Synthesis, antiproliferative, and antiplatelet activities of oxime-containing 3,4-dihydroquinolin-2(1H)-one derivatives

Article abstract of DOI:10.1002/jccs.201000197

Some oxime-containing 3,4-dihydroquinolin-2(1H)-one derivatives were synthesized and evaluated for their antiplatelet and antiproliferative activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with NH

Full text of DOI:10.1002/jccs.201000197

Journal of the Chinese Chemical Society, 2010, 57, 1331-1340
1331
Synthesis, Antiproliferative, and Antiplatelet Activities of
Oxime-containing 3,4-Dihydroquinolin-2(1H)-one Derivatives
Li-Chai Chena (
), I-Li Chenb (
), Chih-Chiang Huangb (
) and Tai-Chi Wangb* (
),
Chang-Hui Liaoc (
), Jhy-Yih Chenb* (
)
aPharmacy Division, ZuoYing Armed Forces General Hospital, Kaohsiung, Taiwan, R.O.C.
bDepartment of Pharmacy, Tajen University, Pingtung 907, Taiwan, R.O.C.
cGraduate Institute of Natural Products, Chang-Gung University, Tao-Yuan 333, Taiwan, R.O.C.
Some oxime-containing 3,4-dihydroquinolin-2(1H)-one derivatives were synthesized and evaluated
for their antiplatelet and antiproliferative activities. These compounds were synthesized via alkylation of
hydroxyl precursors followed by the reaction with NH2OH. The preliminary assays indicated that (Z)-7-
[2-(4-fluorophenyl)-2-(hydroxyimino)ethoxy]-3,4-dihydroquinolin-2(1H)-one (13c) is the most active
against U46619 induced platelet aggregation with an IC50 value of 3.51 mM. For the inhibition of AA-in-
duced aggregation, (E)-6-[2-(hydroxyimino)propoxy]-3,4-dihydroquinolin-2(1H)-one (15) is the most
potent with an IC50 value of 1.85 mM. These oxime-containing 3,4-dihydroquinolin-2(1H)-one deriva-
tives were inactive against thrombin induced platelet aggregation with an IC50 value of greater than 26.78
mM. For the antiproliferative activity, most of these oxime-containing 3,4-dihydroquinolin-2(1H)-one de-
rivatives were inactive while (Z)-7-[2-(hydroxyimino)-2-(naphthalen-2-yl)ethoxy]-3,4-dihydroquinolin-
2(1H)-one (13a) exhibited only marginal activities with GI50 value of 7.63, 7.34 and 6.36 mM against the
growth of NPC-TW01, NCI-H661, and Jurkat respectively.
Keywords: Dihydroquinolinones; Antiproliferative activity; Antiplatelet activity.
INTRODUCTION
Certain quinolin-2(1H)-one (carbostyril) derivatives
uated.20,21 Among them, compound 1 was the most active
against U46619 induced platelet aggregation with an IC50
of 0.56 mM. For the inhibition of AA induced aggregation,
compound 2 exhibited very high activities with an IC50 of
0.58 mM and was inactive against cancer cell prolifera-
tion.21 We have also synthesized certain 3,4-dihydroquino-
lin-2(1H)-one a-methylene-g-butyrolactones (7HQ deriv-
atives), saturated analogs of CCT-62, for pharmacological
evaluation. The results indicated that 7HQ derivatives ex-
ert an inhibitory action on the expression of inducible nitric
oxide synthase and cyclooxygenase-2 via the inhibition of
IkB degradation and NF-kB activation.22 The present re-
port describes the preparation and antiplatelet evaluation of
oxime-bearing 3,4-dihydroquinolin-2(1H)-ones which can
be considered as reduced derivatives of compounds 1 and 2
or as 7HQ derivatives in which the a-methylene-g-butyro-
lactone ring was replaced with an oxime moiety. Certain
quinolin-2(1H)-one derivatives were previously reported
to possess anticancer activity.21,23,24 Therefore, these newly
synthesized 3,4-dihydroquinolin-2(1H)-one derivatives
have been proved to possess antiplatelet, anti-inflamma-
tory, anti-ulcer, vasodilatory, and phosphodiesterase inhib-
itory activities.1-12 The cardiovascular and neuroprotec-
tive activities of certain 3,4-dihydroquinolin-2(1H)-ones
substituted with various side chains have also been re-
ported.2,7,10,11,13 Recently, we have synthesized and evalu-
ated the cardiovascular activities of certain a-methylene-
g-butyrolactones bearing heterocycles such as coumarins,
flavones, xanthones, quinolines, and quinolin-2(1H)-
ones.14-18 Among these heterocycles, quinolin-2(1H)-ones
proved to be the most active against platelet aggregation.
One of the most potent antiplatelet agents, CCT-62, has
been proved to be an inhibitor of phosphodiesterases, and
its antiplatelet effect is mainly mediated by elevation of cy-
clic-AMP levels.19 In the continuation of our search for
more potent antiplatelet agents, a number of CCT-62 deriv-
atives in which the a-methylene-g-butyrolactone ring was
replaced with an oxime moiety were synthesized and eval-
* Corresponding author. Tel: +886-8-7624004 ext. 2833; Fax: +886-8-762-5308; E-mail: tcwang@mail.tajen.edu.tw

1332 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Chen et al.
have also been evaluated in vitro against NPC-TW01
(nasopharygeal cancer), NCI-H661 and A549 (lung can-
cers), MKN45 (gastric cancer), and Jurkat (leukemia) since
these cancers are very popular in Asia including Taiwan.
Through structural modification, we expect to identify po-
tential antiplatelet agents that are devoid of antiprolifera-
tive activity or potential anticancer agents that are devoid
of antiplatelet activity.
ditions gave 6-[2-(naphthalen-2-yl)-2-oxoethoxy]-3,4-di-
hydroquinolin-2(1H)-one (6a), which was then treated
with NH2OH to afford exclusively (Z)-6-[2-(hydroxyimi-
no)-2-(naphthalen-2-yl)ethoxy]-3,4-dihydroquinolin-
2(1H)-one (12a) in a good overall yield. The same syn-
thetic procedure was applied for the synthesis of (Z)-12b-e
from their respective ketone precursor 6b-e.12 Accordingly,
(Z)-13a-e and (Z)-14a-e were prepared from 7a-e and
8a-e,12 respectively. The configuration of the oxime moiety
was confirmed by the 13C-NMR spectra. For the Z-isomer,
the 1’-CH2 group is syn to the oxime OH group, which
shifted the signal upfield to approximately 60.00 ppm.25
Treatment of 3 with 2-bromoacetone under basic condi-
tions gave 6-(2-oxopropoxy)-3,4-dihydroquinolin-2(1H)-
one (9)12 which was then reacted with NH2OH to give ex-
clusively (E)-6-[2-(hydroxyimino)propoxy]-3,4-dihydro-
quinolin-2(1H)-one (15). Accordingly, (E)-16 and (E)-17
were prepared from 10 and 11,12 respectively. The configu-
ration of the oxime moiety was again confirmed by the
13C-NMR spectra. For the E-isomer, the 1’-CH2 group is
anti to the oxime OH group, which shifted the signal down-
field to approximately 70.00 ppm.25
O
O
O
O
O
O
N
H
O
R
N
H
O
7HQ
CCT-62
OH
OH
N
N
O
O
R
R
N
H
O
N
H
O
1: R = Ph
2: R = 4-MeO-Ph
3,4-Dihydroquinolin-2(1H)-ones
RESULTS AND DISCUSSION
Synthesis
Biological activities
The preparation of oxime-containing 3,4-dihydro-
quinolin-2(1H)-one derivatives is illustrated in the Scheme
I. Alkylation of 6-hydroxy-3,4-dihydroquinolin-2(1H)-
one (3) with 2-(bromoacetyl)naphthalene under basic con-
1. Antiplatelet activity
The antiplatelet activities were evaluated in washed
rabbit platelets. Platelet aggregation was induced by throm-
Scheme I
6
(i)
(ii)
N
H
O
N
H
O
7
R
R
O
O
N
O
HO
8
H
N
O
12-14
OH
6-8
3-5
(i)
a: R = Naphthalen-2-yl
b: R = Ph
c: R = 4-F-Ph
(ii)
N
O
Me
HO
N
O
Me
O
O
H
H
d: R = 4-MeO-Ph
e: R = 4-Ph-Ph
N
O
15-17
9-11
3,6,9,12,15: 6-substituted
4,7,10,13,16: 7-substituted
5,8,11,14,17: 8-substituted
Reagents and conditions: (i) RCOCH2Br, K2CO3; (ii) NH2OH

Antiplatelet 3,4-Dihydroquinolin-2(1H)-ones
J. Chin. Chem. Soc., Vol. 57, No. 6, 2010 1333
bin (Thr, 0.1 U/mL), arachidonic acid (AA, 200 mM), and
U46619 (thromboxan A2-like; 2 mM), respectively. The fi-
nal concentration of compounds was 100 mM and the re-
sults are shown in Table 1. For the C-6 substituted 3,4-di-
hydroquinolin-2(1H)-one derivatives, 12b-12d and 15
were capable of inhibiting thrombin, AA, and U46619 in-
duced platelet aggregations completely at a concentration
of 100 mM while at the same concentration, 12a and 12e
were able to completely inhibit AA-induced aggregation
but were inactive against thrombin and U46619 induced
platelet aggregations. These results indicated that a less
bulky substituent such as methyl, phenyl, 4-fluorophenyl,
or 4-methoxyphenyl group is favorable for broad spectrum
antiplatelet activities while a more bulky substituent such
as naphthyl or biphenyl group is favorable for the selective
antiplatelet activity. For the C-7 substituted 3,4-dihydro-
quinolin-2(1H)-one derivatives, compounds 13b-13d pos-
sessed broad antiplatelet activities while 13a and 16 were
active against AA-induced aggregation only. The naphthyl
derivative 13e was inactive. For the C-8 substituted 3,4-di-
hydroquinolin-2(1H)-one derivatives, compounds 14a-14c
and 14e were active against AA-induced aggregation while
14d and 17 were inactive. In general, most of the 3,4-dihy-
droquinolin-2(1H)-one derivatives exhibited strong inhibi-
tory activities against AA-induced aggregation, with few
exceptions, in which compound 13c was weekly active
while 13e, 14d, and 17 were inactive. Compounds 12b-d,
13b-d, 14c, and 15 were found to inhibit U46619-induced
aggregation completely at a concentration of 100 mM. The
effect on antiplatelet aggregation (IC50) of oxime-contain-
ing 3,4-dihydroquinolin-2(1H)-one derivatives are given
in Table 2. The thrombin-induced aggregation was the most
resistant with an IC50 value of greater than 26.78 mM in
each case while the AA-induced aggregation was the most
susceptible and the inhibitory activity decreased in an order
3,4-dihydroquinolin-2(1H)-one-6-yl > 3,4-dihydroquino-
Table 1. Effect of oxime-containing 3,4-dihydroquinolin-2(1H)-one derivatives at a concentration of 100 mM
on the platelet aggregation (%) induced by thrombin (Thr), arachidonic acid (AA), and U46619
Aryl
R
O
NOH
Substituents
Inducer
Compd.
Thr
AA
U46619
Aryl
R
(0.1 U/mL)
(200 mM)
(2 mM)
Control
12a
12b
12c
12d
12e
13a
13b
13c
13d
13e
14a
14b
14c
14d
14e
15
91.69 0.66
86.76 1.82a
89.15 0.88
4.81 1.97c
1.88 1.53c
89.53 0.45
87.65 0.42a
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-6-yl
Quinolinone-7-yl
Quinolinone-8-yl
Naph
Ph
0
0
0
0c
0c
0c
0
0
0
0c
0c
0c
4-F-C6H4
0
0
0
0
0
0c
0c
0c
0c
0c
4-MeO-C6H4
4-Ph-C6H4
Naph
87.94 0.98a
60.95 1.99c
89.53 0.45
85.95 2.24
Ph
0
0c
0
0
0
0c
0c
0c
4-F-C6H4
4-MeO-C6H4
4-Ph-C6H4
Naph
21.57 9.14c
22.02 0.63c
75.27 2.34c
89.04 1.30
89.50 1.00
86.94 1.34a
89.19 0.55a
87.37 1.57a
2.05 1.67c
87.60 0.36c
87.12 0.86b
91.70 1.40
17.34 2.75c
0c
82.92 1.21b
0c
0
82.07 1.70b
87.53 0.44a
87.68 1.22
0
Ph
2.11 0.92c
7.02 3.74c
83.97 0.84b
4.58 5.74c
1.83 0.75c
4-F-C6H4
4-MeO-C6H4
4-Ph-C6H4
Me
0
0c
86.19 1.03a
88.08 0.45
0c
0
16
Me
0
0c
83.14 1.11b
86.60 1.60
83.40 1.27c
88.80 1.50
17
Me
Aspirin
0
0
a Significantly different from control value at p < 0.05
b Significantly different from control value at p < 0.01
c Significantly different from control value at p < 0.001

1334 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Chen et al.
Table 2. IC50 values (mM) of oxime-containing 3,4-dihydroquinolin-2(1H)-one derivatives on the platelet
aggregation induced by thrombin (Thr), arachidonic acid (AA), and U46619
Aryl
R
O
NOH
Substituents
IC50
Compd.
Thr
AA
U46619
Aryl
R
(0.1 U/mL)
(200 mM)
(2 mM)
12a
12b
12c
12d
12e
13a
13b
13c
13d
13e
14a
14b
14c
14d
14e
15
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-6-yl
Quinolinone-7-yl
Quinolinone-8-yl
Naph
Ph
-
8.63 0.13
4.47 0.34
4.49 0.21
4.25 0.13
4.34 0.14
4.07 0.04
4.13 0.13
41.22 2.30
6.24 0.16
-
-
29.97 0.73
14.15 1.49
10.85 1.67
6.70 1.91
-
4-F-C6H4
26.78 0.88
4-MeO-C6H4
4-Ph-C6H4
Naph
28.35 0.56
-
-
-
Ph
29.88 0.63
11.35 1.13
3.51 0.21
9.22 2.42
4-F-C6H4
4-MeO-C6H4
4-Ph-C6H4
Naph
46.42 8.98
46.34 9.04
-
-
-
-
29.44 0.12
31.09 0.28
34.03 2.38
-
Ph
-
-
4-F-C6H4
4-MeO-C6H4
4-Ph-C6H4
Me
-
30.19 0.68
-
-
-
33.54 2.15
1.85 0.40
28.18 0.56
-
-
31.17 0.18
10.37 2.54
16
Me
-
-
-
-
17
Me
lin-2(1H)-one-7-yl > 3,4-dihydroquinolin-2(1H)-one-8-yl.
Among them, (E)-6-[2-(hydroxyimino)propoxy]-3,4-dihy-
droquinolin-2(1H)-one (15) was the most potent with an
IC50 value of 1.85 mM against the platelet aggregation in-
duced by AA.
droquinolin-2(1H)-one derivatives were inactive with an
GI50 value of greater than 10.67 mM in each case.
EXPERIMENTAL SECTION
1. General
2. Antiproliferative activity
Melting points were determined on a Electrothermal
IA9100 melting point apparatus and are uncorrected. Nu-
clear magnetic resonance (1H and 13C) spectra were re-
corded on a Varian-Unity-400 spectrometer. Chemical
shifts were expressed in parts per million (d) with tetra-
methylsilane (TMS) as an internal standard. Thin-layer
chromatography was performed on silica gel 60 F-254
plates purchased from E. Merck and Co. The elemental
analyses were performed in the Instrument Center of Na-
tional Science Council at National Cheng-Kung University
using Heraeus CHN-O Rapid EA, and all values are within
0.4% of the theoretical compositions.
All compounds were evaluated in vitro against a
5-cell line panel consisting of NPC-TW01, NCI-H661,
A549, MKN45, and Jurkat. Results from Table 3 indicated
that these compounds were either weekly active or inac-
tive. For the C-6 substituted 3,4-dihydroquinolin-2(1H)-
one derivatives, (Z)-6-[2-(hydroxyimino)-2-(naphthalen-
2-yl)ethoxy]-3,4-dihydroquinolin-2(1H)-one (12a) was
the most active against the growth of NPC-TW01 and
A549 with an GI50 value of 8.48 and 7.54 mM, respectively.
For the C-7 substituted 3,4-dihydroquinolin-2(1H)-one de-
rivatives, (Z)-7-[2-(hydroxyimino)-2-(naphthalen-2-yl)-
ethoxy]-3,4-dihydroquinolin-2(1H)-one (13a) was the
most active against the growth of NPC-TW01, NCI-H661,
MKN45, and Jurkat with an GI50 value of 7.63, 7.34, 9.40,
and 6.36 mM, respectively. The C-8 substituted 3,4-dihy-
2. Syntheses
6-[2-(Naphthalen-2-yl)-2-oxoethoxy]-3,4-dihydroquino-
lin-2(1H)-one (6a)
6-Hydroxy-3,4-dihydroquinolin-2(1H)-one (3, 0.82

Antiplatelet 3,4-Dihydroquinolin-2(1H)-ones
J. Chin. Chem. Soc., Vol. 57, No. 6, 2010 1335
Table 3. Antiproliferative activity of oxime-containing 3,4-dihydroquinolin-2(1H)-one derivatives
Aryl
R
O
NOH
Substituents
GI50 (mM)a,b
Compd.
Aryl
R
NPC-TW01 NCI-H661
A549
MKN45
Jurkat
12a
12b
12c
12d
12e
13a
13b
13c
13d
13e
14a
14b
14c
14d
14e
15
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-6-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-7-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-8-yl
Quinolinone-6-yl
Quinolinone-7-yl
Quinolinone-8-yl
Naph
Ph
8.48
25.92
24.24
23.19
8.12
16.14
25.92
24.24
23.19
8.12
7.54
19.14
22.85
20.33
17.63
11.56
17.04
17.45
28.45
9.47
14.65
11.80
19.39
11.49
11.65
9.40
18.14
28.34
31.74
27.40
24.70
6.36
4-F-C6H4
4-MeO-C6H4
4-Ph-C6H4
Naph
7.63
7.34
Ph
31.79
29.76
27.98
25.19
28.83
32.29
n.d
40.39
23.97
18.28
8.05
9.55
27.25
26.31
28.78
30.29
29.00
28.19
n.d.
4-F-C6H4
4-MeO-C6H4
4-Ph-C6H4
Naph
9.72
16.67
11.53
17.41
16.31
n.d.
30.86
24.25
n.d.
29.30
31.67
n.d.
Ph
4-F-C6H4
4-MeO-C6H4
4-Ph-C6H4
Me
30.41
27.83
33.03
32.08
34.93
21.19
21.30
25.17
8.27
33.53
31.48
28.34
25.09
36.68
10.67
18.78
20.34
13.86
22.21
27.72
22.72
29.88
24.51
31.73
16
Me
17
Me
35.28
a The concentration that inhibited the growth of 50% of cells (GI50) was determined from the linear portion of the
curve by calculating the concentration of agent that reduced absorbance in treated cells, compared to control cells,
by 50%.
b These cell lines are: NPC-TW01 (Nasopharygeal carcinoma); NCI-H661 and A549 (Lung carcinoma); MKN45
(Gastric cancer); Jurkat (Leukemia).
n.d: not determined.
g, 5 mmol), K2CO3 (0.75 g, 5.5 mmol), and dry DMF (50
mL) were stirred at r.t. for 30 min. To this soln. was added
2-(bromoacetyl)naphthalene (1.37 g, 5.5 mmol) in dry
DMF (10 mL) in one portion. The resulting mixture was
stirred at r.t. for 24 h (TLC monitoring) and then poured
into ice-water (100 mL). The white solid thus obtained was
collected and crystallized from Et2O to give 6a (1.50 g,
7-[2-(Naphthalen-2-yl)-2-oxoethoxy]-3,4-dihydroquino-
lin-2(1H)-one (7a)
From 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (4)
as described for 6a: 88% yield. Mp 184-185 °C. 1H-NMR
(DMSO-d6): 2.39-2.42 (m, 2H, H-C(3)), 2.81-2.85 (m, 2H,
H-C(4)), 5.63 (s, 2H, OCH2), 6.77 (d, 1H, J = 8.4 Hz, H-
C(5)), 6.81 (dd, 1H, J = 8.4, 2.4 Hz, H-C(6)), 6.89 (d, 1H, J
= 2.4 Hz, H-C(8)), 7.64-7.73 (m, 2H, arom. H), 7.99-8.06
(m, 3H, arom. H), 8.08-8.15 (m, 1H, arom. H), 8.76 (s, 1H,
arom. H), 9.92 (s, 1H, NH). 13C-NMR (DMSO): 25.76
(C(4)), 31.01 (C(3)), 71.20 (CH2O), 113.93, 114.88,
116.40, 124.01, 125.52, 127.80, 128.47, 129.13, 129.57,
130.26, 130.49, 132.42, 132.80, 135.97, 139.95, 153.88,
170.46 (C(2)), 195.36 (C=O). Anal. Calcd for C21H17NO3:
C, 76.12; H, 5.17; N, 4.23. Found: C, 75.83; H, 5.18; N,
4.12.
1
91%). Mp 194-195 °C. H-NMR (DMSO-d6): 2.40-2.43
(m, 2H, H-C(3)), 2.77-2.81 (m, 2H, H-C(4)), 5.64 (s, 2H,
OCH2), 6.49 (d, 1H, J = 2.4 Hz, H-C(5)), 6.57 (dd, 1H, J =
8.4, 2.4 Hz, H-C(7)), 7.06 (d, 1H, J = 8.4 Hz, H-C(8)),
7.64-7.73 (m, 2H, arom. H), 7.99-8.06 (m, 3H, arom. H),
8.08-8.15 (m, 1H, arom. H), 8.76 (s, 1H, arom. H), 9.96 (s,
1H, NH). 13C-NMR (DMSO): 24.68 (C(4)), 31.38 (C(3)),
70.92 (CH2O), 102.76, 108.18, 116.77, 123.98, 127.83,
128.47, 129.02, 129.16, 129.61, 130.26, 130.51, 132.36,
132.80, 135.99, 139.90, 157.90, 170.94 (C(2)), 195.24
(C=O). Anal. Calcd for C21H17NO3: C, 76.12; H, 5.17; N,
4.23. Found: C, 75.91; H, 5.21; N, 4.17.
8-[2-(Naphthalen-2-yl)-2-oxoethoxy]-3,4-dihydroquino-
lin-2(1H)-one (8a)
From 8-hydroxy-3,4-dihydroquinolin-2(1H)-one (5)

1336 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Chen et al.
as described for 6a: 85% yield. Mp 159-160 °C. 1H-NMR
(DMSO-d6): 2.47-2.51 (m, 2H, H-C(3)), 2.88-2.92 (m, 2H,
H-C(4)), 5.73 (s, 2H, OCH2), 6.82-6.91 (m, 3H, arom. H),
7.64-7.72 (m, 2H, arom. H), 7.96-8.05 (m, 3H, arom. H),
8.07-8.15 (m, 1H, arom. H), 8.78 (s, 1H, arom. H), 9.01 (s,
1H, NH). 13C-NMR (DMSO): 24.85 (C(4)), 30.45 (C(3)),
71.77 (CH2O), 112.04, 115.43, 120.63, 121.35, 122.11,
123.25, 125.99, 127.13, 127.78, 128.49, 128.96, 129.61,
130.03, 135.33, 139.56, 144.81, 169.59 (C(2)), 194.93
(C=O). Anal. Calcd for C21H17NO3: C, 76.12; H, 5.17; N,
4.23. Found: C, 75.85; H, 5.17; N, 4.14.
Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found:
C, 68.71; H, 5.40; N, 9.39.
(Z)-6-[2-(4-Fluorophenyl)-2-(hydroxyimino)ethoxy]-
3,4-dihydroquinolin-2(1H)-one (12c)
Yield: 73%; Mp 233-234 °C. 1H-NMR (DMSO-d6):
2.34-2.38 (m, 2H, H-C(3)), 2.76-2.79 (m, 2H, H-C(4)),
5.15 (s, 2H, OCH2), 6.68 (d, 1H, J = 8.0 Hz, H-C(8)), 6.73
(dd, 1H, J = 8.0, 2.0 Hz, H-C(7)), 6.78 (d, 1H, J = 2.0 Hz,
H-C(5)), 7.17-7.23 (m, 2H, arom. H), 7.63-7.68 (m, 2H,
arom. H), 9.90 (s, 1H, NH), 11.86 (s, 1H, NOH). 13C-NMR
(DMSO) d: 25.74 (C(4)), 30.96 (C(3)), 59.67 (CH2O),
113.43, 114.81, 115.80, 116.02, 116.41, 125.62, 129.19,
129.28, 131.47, 131.50, 132.90, 152.89, 153,65, 161.92,
164.36, 170.46 (C(2)). Anal. Calcd for C17H15FN2O3 · 0.25
H2O: C, 64.09; H, 4.91; N, 8.79. Found: C, 64.28; H, 4.93;
N, 8.74.
(Z)-6-[2-(Hydroxyimino)-2-(naphthalen-2-yl)ethoxy]-
3,4-dihydroquinolin-2(1H)-one (12a)
To a soln. of 6a (0.33 g, 1 mmol) in EtOH (20 mL)
was added a soln. of hydroxylamine hydrochloride (0.14 g,
2 mmol) in EtOH (2 mL). The mixture was heated at reflux
for 4 h (TLC monitoring) and evaporated to give a residual
solid. The white solid thus obtained was collected and puri-
fied by flash column chromatography (FC; silica gel;
CH2Cl2/AcOEt 2:1) and recrystallized from CH2Cl2 to give
12a (0.25 g, 72%). Mp 230-231 °C. 1H-NMR (DMSO-d6):
2.36-2.40 (m, 2H, H-C(3)), 2.78-2.81 (m, 2H, H-C(4)),
5.29 (s, 2H, OCH2), 6.74 (d, 1H, J = 8.4 Hz, H-C(8)), 6.77
(dd, 1H, J = 8.4, 2.4 Hz, H-C(7)), 6.84 (d, 1H, J = 2.4 Hz,
H-C(5)), 7.52-7.54 (m, 2H, arom. H), 7.84-7.86 (m, 1H,
arom. H), 7.89-7.96 (m, 3H, arom. H), 8.17 (m, 1H, arom. H),
9.91 (s, 1H, NH), 11.98 (s, 1H, NOH). 13C-NMR (DMSO):
25.73 (C(4)), 30.94 (C(3)), 59.50 (CH2O), 113.44, 114.84,
116.43, 124.40, 125.64, 126.72, 127.15, 127.35, 128.20,
128.42, 129.05, 132.51, 132.82, 133.34, 133,67, 153.59,
153.82, 170.53 (C(2)). Anal. Calcd for C21H18N2O3: C,
72.82; H, 5.24; N, 8.09. Found: C, 72.53; H, 5.23; N, 8.08.
The same procedure was applied to convert 7a to 13a;
8a to 14a; 6b-f to 12b-f; 7b-f to 13b-f; 8b-f to 14b-f; and
9-11 to 15-17, respectively.
(Z)-6-[2-(Hydroxyimino)-2-(4-methoxyphenyl)ethoxy]-
quinolin-2(1H)-one (12d)
Yield: 71%; Mp 214-215 °C. 1H-NMR (DMSO-d6):
2.34-2.38 (m, 2H, H-C(3)), 2.76-2.79 (m, 2H, 2H-C(4)),
3.74 (s, 3H, MeO), 5.11 (s, 2H, OCH2), 6.68 (d, 1H, J = 8.0
Hz, H-C(8)), 6.71 (dd, 1H, J = 8.0, 2.0 Hz, H-C(7)), 6.78
(d, 1H, J = 2.0 Hz, H-C(5)), 6.90-6.96 (m, 2H, arom. H),
7.55-7.69 (m, 2H, arom. H), 9.90 (s, 1H, NH) 11.63 (s, 1H,
NOH). 13C-NMR (DMSO): 24.65 (C(4)), 31.33 (C(3)),
55.81 (MeO), 59.38 (CH2O), 102.78, 107.54, 114.41,
116.91, 127.30, 128.40, 129.12, 139.88, 153.09, 157.84,
160.46, 171.06 (C(2)). Anal. Calcd for C18H18N2O4: C,
66.25; H, 5.56; N, 8.58. Found: C, 66.21; H, 5.55; N, 8.57.
(Z)-6-[2-(Biphenyl-4-yl)-2-(hydroxyimino)ethoxy]-3,4-
dihydroquinolin-2(1H)-one (12e)
Yield: 67%; Mp 240-241 °C. 1H-NMR (DMSO-d6):
2.35-2.39 (m, 2H, H-C(3)), 2.79-2.82 (m, 2H, H-C(4)),
5.32 (s, 2H, OCH2), 6.77 (d, 1H, J = 8.0 Hz, H-C(8)), 6.88
(dd, 1H, J = 8.0, 2.0 Hz, H-C(7)), 6.97 (d, 1H, J = 2.0 Hz,
H-C(5)), 7.35-7.48 (m, 3H, arom. H), 7.65-7.69 (m, 4H,
arom. H), 7.82-7.84 (m, 2H, arom. H), 8.77 (s, 1H, NH),
12.02 (s, 1H, NOH). 13C-NMR (DMSO): 24.76 (C(4)),
30.34 (C(3)), 59.75 (CH2O), 110.77, 120.48, 122.16,
124.60, 126.48, 126.62, 127.09, 127.12, 127.71, 128.99,
133.03, 139.51, 140.47, 144.38, 152.64, 169.61 (C(2)).
Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52.
Found: C, 73.96; H, 5.49; N, 7.49.
(Z)-6-[2-(Hydroxyimino)-2-phenylethoxy]-3,4-dihydro-
quinolin-2(1H)-one (12b)
Yield: 71%; Mp 229-230 °C. 1H-NMR (DMSO-d6):
2.37-2.40 (m, 2H, H-C(3)), 2.78-2.82 (m, 2H, H-C(4)),
5.17 (s, 2H, OCH2), 6.74 (d, 1H, J = 8.4 Hz, H-C(8)), 6.77
(dd, 1H, J = 8.4, 2.4 Hz, H-C(7)), 6.80 (d, 1H, J = 2.4 Hz,
H-C(5)), 7.37-7.39 (m, 3H, arom. H), 7.63-7.65 (m, 2H,
arom. H), 9.91 (s, 1H, NH), 11.85 (s, 1H, NOH). 13C-NMR
(DMSO): 24.96 (C(4)), 30.18 (C(3)), 58.82 (CH2O),
112.61, 114.01, 115.61, 124.80, 126.24, 128.18, 128.74,
132.06, 134.27, 152.83, 152.98, 169.65 (C(2)). Anal.
(Z)-7-[2-(Hydroxyimino)-2-(naphthalen-2-yl)ethoxy]-
3,4-dihydroquinolin-2(1H)-one (13a)
Yield: 72%; Mp 198-199 °C. 1H-NMR (DMSO-d6):

Antiplatelet 3,4-Dihydroquinolin-2(1H)-ones
J. Chin. Chem. Soc., Vol. 57, No. 6, 2010 1337
2.37-2.41 (m, 2H, H-C(3)), 2.75-2.78 (m, 2H, 2H-C(4)),
5.29 (s, 2H, OCH2), 6.43 (d, 1H, J = 2.4 Hz, H-C(8)), 6.58
(dd, 1H, J = 8.4, 2.4 Hz, H-C(6)), 7.05 (d, 1H, J = 8.4 Hz,
H-C(5)), 7.52-7.55 (m, 2H, arom. H), 7.83-7.96 (m, 4H,
arom. H), 8.16 (m, 1H, arom. H), 9.97 (s, 1H, NH), 11.98
(s, 1H, NOH). 13C-NMR (DMSO): 23.89 (C(4)), 30.56
(C(3)), 58.58 (CH2O), 102.04, 106.86, 116.17, 123.64,
125.96, 126.35, 126.56, 127.41, 127.62, 128.26, 128.33,
131.63, 132.55, 132.89, 139.16, 152.72, 157.10, 170.15
(C(2)). Anal. Calcd for C21H18N2O3: C, 72.82; H, 5.24; N,
8.09. Found: C, 72.43; H, 5.18; N, 7.96.
55.81 (MeO), 59.38 (CH2O), 102.78, 107.54, 114.41,
116.91, 127.30, 128.40, 129.12, 139.88, 153.09, 157.84,
160.46, 171.06 (C(2)). Anal. Calcd for C18H18N2O4: C,
66.25; H, 5.56; N, 8.58. Found: C, 66.16; H, 5.67; N, 8.57.
(Z)-7-[2-(Biphenyl-4-yl)-2-(hydroxyimino)ethoxy]-3,4-
dihydroquinolin-2(1H)-one (13e)
Yield: 73%; Mp 190-191 °C. 1H-NMR (DMSO-d6):
2.38-2.42 (m, 2H, H-C(3)), 2.76-2.79 (m, 2H, H-C(4)),
5.21 (s, 2H, OCH2), 6.44 (d, 1H, J = 2.8 Hz, H-C(8)), 6.57
(dd, 1H, J = 8.4, 2.8 Hz, H-C(6)), 7.06 (d, 1H, J = 8.4 Hz,
H-C(5)), 7.36-7.40 (m, 1H, arom. H), 7.46-7.49 (m, 2H,
arom. H), 7.69-7.75 (m, 6H, arom. H), 9.99 (s, 1H, NH),
11.92 (s, 1H, NOH). 13C-NMR (DMSO): 24.68 (C(4)),
31.35 (C(3)), 59.41 (CH2O), 102.83, 107.58, 116.99,
127.22, 127.29, 127.59, 128.39, 129.14, 129.68, 134.02,
139.97, 140.13, 141.12, 153.22, 157.87, 170.97 (C(2)).
Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52.
Found: C, 74.15; H, 5.40; N, 7.52.
(Z)-7-[2-(Hydroxyimino)-2-phenylethoxy]-3,4-dihydro-
quinolin-2(1H)-one (13b)
Yield: 71%; Mp 167-168 °C. 1H-NMR (DMSO-d6):
2.38-2.42 (m, 2H, H-C(3)), 2.75-2.79 (m, 2H, H-C(4)),
5.17 (s, 2H, OCH2), 6.40 (d, 1H, J = 2.8 Hz, H-C(8)), 6.53
(dd, 1H, J = 8.4, 2.8 Hz, H-C(6)), 7.04 (d, 1H, J = 8.4 Hz,
H-C(5)), 7.37-7.40 (m, 3H, arom. H), 7.62-7.64 (m, 2H,
arom. H), 9.98 (s, 1H, NH), 11.85 (s, 1H, NOH). 13C-NMR
(DMSO): 23.89 (C(4)), 30.56 (C(3)), 58.70 (CH2O),
102.01, 106.78, 116.16, 126.28, 128.19, 128.33, 128.76,
134.18, 139.16, 152.79, 157.07, 170.18 (C(2)). Anal.
Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found:
C, 69.07; H, 5.46; N, 9.46.
(Z)-8-[2-(Hydroxyimino)-2-(naphthalen-2-yl)ethoxy]-
3,4-dihydroquinolin-2(1H)-one (14a)
Yield: 69%; Mp 185-186 °C. 1H-NMR (DMSO-d6):
2.33-2.36 (m, 2H, H-C(3)), 2.77-2.80 (m, 2H, H-C(4)),
5.41 (s, 2H, OCH2), 6.75-6.76 (m, 1H, arom. H), 6.86-6.89
(m, 1H, arom. H), 6.99-7.01 (m, 1H, arom. H), 7.51-7.53
(m, 2H, arom. H), 7.86-7.92 (m, 3H, arom. H), 7.98-8.00
(m, 1H, arom. H), 8.34 (m, 1H, arom. H), 8.84 (s, 1H, NH),
12.10 (s, 1H, NOH). 13C-NMR (DMSO): 25.39 (C(4)),
30.97 (C(3)), 60.28 (CH2O), 111.33, 121.11, 122.81,
124.30, 125.23, 127.03, 127.04, 127.32, 127.76, 128.13,
128.29, 129.15, 132.01, 133.43, 133,66, 144.99, 153.47,
170.29 (C(2)). Anal. Calcd for C21H18N2O3: C, 72.82; H,
5.24; N, 8.09. Found: C, 72.63; H, 5.21; N, 8.05.
(Z)-7-[2-(4-Fluorophenyl)-2-(hydroxyimino)ethoxy]-
3,4-dihydroquinolin-2(1H)-one (13c)
Yield: 73%; Mp 172-173 °C. 1H-NMR (DMSO-d6):
2.38-2.42 (m, 2H, H-C(3)), 2.75-2.79 (m, 2H, 2H-C(4)),
5.18 (s, 2H, OCH2), 6.40 (d, 1H, J = 2.4 Hz, H-C(8)), 6.52
(dd, 1H, J = 8.4, 2.4 Hz, H-C(6)), 7.04 (d, 1H, J = 8.4 Hz,
H-C(5)), 7.20-7.24 (m, 2H, arom. H), 7.65-7.69 (m, 2H,
arom. H), 9.98 (s, 1H, NH), 11.87 (s, 1H, NOH). 13C-NMR
(DMSO): 23.89 (C(4)), 30.56 (C(3)), 58.75 (CH2O),
102.01, 106.81, 115.02, 115.24, 116.22, 128.33, 128.45,
128.52, 130.59, 130.62, 139.17, 152.06, 156.95, 161.13,
163.58, 170.17 (C(2)). Anal. Calcd for C17H15FN2O3: C,
64.96; H, 4.81; N, 8.91. Found: C, 65.04; H, 4.95; N, 9.21.
(Z)-7-[2-(Hydroxyimino)-2-(4-methoxyphenyl)ethoxy]-
3,4-dihydroquinolin-2(1H)-one (13d)
Yield: 74%; Mp 165-166 °C. 1H-NMR (DMSO-d6):
2.35-2.39 (m, 2H, H-C(3)), 2.72-2.76 (m, 2H, H-C(4)),
3.74 (s, 3H, MeO), 5.11 (s, 2H, OCH2), 6.38 (d, 1H, J = 2.8
Hz, H-C(8)), 6.51 (dd, 1H, J = 8.4, 2.8 Hz, H-C(6)), 6.90-
6.92 (m, 2H, arom. H), 7.02 (d, 1H, J = 8.4 Hz, H-C(5)),
7.53-7.56 (m, 2H, arom. H), 9.97 (s, 1H, NH), 11.63 (s, 1H,
NOH). 13C-NMR (DMSO): 24.65 (C(4)), 31.33 (C(3)),
(Z)-8-[2-(Hydroxyimino)-2-phenylethoxy]-3,4-dihydro-
quinolin-2(1H)-one (14b)
Yield: 72%; Mp 146-147 °C. 1H-NMR (DMSO-d6):
2.37-2.41 (m, 2H, H-C(3)), 2.79-2.83 (m, 2H, H-C(4)),
5.28 (s, 2H, OCH2), 6.76-6.96 (m, 3H, arom. H), 7.35-7.38
(m, 3H, arom. H), 7.72-7.74 (m, 2H, arom. H), 8.66 (s, 1H,
NH), 11.95 (s, 1H, NOH). 13C-NMR (DMSO): 24.66 (C(4)),
30.24 (C(3)), 59.72 (CH2O), 110.67, 120.37, 122.07,
124.46, 126.44, 126.98, 128.16, 128.82, 133.87, 144.25,
152.89, 169.50 (C(2)). Anal. Calcd for C17H16N2O3: C,
68.91; H, 5.44; N, 9.45. Found: C, 69.20; H, 5.48; N, 9.47.
(Z)-8-[2-(4-Fluorophenyl)-2-(hydroxyimino)ethoxy]-
3,4-dihydroquinolin-2(1H)-one (14c)
Yield: 70%; Mp 166-167 °C. 1H-NMR (DMSO-d6):

1338 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Chen et al.
2.37-2.41 (m, 2H, H-C(3)), 2.80-2.83 (m, 2H, 2H-C(4)),
5.29 (s, 2H, OCH2), 6.76-6.78 (m, 1H, arom. H), 6.84-6.93
(m, 2H, arom. H), 7.16-7.21 (m, 2H, arom. H), 7.76-7.79
(m, 2H, arom. H), 8.75 (s, 1H, NH), 11.98 (s, 1H, NOH).
13C-NMR (DMSO): 25.40 (C(4)), 30.99 (C(3)), 60.40
(CH2O), 111.34, 115.70, 115.91, 121.16, 122.83, 125.26,
127.71, 129.38, 129.47, 131.02, 131.05, 144.91, 152.89,
161.93, 164.38, 170.35 (C(2)). Anal. Calcd for C17H15FN2O3:
C, 64.96; H, 4.81; N, 8.91. Found: C, 64.69; H, 5.00; N,
9.13.
Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96. Found:
C, 61.54; H, 6.05; N, 11.98.
(E)-7-[2-(Hydroxyimino)propoxy]-3,4-dihydroquinolin-
2(1H)-one (16)
Yield: 73%; Mp 215-216 °C. 1H-NMR (DMSO-d6):
1.82 (s, 3H, Me), 2.39-2.43 (m, 2H, H-C(3)), 2.76-2.80 (m,
2H, H-C(4)), 4.48 (s, 2H, OCH2), 6.46 (d, 1H, J = 2.4 Hz,
H-C(8)), 6.54 (dd, 1H, J = 8.4, 2.4 Hz, H-C(6)), 7.05 (d,
1H, J = 8.4 Hz, H-C(5)), 10.00 (s, 1H, NH), 10.91 (s, 1H,
NOH). 13C-NMR (DMSO): 11.36 (Me), 23.90 (C(4)),
30.59 (C(3)), 69.38 (CH2O), 102.20, 107.60, 116.08,
128.27, 139.13, 151.81, 157.23, 170.18 (C(2)). Anal.
Calcd for C12H14N2O4: C, 61.53; H, 6.02; N, 11.96. Found:
C, 61.35; H, 6.04; N, 11.88.
(Z)-8-[2-(Hydroxyimino)-2-(4-methoxyphenyl)ethoxy]-
3,4-dihydroquinolin-2(1H)-one (14d)
Yield: 67%; Mp 152-153 °C. 1H-NMR (DMSO-d6):
2.35-2.39 (m, 2H, H-C(3)), 2.77-2.81 (m, 2H, H-C(4)),
3.73 (s, 3H, MeO), 5.23 (s, 2H, OCH2), 6.73-6.93 (m, 5H,
arom. H), 7.64-7.66 (m, 2H, arom. H), 8.67 (s, 1H, NH),
11.74 (s, 1H, NOH). 13C-NMR (DMSO) d: 25.40 (C(4)),
30.99 (C(3)), 55.80 (MeO), 60.37 (CH2O), 111.36, 114.33,
121.08, 122.84, 125.20, 127.68, 128.58, 131.25, 145.01,
153.17, 160.48, 170.33 (C(2)). Anal. Calcd for C18H18N2O4:
C, 66.25; H, 5.56; N, 8.58. Found: C, 66.20; H, 5.83; N,
8.46.
(E)-8-[2-(Hydroxyimino)propoxy]-3,4-dihydroquinolin-
2(1H)-one (17)
Yield: 68%; Mp 147-148 °C. 1H-NMR (DMSO-d6):
1.85 (s, 3H, Me), 2.41-2.44 (m, 2H, H-C(3)), 2.82-2.86 (m,
2H, H-C(4)), 4.55 (s, 2H, OCH2), 6.76-6.78 (m, 1H, arom.
H), 6.83-6.89 (m, 2H, arom. H), 9.10 (s, 1H, NH), 10.92 (s,
1H, NOH). 13C-NMR (DMSO): 12.23 (Me), 25.56 (C(4)),
31.19 (C(3)), 70.71 (CH2O), 111.66, 120.87, 122.79,
125.48, 127.75, 145.44, 152.90, 170.54 (C(2)). Anal.
Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96. Found:
C, 61.55; H, 6.20; N, 11.94.
(Z)-8-[2-(Biphenyl-4-yl)-2-(hydroxyimino)ethoxy]-3,4-
dihydroquinolin-2(1H)-one (14e)
1
Yield: 67%; Mp 200-20 °C. H-NMR (DMSO-d6):
2.36-2.40 (m, 2H, H-C(3)), 2.79-2.83 (m, 2H, H-C(4)),
5.33 (s, 2H, OCH2), 6.77-6.79 (m, 1H, arom. H), 6.87-6.90
(m, 1H, arom. H), 6.96-6.98 (m, 1H, arom. H), 7.36-7.40
(m, 1H, arom. H), 7.45-7.49 (m, 2H, arom. H), 7.65-7.69
(m, 4H, arom. H), 7.82-7.85 (m, 2H, arom. H), 8.76 (s, 1H,
NH), 12.04 (s, 1H, NOH). 13C-NMR (DMSO) d: 25.40
(C(4)), 30.97 (C(3)), 60.42 (CH2O), 111.43, 121.16,
122.88, 125.27, 127.14, 127.27, 127.72, 127.76, 128.38,
129.68, 133.65, 140.15, 141.15, 145.02, 153.38, 170.38
(C(2)). Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N,
7.52. Found: C, 73.83; H, 5.42; N, 7.48.
3. Antiproliferative Activity
1. Cell Lines - Human non-small cell lung carcinoma
(NCI-H661, A549), gastric cancer (MKN45), and T-cell
leukemia (Jurkat) was purchased from American Type Cul-
ture Collection (ATCC; Rockville, MD). Nasopharyngeal
carcinoma (NPC-TW01) was purchased from Bioresource
Collection and Research Center (BCRC, Taiwan). All the
tumor cell lines were maintained in either RPMI-1640 or
Modified essential medium (MEM) supplied with 10% fe-
tal bovine serum at 37 °C in a humidified atmosphere of 5%
CO2/95% air in the absence of antibiotics.
(E)-6-[2-(Hydroxyimino)propoxy]-3,4-dihydroquinolin-
2. Growth Inhibition Assay - Logarithmic phase cells
were seeded in a 96-well plate and incubated overnight
prior to addition of the designated compounds. After incu-
bation with different concentrations of the tested com-
pounds for 72 h, cells were incubated with MEM contain-
ing 0.4 mg/mL MTT for 2 h. The conversion of MTT to
formazan by metabolically viable cells was measured by
the absorbance at 570 nm in a 96-well microtiter plate
reader. The percentage conversion by mock-treated control
cells was used to evaluate the effect of the chemicals on cell
2(1H)-one (15)
Yield: 68%; Mp 200-201 °C. 1H-NMR (DMSO-d6):
1.82 (s, 3H, Me), 2.38-2.42 (m, 2H, H-C(3)), 2.80-2.84 (m,
2H, H-C(4)), 4.48 (s, 2H, OCH2), 6.72 (d, 1H, J = 8.4 Hz,
H-C(8)), 6.78 (dd, 1H, J = 8.4, 2.4 Hz, H-C(7)), 6.83 (d,
1H, J = 2.4 Hz, H-C(5)), 9.92 (s, 1H, NH), 10.90 (s, 1H,
NOH). 13C-NMR (DMSO) d: 11.37 (Me), 24.97 (C(4)),
30.20 (C(3)), 69.74 (CH2O), 113.35, 114.46, 115.61,
124.74, 132.06, 152.02, 153.17, 169.66 (C(2)). Anal.

Antiplatelet 3,4-Dihydroquinolin-2(1H)-ones
J. Chin. Chem. Soc., Vol. 57, No. 6, 2010 1339
growth and to determine the concentration that inhibited
50% of growth (GI50).
ence Council of the Republic of China is gratefully ac-
knowledged. We also thank National Cancer Institute
(NCI) of the United States for the anticancer screenings and
the National Center for High-Performance Computing for
providing computer resources and chemical database ser-
vices.
4. Antiplatelet Evaluation
Reagents: Collagen (type 1, bovine Achilles tendon)
obtained from Sigma Chem. Co. was homogenized in 25
mM AcOH and stored (1 mg/mL) at -70o. Arachidonic acid
(AA), EDTA, and bovine serum albumin were purchased
from Sigma Chem. Co. and dissolved in CHCl3.
Received May 27, 2010.
Platelet aggregation: Blood was collected from the
rabbit marginal ear vein, anticoagulated with EDTA (6
mM) and centrifuged for 10 min at 90 ´ g and at r.t. Platelet
suspensions were prepared from the plasma according to
the washing procedures previously described.26 Platelet
numbers were determined with a Coulter counter (Model
ZM) and adjusted to 4.5 ´ 108 platelets/mL. The platelet
pellets were suspended in Tyrode’s solution of the follow-
ing composition (mM): NaCl (136.8), KCl (2.8), NaHCO3
(11.9), MgCl2 (2.1), NaH2PO4 (0.33), CaCl2 (1.0) and glu-
cose (11.2), containing bovine serum albumin (0.35%).
The platelet suspension was stirred at 1200 rpm and the ag-
gregation was measured at 37o by the turbidimetric method
as described by O’Brien27 using a Chrono-Log Lumi-
aggregometer. To eliminate solvent effects on aggregation,
the final concentration of dimethylsulfoxide (DMSO) was
fixed at 0.5%. Percentage of aggregation was calculated
using the absorbance of a platelet suspension as 0% aggre-
gation and the absorbance of Tyrode’s solution as 100% ag-
gregation.
REFERENCES
1. Tominaga, M.; Tone, H.; Nakagawa K.; Takada, K.; Hoshino,
Y.; Watanabe, K. Chem. Pharm. Bull. 1981, 29, 2166.
2. Nishi, T.; Yamamoto, K.; Shimizu, T.; Kanbe, T.; Kimura,
Y.; Nakagawa, K. Chem. Pharm. Bull. 1983, 31, 798.
3. Nishi, T.; Tabusa, F.; Tanaka, T.; Shimizu, T.; Kanbe, T.;
Kimura, Y.; Nakagawa, K. Chem. Pharm. Bull. 1983, 31,
1151.
4. Nishi, T.; Tabusa, F.; Tanaka, T.; Ueda, H.; Shimizu, T.;
Kanbe, T.; Kimura, Y.; Nakagawa, K. Chem. Pharm. Bull.
1983, 31, 852.
5. Nishi, T.; Tabusa, F.; Tanaka, T.; Shimizu, T.; Nakagawa, K.
Chem. Pharm. Bull. 1985, 33, 1140.
6. Tominaga, M.; Yo, E.; Ogawa, H.; Yamashita, S.; Yabuuchi,
Y.; Nakagawa, K. Chem. Pharm. Bull. 1984, 32, 2100.
7. Tominaga, M.; Ogawa, H.; Yo, E.; Yamashita, S.; Yabuuchi,
Y.; Nakagawa, K. Chem. Pharm. Bull. 1987, 35, 3699.
8. Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.;
Henderson, C. G.; Roberts, D. A.; Ruddock, K. S.; Samuels,
G. M. R.; Stefaniak, M. H. J. Med. Chem. 1988, 31, 2048.
9. Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.;
Henderson, C. G.; Morris, D. S.; Roberts, D. A.; Ruddock, K.
S.; Samuels, G. M. R.; Stefaniak, M. H. J. Med. Chem. 1989,
32, 575.
CONCLUSION
A number of oxime-containing 3,4-dihydroquinolin-
2(1H)-one derivatives were synthesized and evaluated for
their antiplatelet and antiproliferative activities. The pre-
liminary results indicated that (Z)-7-[2-(4-fluorophenyl)-
2-(hydroxyimino)ethoxy]-3,4-dihydroquinolin-2(1H)-one
(13c) was the most active against U46619 induced platelet
aggregation with an IC50 value of 3.51 mM while (E)-6-[2-
(hydroxyimino)propoxy]-3,4-dihydroquinolin-2(1H)-one
(15) was the most active against AA-induced aggregation
with an IC50 value of 1.85 mM. Both 13c and 15 exhibited
very weak antiproliferative effects implied their highly po-
tential to be developed as antiplatelet agents. Further struc-
tural optimization is on-going.
10. Fujioka, T.; Teramoto, S.; Mori, T.; Hosokawa, T.; Sumida,
T.; Tominaga, M.; Yabuuchi, Y. J. Med. Chem. 1992, 35,
3607.
11. Uno, T.; Ozeki, Y.; Koga, Y.; Chu, G. N.; Okada, M.; Tamura,
K.; Igawa, T.; Unemi, F.; Kido, M.; Nishi, T. Chem. Pharm.
Bull. 1995, 43, 1724.
12. Tzeng, C. C.; Chen, I. L.; Chen, Y. L.; Wang, T. C.; Chang, Y.
L.; Teng, C. M. Helv. Chim. Acta 2000, 83, 349.
13. Desos, P.; Lepagnol, J. M.; Morain, P.; Lestage, P.; Cordi, A.
J. Med Chem. 1996, 39, 197.
14. Tzeng, C. C.; Wang, T. C.; Chen, Y. L.; Wang, C. J.; Chang,
Y. L.; Teng, C. M. Helv. Chim. Acta 1997, 80, 1161.
15. Wang, T. C.; Chen, Y. L.; Tzeng, C. C.; Liou, S. S.; Tzeng, W.
F.; Chang, Y. L.; Teng, C. M. Helv. Chim. Acta 1998, 81,
1038.
16. Chen, Y. L.; Wang, T. C.; Fang, K. C.; Chang, N. C.; Tzeng,
C. C. Heterocycles 1999, 50, 453.
ACKNOWLEDGEMENTS
Financial support of this work by the National Sci-

1340 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Chen et al.
17. Chen, Y. L.; Wang, T. C.; Chang, N. C.; Chang, Y. L.; Teng,
C. M.; Tzeng, C. C. Chem. Pharm. Bull. 1998, 46, 962.
18. Chen, Y. L.; Wang, T. C.; Liang, S. C.; Teng, C. M.; Tzeng,
C. C. Chem. Pharm. Bull. 1996, 44, 1591.
T. L.; Liao, C. H.; Tzeng, C. C.; Teng, C. M. Eur. J. Phar-
macol. 2001, 418, 133.
23. Wang, T. C.; Lee, K. H.; Chen, Y. L.; Liou, S. S.; Tzeng, C.
C. Bioorg. Med. Chem. Lett. 1998, 8, 2773.
19. Liao, C. H. ; Tzeng, C. C. ; Teng, C. M. Eur. J. Pharmacol.
1998, 349, 107.
24. Tzeng, C. C.; Lee, K. H.; Wang, T. C.; Han, C. H.; Chen, Y.
L. Pharm. Res. 2000, 17, 715.
20. Wang, T. C.; Chen, I. L.; Lu, P. J.; Wong, C. H.; Liao, C. H.;
Tsiao, K. C.; Chang, K. M.; Chen, Y. L.; Tzeng, C. C. Bioorg.
Med. Chem. 2005, 13, 6045.
25. Silverstein, R. M.; Webster, F. X. 13C NMR Spectrometry. In
Spectrometric Identification of Organic Compounds, 6th ed.;
Rose N., Ed.; John Wiley and Sons: New York, 1998; p 217.
26. Teng, C. M.; Ko, F. N. Thremb. Haemost. 1988, 59, 304.
27. O’Brien, J. R. J. Clin. Pathol. 1962, 15, 452.
21. Chen, I. L.; Chang, K. M.; Miaw, C. L.; Liao, C. H.; Chen, J.
J.; Wang, T. C. Bioorg. Med. Chem. 2007, 15, 6527.
22. Huang, Y. C.; Guh, J. H.; Cheng, Z. J.; Chang, Y. L.; Hwang,