08
0.66±0.12
41.98±5.36
>100
>100
>169.49
>50
>57.47
>169.49
>285.71
Taxol and
DDP were
used as the
positive
reference
drugs.
4
n
4-CH
4-CH CH
4-OCH CH
3
>100
>100
4o
2
3
>100
>100
>76.92
4p
4q
4r
2
3
7.77±0.43
>100
>100
>769.23 >151.52
4-O(CH
4-O(CH
2
)
2
CH
CH
3
>100
>7.06
>2.38
2
)
3
3
>100
>100
4
s
t
4-OCH
2
CH(CH
3
)
2
>100
>100
>100
>100
4
4-OBn
>100
>100
>100
>100
4
u
v
2-O(CH
2
)
2
CH
3
>100
>100
>100
>100
4
3-OCH
3
>100
>100
>100
>100
4
w
3-OCH
2
CH
3
>100
>100
>100
>100
4
x
y
z
2-Cl, 6-F
>100
>100
>100
>100
4
2,4,6-CH
3,4,5-OCH
X=S
3
>100
>100
>100
>100
4
5
5
5
5
3
>100
>100
>100
>100
a
b
c
31.61±4.38
3.31±0.02
>100
36.66±6.56
75.72±12.65
26.43±8.62
80.47±7.44
>100
>3.16
>30.21
3.59
>2.73
>1.32
2.78
X=O
111.59±16.39
>100
>100
Naphthalene-1-yl 20.45±1.81
Pyridine-2-yl 5.15±1.78
73.58±10.09
75.53±3.15
d
56.04±6.74
14.66
1.57
0.94
0.71
Res
62.61±3.75 120.27±24.01
139.03±6.10 98.60±21.11
Taxo
l
<0.1
12.95±0.47
<0.1
>100
>1000
>1000
DDP
>200
>200
>200
>200
9

Table 2. Selectivity index values of compounds relative to effects on L-02
cells.
Compd
4d
IC50(L02)/ IC50 (HCT116)
>8.79
IC50(L02)/IC50 (HeLa)
IC50(L02)/IC50(BEL7402)
-
-
: not suitable
for
>23.81
calculation.
4m
>169.49
>50
>76.92
>769.23
1.57
-
-
-
>57.47
>169.49
>285.71
>151.52
0.71
4n
4o
4p
>12.87
0.82
>7.72
Res
Taxol
>1000
>1000
10