Synthesis and antiproliferative activity of novel aminoalkylated flavones

Article abstract of DOI:10.1007/s10593-017-2132-7

(Figure presented.) Naturally occurring 5-hydroxy-4',7-dimethoxyflavone (acacetin-7-O-methyl ether) was synthesized through dehydrogenation, glycoside hydrolysis, and selective O-methylation, using naringin as starting material. Two series of sixteen novel aminoalkylated flavones were synthesized from 5-hydroxy-4',7-dimethoxyflavone. Furthermore, antiproliferative activity of the compounds was evaluated in vitro on a panel of three human cancer cell lines (HeLa, HCC1954, and SK-OV-3) using Cell Counting Kit-8 assay. The result showed that most of the synthetic compounds exhibited moderate to potent antiproliferative activities against the three human cancer cell lines with IC₅₀ values of 6.95–64.50 μΜ.

Full text of DOI:10.1007/s10593-017-2132-7

DOI 10.1007/s10593-017-2132-7
Chemistry of Heterocyclic Compounds 2017, 53(8), 871–875
Synthesis and antiproliferative activity
of novel aminoalkylated flavones
1
1
1
2
Lili Yan , Haoran Liu , Qiuan Wang *, Gangqiang Wang
1
College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China; e-mail: WangQA@hnu.edu.cn
2
School of Nuclear Technology and Chemistry & Biology,
Hubei University of Science and Technology,
Hubei 437100, China; e-mail: wgq20008@163.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted March 22, 2017
Accepted April 28, 2017
2
017, 53(8), 871–875
Naturally occurring 5-hydroxy-4',7-dimethoxyflavone (acacetin-7-O-methyl ether) was synthesized through dehydrogenation, glycoside
hydrolysis, and selective O-methylation, using naringin as starting material. Two series of sixteen novel aminoalkylated flavones were
synthesized from 5-hydroxy-4',7-dimethoxyflavone. Furthermore, antiproliferative activity of the compounds was evaluated in vitro on a
panel of three human cancer cell lines (HeLa, HCC1954, and SK-OV-3) using Cell Counting Kit-8 assay. The result showed that most of
the synthetic compounds exhibited moderate to potent antiproliferative activities against the three human cancer cell lines with IC50
values of 6.95–64.50 μΜ.
Keywords: 5-hydroxy-4',7-dimethoxyflavone, aminoalkylated flavones, antiproliferative activity, cancer cells, synthesis.
Flavones are ubiquitous structures present in a large
number of natural compounds comprising a broad range of
alkoxy side chain at position 5 and introducing amine–
hydrogen bond receptor at the end of the side chain.
Furthermore, the in vitro antiproliferative activity of the
synthesized compounds against three human cancer cell
lines HeLa (cervical carcinoma), HCC1954 (breast cancer),
and SK-OV-3 (ovarian cancer) was evaluated using Cell
Counting Kit-8 (CCK-8) assay.
1
powerful biological activities. For example, 5-hydroxy-
4
',7-dimethoxyflavone (acacetin-7-O-methyl ether or apigenin-
,4-dimethyl ether) (1) (Scheme 1), a natural flavone
7
isolated from plant Turnera diffusa, not only possess a
2
'
'powerful aphrodisiac effects'' but also has antiprolife-
3
rative activity for HeLa cells to some extent. Flavonoids
display specific cytotoxic activity toward different cancer
cell lines with little or no toxicity toward normal cells at
concentrations that are lethal to tumor cells, which has
generated large interest in developing flavonoid-based
Synthesis of novel aminoalkylated flavone derivatives
2a–h and 3a–h from flavone 1 is shown in Scheme 1.
8
According to our previous procedure, acacetin-7-O-methyl
ether (1) could be obtained from the corresponding flavo-
noid glycoside naringin, which is commercially available at
a low cost, by a sequence of dehydrogenation, hydrolysis of
glycosidic bond, and regioselective methylation. Because the
5-OH group in compound 1 was stabilized by the hydrogen
bond, trimethoxy-substituted compounds were not
produced under these conditions. Compounds 4 and 5 were
the key intermediates, usually prepared from alkylation of
the 5-OH group by using dihaloalkanes in the presence of a
base. Thus, alkylation of compound 1 with an excess
amount of 1,2-dibromoethane or 1,4-dibromobutane in the
4
cytostatics for anticancer therapy. The interest, created by
biological studies, to develop structural analogs of
antitumor agents containing nitrogen heterocycle has often
5
led to enhanced bioactivity. The results obtained in several
classes of polyaromatic antitumor agents indicate that the
introduction of an aminoalkyloxy side chain can increase
significantly biological activity and the potency of the
6
parent compounds.
As part of our screening program dedicated to the search
for derivatives of natural flavonoids with anticancer pro-
presence of K
intermediates 4,
corresponding secondary amines in the presence of K
in acetone and catalytic amount of KI to provide the final
2
CO
3
in dry acetone at 60–65°C resulted in
which were reacted with the
CO
7
perties, we herein report the synthesis of two series of six-
5
teen novel aminoalkylated flavone derivatives obtained
2
3
from 5-hydroxy-4',7-dimethoxyflavone (1) through extending
0
009-3122/17/53(08)-0871©2017 Springer Science+Business Media New York
871

Chemistry of Heterocyclic Compounds 2017, 53(8), 871–875
Scheme 1
OH
O
OH
OMe
O
O
O
HO
1. I , Py, 
2
K2CO3 (2.5 equiv)
2
. concd H SO , EtOH,  MeO
O
Br(CH ) Br (1.5 equiv)
2
4
2 n
HO
Me
O
3. K2CO3 (2.0 equiv)
Me SO (2.0 equiv)
Me2CO
, 12 h
O
OH
2
4
Me2CO, 45°C, 30 min
OH
O
HO
OH
1
(44%)
OH
Naringin
3
'
OMe
HNR1R2 (1.2 equiv)
OMe
2
'
1
4
'
K CO (2.5 equiv)
8
2
3
1'
MeO
Br
O
MeO
8a O
5'
KI (0.05 equiv)
7
6
2
6'
4a
Me2CO
, 45 min to 1 h
3
5
4

1
2
O
O
R R N
O
n
O
n
4
5
n = 2 (74%)
n = 4 (80%)
2
a–h n = 2 (79–85%)
3
a–h n = 4 (76–79%)
1
2
1
2
1
2
1
2
1
2
2
, 3 a NR R = NMe2, b NR R = NEt2, c NR R =N
, d NR R = N
, f NR R = N
O,
N
1
2
1
2
1
2
1 2
g NR R = N
N Me , h NR R = N
2
OH ; 2e NR R = NPr ; 3e NR R = N
aminoalkylated flavones. This process produced the desired
target compounds 2a–h and 3a–h in moderate to good
yields. All new compounds were purified by recrystal-
lization or chromatography, and the analytical and spectro-
scopic data confirmed their structures, as detailed in the
Experimental section.
Table 1. Half-maximal inhibitory concentrations (IC50 in μM)
of compounds 1, 2a–h, and 3a–h on the human cancer cell lines
Compound
HeLa
7.23
HCC1954
23.66
12.54
12.80
16.10
8.26
SK-OV-3
1
＞100
28.42
24.66
24.32
17.59
20.92
2
a
34.98
23.06
12.86
14.40
27.83
14.88
50.98
18.32
17.21
16.90
17.23
16.27
36.27
19.51
17.82
14.22
13.30
0.0055
0.0112
2
b
All the synthetic aminoalkylated flavone derivatives 2a–h
and 3a–h were tested in vitro for their antiproliferative
activity against three human cancer cell lines (HeLa,
HCC1954, and SK-OV-3) by the CCK-8 method using
cisplatin, paclitaxel, and staurosporine as positive controls.
Their activities were expressed by the concentration of
drug inhibiting 50% cell growth (IC50), and the data
presented in the Table 1 is a result of at least three separate
experiments. The results showed that most of the synthe-
sized target compounds exhibited moderate to potent anti-
proliferative activities with IC50 values of 6.90–64.50 μΜ
toward these three cancer cell lines. In general,
aminoalkylation of flavone 1 causes a significant increase
of antiproliferative activity on HCC1954 and SK-OV-3
cells. However, aminoalkylation of flavone 1 causes a
marked decrease of activity in HeLa cells. Compounds 1,
2
c
2d
2
e
8.68
2
f
＞100
34.62
12.69
27.88
12.60
14.23
6.95
＞100
64.50
19.83
43.81
17.33
23.39
15.59
48.47
24.70
24.29
23.80
18.66
0.0028
0.0031
2
g
2
h
a
3
3b
3c
3
d
3
e
37.14
13.13
12.48
11.27
29.32
0.009
0.037
3
f
3
g
3
h
2
c,d,f, and 3h were equal or more potent against HeLa
cells with IC50 values of 7.23–14.88 μΜ than the positive
control cisplatin (IC50 13.30 μΜ), all compounds except
Cisplatin*
Paclitaxel*
2
f,g, and 3e were more potent aginst HCC1954 cells with
Staurosporine*
IC50 values of 6.95–27.88 μΜ than the positive control
cisplatin (IC50 29.32 μΜ), and compounds 2d, 3b,d were
more potent against SK-OV-3 cells with IC50 values of
*
Cisplatin, paclitaxel, and staurosporine were employed as positive control.
1
5.59–17.59 μΜ than the positive control cisplatin
Although parent flavone 1 is inactive against SK-OV-3
(IC50 >100 μΜ), all of aminoalkyl-substituted flavones
except 2f presented moderate antiproliferative activity
against SK-OV-3 cells (IC50 15.59–64.50 μΜ). In
particular, compound 1 on HeLa cells, compounds 2d,e and
3d on HCC1954 cells showed the gratest potency with IC50
(
IC50 18.66 μΜ).
It is interesting to note that all compounds except 2f,g
and 3a,e had more pronounced antiproliferative activities
against HCC1954 cells (IC50 6.95–16.10 μΜ) than the
parent acacetin-7-O-methyl ether (1) (IC50 23.66 μΜ).
8
72

Chemistry of Heterocyclic Compounds 2017, 53(8), 871–875
value below 10 μΜ. Compound 2f showed selective
(1H, s, H-8); 6.44 (1H, s, H-3); 6.25 (1H, s, H-6); 4.01 (2H,
t, J = 5.9, 5-OCH ); 3.82 (3H, s, 4'-OCH ); 3.79 (3H, s,
7-OCH ); 3.51 (2H, t, J = 6.4, CH Br); 2.19–2.11 (2H, m,
CH ); 2.03–1.96 (2H, m, CH ). C NMR spectrum, δ, ppm:
antiproliferative activity against HeLa cells. Molecular
recognition in the target binding site in these cancer cells
may be the reason for different behavior of these
compounds.
2
3
3
2
13
2
2
177.4; 163.8; 162.0; 160.6; 160.1; 159.8; 127.6; 123.9;
114.3; 109.4; 107.7; 97.0; 92.9; 68.2; 55.7; 55.5; 34.1;
In summary, two series of sixteen novel aminoalkylated
flavones derivatives were synthesized from 5-hydroxy-4',7-
dimethoxyflavone. The biological activity study results
showed that most of synthesized target compounds exhibit
moderate antiproliferative activities toward three cancer
cell lines. While aminoalkylation of the parent flavone
causes a significant increase of antiproliferative activity
toward HCC1954 and SK-OV-3 cells it appears to decrease
the activity toward HeLa cells. Synthesized compounds are
potential and selective anticancer agent and worthy of
further investigation.
+
29.4; 27.6. Mass spectrum (ESI), m/z (Irel, %): 433 [M+H]
+
(100). Found, m/z: 432.0567 [M] . C21
m/z: 432.0572.
H
21BrO . Calculated,
5
Synthesis of 5-O-aminoalkyled flavones 2a–h and 3a–h
(General method). The bromoalkyled flavone intermediate
4 or 5 (0.5 mmol) and anhydrous K
2
CO (172.5 mg,
3
1.25 mmol) were added to anhydrous acetone (15 ml), the
mixture refluxed for 1 h. Then corresponding secondary
amine (0.6 mmol) and KI (4.2 mg, 0.025 mmol) were
added and mixture refluxed for 45 min to 1 h. The mixture
was cooled to room temperature, precipitate filtered off and
filtrate evaporated to dryness. Then water (30 ml) was
slowly added, the aqueous phase was extracted with dichloro-
methane (3×25 ml). The organic phases were combined,
Experimental
H and C NMR spectra were recorded in CDCl
1
13
3
on a
Bruker-AV400 spectrometer (400 and 100 MHz, respec-
tively) with TMS as internal standard. Mass spectra were
recorded on a Mat 95 XP spectrometer by the EI (70 eV)
method or paper spray tandem mass spectrometry
dried over anhydrous Na
2
SO . The solvent was removed
4
under reduced pressure and the residue was purified by
column chromatography, eluent petroleum ether–EtOAc,
(
PS-MS/MS) by the ESI method. High-resolution mass
4:1 gradient to 1:1, with several drops of Et N added.
3
spectra were recorded on a Mat 95 XP spectrometer using
the EI (70 eV) method. Melting points were determined by
an XRC-1 apparatus and are uncorrected. Column chroma-
tography was carried out on silica gel 200–300 mesh
5-[2-(Dimethylamino)ethoxy]-7-methoxy-2-(4-methoxy-
phenyl)-4H-chromen-4-one (2a). Yield 153 mg (82%),
1
white solid, mp 165–167°C. H NMR spectrum, δ, ppm
(J, Hz): 7.75 (2H, d, J = 8.3, H-2',6'); 6.93 (2H, d, J = 8.3,
(
Qingdao Ocean Chemical Products of China).
Starting compounds and analytical reagents were
H-3',5'); 6.52 (1H, s, H-8); 6.46 (1H, s, H-3); 6.33 (1H, s,
H-6); 4.23 (2H, t, J = 5.2, 5-OCH
2
); 3.83 (3H, s, 4'-OCH
3
);
obtained from commercial sources and utilized without
further purification. Solvents were dehydrated and distilled
using standard experimental procedures. Acacetin-7-O-
methyl ether (1) was prepared from the corresponding
flavonoid glycoside naringin according to previously
3.81 (3H, s, 7-OCH
3
); 3.15 (2H, t, J = 5.2, CH
2
); 2.60 (6H,
13
s, 2NCH ). C NMR spectrum, δ, ppm: 176.6; 163.1;
3
161.3; 160.2; 158.6; 158.3; 126.7; 124.6; 122.7; 113.5;
106.4; 96.8; 92.8; 65.6; 56.0; 54.6; 54.0; 44.0. Mass spectrum
+
(ESI), m/z (Irel, %): 370 [M+H] (100).
8
described procedure.
5-[2-(Diethylamino)ethoxy]-7-methoxy-2-(4-methoxy-
Synthesis of 5-(2-bromoethoxy)-7-methoxy-2-(4-methoxy-
phenyl)-4H-chromen-4-one (2b). Yield 159 mg (80%),
1
phenyl)-4H-chromen-4-one (4) and 5-(4-bromobutoxy)-
white solid, mp 86–88°C. H NMR spectrum, δ, ppm
7
-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (5)
(J, Hz): 7.69 (2H, d, J = 8.6, H-2',6'); 6.88 (2H, d, J = 8.6,
(
General method). Compound 1 (1.00 g, 3.4 mmol) was
dissolved in dry acetone (25 ml); anhydrous K CO
1.17 g, 8.5 mmol) was added and the reaction was
H-3',5'); 6.44 (2H, s, H-3,8); 6.28 (1H, s, H-6); 4.04 (2H, t,
2
3
J = 6.4, 5-OCH
7-OCH
2CH
2
); 3.79 (3H, s, 4'-OCH ); 3.76 (3H, s,
3
(
3
); 2.94 (2H, t, J = 6.4, CH ); 2.61 (4H, q, J = 7.1,
2
13
refluxed for about 45 min. Then dibromoethane or
dibromobutane (5.1 mmol) was added dropwise and
refluxed for about 12 h, the reaction mixture was cooled to
room temperature, filtered, and evaporated to dryness, the
residue was purified by column chromatography, eluent
petroleum ether–EtOAc, 1:1.
2
); 1.01 (6H, t, J = 7.1, 2CH ). C NMR spectrum,
δ, ppm: 176.4; 162.8; 160.9; 159.5; 159.0; 158.7; 126.5;
3
122.7; 113.3; 108.2; 106.5; 95.9; 92.0; 67.2; 54.7; 54.4; 50.4;
+
46.9. Mass spectrum (ESI), m/z (Irel, %): 398 [M+H] (100).
7-Methoxy-2-(4-methoxyphenyl)-5-[2-(pyrrolidin-1-yl)-
ethoxy]-4H-chromen-4-one (2c). Yield 156 mg (79%),
1
5
-(2-Bromoethoxy)-7-methoxy-2-(4-methoxyphenyl)-
white solid, mp 139–141°C. H NMR spectrum, δ, ppm
4
H-chromen-4-one (4). Yield 1.02 g (74%), yellow solid,
(J, Hz): 7.74 (2H, d, J = 7.8, H-2',6'); 6.92 (2H, d, J = 7.8,
1
mp 187–189°C. H NMR spectrum, δ, ppm (J, Hz): 7.75
H-3',5'); 6.48 (1H, s, H-8); 6.46 (1H, s, H-3); 6.31 (1H, s,
(
(
2H, d, J = 8.2, H-2',6'); 6.93 (2H, d, J = 8.3, H-3',5'); 6.54
H-6); 4.15 (2H, t, J = 5.9, 5-OCH
2
); 3.82 (3H, s, 4'-OCH
3
);
1H, s, H-8); 6.48 (1H, s, H-3); 6.34 (1H, s, H-6); 4.31 (2H,
3.80 (3H, s, 7-OCH
3
); 3.02 (2H, t, J = 5.9, CH
). C NMR
2
); 2.71–2.65
13
t, J = 6.9, 5-OCH
-OCH
2
); 3.83 (3H, s, 4'-OCH
3
); 3.81 (3H, s,
(4H, m, 2NCH ); 1.77–1.73 (4H, m, 2CH
2
2
1
3
7
3
); 3.69 (2H, t, J = 6.9, CH
2
Br). C NMR spectrum,
spectrum, δ, ppm: 176.4; 162.8; 161.0; 159.6; 159.0; 158.8;
126.6; 122.9; 113.3; 110.4; 106.7; 96.1; 92.1; 67.6; 54.7;
54.5; 53.8; 53.4; 22.6. Mass spectrum (ESI), m/z (Irel, %):
δ, ppm: 176.2; 162.7; 161.1; 160.9; 159.9; 158.7; 158.2;
1
26.6; 122.8; 113.4; 106.6; 97.9; 93.2; 68.9; 54.6; 54.2; 27.2.
+
+
5
-(4-Bromobutoxy)-7-methoxy-2-(4-methoxyphenyl)-
396 [M+H] (100). Found, m/z: 395.1727 [M] . C23
H
25NO .
5
4
H-chromen-4-one (5). Yield 1.18 g (80%), yellow solid,
Calculated, m/z: 395.1733.
1
mp 160–162°C. H NMR spectrum, δ, ppm (J, Hz): 7.72
2H, d, J = 8.8, H-2',6'); 6.91 (2H, d, J = 8.8, H-3',5'); 6.46
7-Methoxy-2-(4-methoxyphenyl)-5-[2-(piperidin-1-yl)-
(
ethoxy]-4H-chromen-4-one (2d). Yield 162 mg (79%),
8
73

Chemistry of Heterocyclic Compounds 2017, 53(8), 871–875
1
1
white solid, mp 138–140°C. H NMR spectrum, δ, ppm
J, Hz): 7.74 (2H, d, J = 8.3, H-2',6'); 6.93 (2H, d, J = 8.3,
H-3',5'); 6.49 (1H, s, H-8); 6.47 (1H, s, H-3); 6.31 (1H, s,
H-6); 4.17 (2H, t, J = 5.9, 5-OCH ); 3.82 (3H, s, 4'-OCH );
); 2.94 (2H, t, J = 5.8, CH ); 2.67–2.53
); 1.61–1.55 (4H, m, 2CH ); 1.41 (2H, d,
). C NMR spectrum, δ, ppm: 123.7; 122.8;
white solid, mp 119–121°C. H NMR spectrum, δ, ppm
(
(J, Hz): 7.74 (2H, d, J = 8.3, H-2',6'); 6.92 (2H, d, J = 8.3,
H-3',5'); 6.47 (1H, s, H-8); 6.45 (1H, s, H-3); 6.28 (1H, s,
2
3
H-6); 3.99 (2H, t, J = 6.5, 5-OCH
2
); 3.82 (3H, s, 4'-OCH
3
);
); 2.35 (6H,
); 1.85–1.76 (2H, m,
3
(
.80 (3H, s, 7-OCH
3
2
3.80 (3H, s, 7-OCH
3
); 2.62 (2H, t, J = 5.6, CH
2
4H, m, 2NCH
2
2
s, 2NCH ); 1.94–1.86 (2H, m, CH
3
2
13
13
J = 4.6, CH
2
CH ). C NMR spectrum, δ, ppm: 176.5; 162.9; 161.0;
2
1
9
22.1; 113.3; 111.5; 108.3; 107.4; 106.6; 98.5; 96.1; 95.9;
159.7; 159.1; 158.8; 126.6; 122.8; 113.3; 108.3; 106.6;
96.0; 91.9; 68.1; 57.8; 54.7; 54.5; 43.7; 25.5; 22.5. Mass
2.2; 66.2; 56.2; 54.7; 54.5; 54.1; 24.6; 22.9. Mass
+
spectrum (EI), m/z (Irel, %): 111 (100), 298 (31).
spectrum (ESI), m/z (Irel, %): 398 [M+H] (100).
5
-[2-(Dipropylamino)ethoxy]-7-methoxy-2-(4-methoxy-
5-[4-(Diethylamino)butoxy]-7-methoxy-2-(4-methoxy-
phenyl)-4H-chromen-4-one (2e). Yield 168 mg (79%),
phenyl)-4H-chromen-4-one (3b). Yield 161 mg (76%),
1
1
yellow solid, mp 91–93°C. H NMR spectrum, δ, ppm
yellow solid, mp 77–80°C. H NMR spectrum, δ, ppm
(
J, Hz): 7.74 (2H, d, J = 8.7, H-2',6'); 6.92 (2H, d, J = 8.7,
(J, Hz): 7.78 (2H, d, J = 8.8, H-2',6'); 6.96 (2H, d, J = 8.9,
H-3',5'); 6.47 (2H, s, H-3,8); 6.32 (1H, s, H-6); 4.06 (2H, t,
H-3',5'); 6.54 (1H, s, H-8); 6.48 (1H, s, H-3); 6.32 (1H, d,
J = 6.6, 5-OCH
2
); 3.82 (3H, s, 4'-OCH
); 2.98 (2H, t, J = 6.6, CH ); 2.53–2.43 (4H, m,
); 1.45 (4H, dd, J = 15.0, J = 7.4, 2CH ); 0.82 (6H,
). C NMR spectrum, δ, ppm: 176.4; 162.8;
61.0; 159.6; 159.2; 158.8; 126.6; 122.9; 113.3; 108.4;
06.7; 96.1; 92.1; 67.2; 56.1; 54.7; 54.5; 51.6; 19.3; 10.8.
3
); 3.80 (3H, s,
J = 2.2, H-6); 4.05 (2H, t, J = 6.5, 5-OCH ); 3.87 (3H, s,
2
7
2
-OCH
NCH
3
2
4'-OCH
3NCH ); 1.95–1.90 (2H, m, CH
J = 7.5, CH
3
); 3.85 (3H, s, 7-OCH
3
); 2.57 (6H, q, J = 7.3,
); 1.73 (2H, dt, J = 15.1,
2
2
2
2
13
13
t, J = 7.3, 2CH
3
2
); 1.03 (6H, t, J = 7.2, 2CH ). C NMR
3
1
1
spectrum, δ, ppm: 177.4; 163.7; 161.9; 160.4; 160.2; 159.7;
127.5; 123.8; 114.2; 109.3; 107.5; 96.9; 92.7; 69.1; 55.6;
+
Mass spectrum (ESI), m/z (Irel, %): 426 [M+H] (100).
55.4; 52.3; 46.6; 26.9; 23.0; 11.3. Found, m/z: 425.2197
+
7
-Methoxy-2-(4-methoxyphenyl)-5-(2-morpholinoethoxy)-
[M] . C25
H
31NO . Calculated, m/z: 425.2202.
5
4
H-chromen-4-one (2f). Yield 175 mg (85%), white solid,
7-Methoxy-2-(4-methoxyphenyl)-5-[4-(pyrrolidin-1-yl)-
1
mp 174–176°C. H NMR spectrum, δ, ppm (J, Hz): 7.74
butoxy]-4H-chromen-4-one (3c). Yield 167 mg (79%),
1
(
(
2H, d, J = 8.6, H-2',6'); 6.92 (2H, d, J = 8.6, H-3',5'); 6.46
white solid, mp 136–138°C. H NMR spectrum, δ, ppm
1H, s, H-8); 6.48 (1H, s, H-3); 6.29 (1H, s, H-6); 4.13 (2H,
(J, Hz): 7.73 (2H, d, J = 8.5, H-2',6'); 6.91 (2H, d, J = 8.5,
t, J = 5.6, 5-OCH
2
); 3.82 (3H, s, 4'-OCH
3
); 3.80 (3H, s,
H-3',5'); 6.45 (2H, s, H-8 and H-3); 6.27 (1H, s, H-6); 4.00
7
-OCH
CH ); 2.73–2.58 (4H, m, N(CH
δ, ppm: 176.3; 162.8; 161.0; 159.7; 158.8; 158.8; 126.6; 122.8;
3
); 3.73–3.65 (4H, m, O(CH
2
)
2
); 2.89 (2H, t, J = 5.6,
(2H, t, J = 6.4, 5-OCH
2
); 3.81 (3H, s, 4'-OCH ); 3.79 (3H,
3
1
3
2
2
)
2
). C NMR spectrum,
s, 7-OCH
CH ); 1.81–1.70 (6H, m, 3CH ). C NMR spectrum, δ,
3
); 2.61–2.49 (6H, m, 3NCH ); 1.94–1.86 (2H, m,
2
13
2
2
1
5
13.3; 108.4; 106.6; 96.2; 92.1; 66.8; 66.0; 56.2; 54.7; 54.5;
ppm: 176.5; 162.8; 160.1; 159.5; 159.2; 158.8; 126.6;
122.9; 113.3; 108.4; 106.6; 95.9; 91.8; 68.2; 54.9; 54.7;
+
3.3. Mass spectrum (ESI), m/z (Irel, %): 412 [M+H] (100).
+
Found, m/z: 411.1676 [M] . C23
H
25NO
6
. Calculated, m/z:
54.5; 53.0; 25.9; 24.1; 22.4. Mass spectrum (EI), m/z (Irel, %):
+
4
11.1682.
-Methoxy-2-(4-methoxyphenyl)-5-[2-(4-methylpipera-
zin-1-yl)ethoxy]-4H-chromen-4-one (2g). Yield 176 mg
298 (100). Found, m/z: 423.2040 [M] . C25
lated, m/z: 423.2046.
H
29NO . Calcu-
5
7
7-Methoxy-2-(4-methoxyphenyl)-5-[4-(piperidin-1-yl)-
1
(
83%), white solid, mp 129–131°C. H NMR spectrum,
butoxy]-4H-chromen-4-one (3d). Yield 170 mg (78%),
1
δ, ppm (J, Hz): 7.74 (2H, d, J = 8.5, H-2',6'); 6.93 (2H, d,
J = 8.5, H-3',5'); 6.49 (1H, s, H-8); 6.46 (1H, s, H-3); 6.30
white solid, mp 116–118°C. H NMR spectrum, δ, ppm
(J, Hz): 7.80 (2H, d, J = 8.8, H-2',6'); 6.98 (2H, d, J = 8.8,
H-3',5'); 6.53 (1H, d, J = 2.1, H-8); 6.51 (1H, s, H-3); 6.33
(
1H, s, H-6); 4.14 (2H, t, J = 5.4, 5-OCH
2
); 3.83 (3H, s,
); 2.95 (2H, t, J = 5.3, CH );
); 2.63–2.53 (4H, m, 2CH ); 2.33
4
2
'-OCH
3
); 3.81 (3H, s, 7-OCH
3
2
(1H, d, J = 2.1, H-6); 4.06 (2H, t, J = 5.6, 5-OCH
2
); 3.88
); 2.75 (2H, t, J = 7.2,
); 1.96–1.92 (4H, m, 2CH );
); 1.54–1.47 (2H, m, CH ).
.83–2.75 (4H, m, 2CH
2
2
(3H, s, 4'-OCH
CH ); 2.72–2.62 (4H, m, 2NCH
1.75–1.70 (4H, m, 2CH
3
); 3.86 (3H, s, 7-OCH
3
13
(
3H, s, CH
3
). C NMR spectrum, δ, ppm: 176.4; 162.8;
2
2
2
1
1
61.1; 159.8; 158.8; 126.6; 122.8; 113.4; 108.3; 107.9;
2
2
13
06.6; 96.4; 92.3; 66.6; 55.4; 54.7; 54.5; 53.6; 52.0; 44.4.
C NMR spectrum, δ, ppm: 177.4; 163.8; 162.0; 160.6;
+
Mass spectrum (ESI), m/z (Irel, %): 425 [M+H] (100).
160.0 (2C); 127.5; 123.7; 114.3; 109.2; 107.4; 96.9; 92.9;
5
-[2-(4-Hydroxypiperidin-1-yl)ethoxy]-7-methoxy-
69.1; 58.3, 55.7; 55.4; 53.9; 26.6; 24.7; 23.6; 22.6.
+
2
(
-(4-methoxyphenyl)-4H-chromen-4-one (2h). Yield 174 mg
Found, m/z: 437.2197 [M] . C26
H
31NO . Calculated, m/z:
5
1
82%), yellow solid, mp 189–191°C. H NMR spectrum,
437.2202.
δ, ppm (J, Hz): 7.75 (2H, d, J = 7.8, H-2',6'); 6.93 (2H, d,
J = 7.9, H-3',5'); 6.50 (1H, s, H-8); 6.47 (1H, s, H-3); 6.31
5-[4-(1H-Imidazol-1-yl)butoxy]-7-methoxy-2-(4-methoxy-
phenyl)-4H-chromen-4-one (3e). Yield 166 mg (79%),
1
(
1H, s, H-6); 4.16 (2H, t, J = 5.1, 5-OCH
2
); 3.83 (3H, s,
); 3.70–3.64 (1H, m, CH);
); 2.45–2.43 (2H, m, NCH );
). C NMR spectrum, δ, ppm:
76.5; 162.9; 161.1; 159.8; 158.8; 126.6; 122.9; 113.4; 108.4;
06.6; 96.3; 92.3; 85.4; 66.5; 55.5; 54.7; 54.5; 50.5; 33.1.
white solid, mp 98–100°C. H NMR spectrum, δ, ppm
4
2
1
'-OCH
3
); 3.81 (3H, s, 7-OCH
3
(J, Hz): 7.74 (2H, d, J = 8.6, H-2',6'); 7.50 (1H, s, H-2
imidazole); 6.96 (2H, d, J = 9.4, H-4,5 imidazole); 6.92
(2H, d, J = 8.6, H-3',5'); 6.48 (1H, s, H-8); 6.46 (1H, s,
.97–2.92 (4H, m, 2NCH
2
2
1
3
.97–1.84 (4H, m, 2CH
2
1
H-3); 6.23 (1H, s, H-6); 4.10 (2H, t, J = 7.0, 5-OCH
2
); 3.97
); 3.80 (3H, s,
); 1.84–1.76 (2H, m,
). C NMR spectrum, δ, ppm: 177.4; 163.8; 162.1;
160.8; 160.0; 159.8; 137.3; 129.2, 127.6; 123.8; 119; 114.4;
1
(2H, t, J = 5.7, CH
2
); 3.82 (3H, s, 4'-OCH
3
+
Mass spectrum (ESI), m/z (Irel, %): 426 [M+H] (100).
-[4-(Dimethylamino)butoxy]-7-methoxy-2-(4-methoxy-
phenyl)-4H-chromen-4-one (3a). Yield 153 mg (77%),
7-OCH ); 2.10–2.04 (2H, m, CH
3
2
13
5
CH
2
8
74

Chemistry of Heterocyclic Compounds 2017, 53(8), 871–875
1
09.3; 107.6; 97.0; 93.0; 68.7; 55.8; 55.5; 46.7; 28.1; 25.8.
Supplementary information file containing analytical
data characterizing the synthesized compounds and dose-
response curves is available at the journal website http://
link.springer.com/journal/10593.
Mass spectrum (EI), m/z (Irel, %): 327 (6), 355 (16), 385
+
(
100), 403 (9), 418 (73). Found, m/z: 420.1680 [M] .
C
24
7
H
24
N
2
O
5
. Calculated, m/z: 420.1685.
-Methoxy-2-(4-methoxyphenyl)-5-[4-morpholino-
butoxy]-4H-chromen-4-one (3f). Yield 169 mg (77%),
yellow solid, mp 166–168°C. H NMR spectrum, δ, ppm
We thank the National Natural Science Foundation of
China (NO.J1210040) and Education Department of Hubei
Province Science and Technology Research Project of
China (NO.Q20162803) for the financial support.
1
(
J, Hz): 7.71 (2H, d, J = 7.3, H-2',6'); 6.89 (2H, d, J = 7.5,
H-3',5'); 6.44 (2H, s, H-3,8); 6.25 (1H, s, H-6); 3.99 (2H, t,
J = 6.4, 5-OCH
2
); 3.77 (3H, s, 4'-OCH
3
); 3.80 (3H, s,
References
7
-OCH
NCH
3
); 3.62 (4H, t, 2OCH ); 2.36 (6H, t, J = 16.3,
2
3
2
); 1.90–1.85 (2H, m, CH
2
); 1.74–1.66 (2H, m, CH
2
).
1. (a) Verma, A. K.; Pratap, R. Tetrahedron 2012, 68, 8523.
(b) Li, S.; Pan, M. H.; Lai, C. S.; Lo, C. Y.; Dushenkov, S.;
Ho, C. T. Bioorg. Med. Chem. 2007, 15, 3381. (c) Liu, H. R.;
Huang, X. Q.; Lou, D. H.; Liu, X. J.; Liu, W. K.; Wang, Q. A.
Bioorg. Med. Chem. Lett. 2014, 24, 4749. (d) Soltesova-
Prnova, M.; Milackova, I.; Stefek, M. Chem. Pap. 2016, 70, 1439.
1
3
C NMR spectrum, δ, ppm: 176.2; 162.8; 160.8; 159.5;
1
6
59.1; 158.5; 126.6; 122.9; 113.0; 108.3; 106.6; 95.9; 91.7;
8.0; 66.0; 57.7; 54.7; 54.2; 52.2; 25.4; 21.0. Found, m/z:
+
4
39.1989 [M] . C25
H
29NO . Calculated, m/z: 439.1995.
6
7
-Methoxy-2-(4-methoxyphenyl)-5-[4-(4-methylpipera-
2
.
(a) Zhao, J.; Pawar, R. S.; Ali Z.; Kham, I. A. J. Nat. Prod.
zin-1-yl)butoxy]-4H-chromen-4-one (3g). Yield 176 mg
2
007, 70, 289. (b) Kou, L. Q.; Cheng, X. L. Zhang, Z. T. J.
1
(
78%), white solid, mp 124–126°C. H NMR spectrum,
Chem. Crystallogr. 2008, 38, 21.
δ, ppm (J, Hz): 7.73 (2H, d, J = 8.5, H-2',6'); 6.91 (2H, d,
J = 8.5, H-3',5'); 6.46 (2H, s, H-3,8); 6.27 (1H, s, H-6);
3.
(a) Kuo, Y. J.; Hwang, S. Y.; Wu, M. D.; Liao, C. C.;
Liang, Y. H.; Kuo, Y. H.; Ho, H. O. Chem. Pharm. Bull. 2008,
56, 585. (b) Mori, A.; Nishino, C.; Enoki, N.; Tawata, S.
Phytochemistry 1988, 27, 1017. (c) Wongsrikaew, N.; Kim, H.;
Vichitphan, K.; Cho, S. K.; Han, J. J. Korean Soc. Appl. Biol.
Chem. 2012, 55, 813.
4
.00 (2H, t, J = 6.4, 5-OCH
2
); 3.82 (3H, s, 4'-OCH
3
); 3.80
(
3H, s, 7-OCH
3
); 2.38 (10H, m, 5NCH
2
); 2.20 (3H, s,
NCH
3
); 1.93–1.83 (2H, m, CH
2
); 1.75–1.65 (2H, m, CH ).
2
1
3
C NMR spectrum, δ, ppm: 176.4; 162.8; 161.0; 159.5;
1
6
59.3; 158.8; 126.6; 122.9; 113.3; 108.4; 106.7; 95.9; 91.7;
4. (d) Manthey, J. A.; Grohmann, K.; Guthrie, N. Curr. Med.
Chem. 2001, 8, 135. (b) Kesarkar, S.; Bhandage, A.;
Deshmukh, S.; Abhyankar, M. J. Pharm. Res. 2009, 2, 1148.
(a) Li, X.; Chen, G. L.; Zhang, X. J.; Zhang, Q.; Zheng, S. L.;
Wang, G. D.; Chen, Q. H. Bioorg. Med. Chem. Lett. 2016, 26,
8.1; 57.1; 54.7; 54.4; 54.1; 52.1; 45.0; 25.9; 22.3. Mass
+
spectrum (ESI), m/z (Irel, %): 453 [M+H] (100). Found, m/z:
+
4
52.2306 [M] . C26
H
32
N
2
O
5
. Calculated, m/z: 452.2311.
5
-[4-(4-Hydroxypiperidin-1-yl)butoxy]-7-methoxy-
4
241. (b) Yuan, J.; Wong, I.; Jiang, T.; Wang, S. W.; Liu, T.;
2
-(4-methoxyphenyl)-4H-chromen-4-one (3h). Yield 174 mg
Wen, B. J.; Chow, L. M.; Wan, S. B. Eur. J. Med. Chem. 2012,
1
(
77%), white solid, mp 182–184°C. H NMR spectrum,
5
4, 413. (c) Amrutha, K.; Pandurangan, N. J.; Shaji, S. K.;
δ, ppm (J, Hz): 7.80 (2H, d, J = 8.9, H-2',6'); 6.98 (2H, d,
J = 9.0, H-3',5'); 6.53 (1H, s, H-8); 6.52 (1H, d, J = 2.3,
H-3); 6.34 (1H, d, J = 2.3, H-6); 4.07 (2H, t, J = 6.5,
Sunilkumar, D.; Subhalakshmi, K.; Rajakrishna, L.; Banerji, A.
Bioorg. Med. Chem. Lett. 2014, 24, 4735.
5
.
(a) Kovaleva, K. S.; Yarovaya, O. I.; Shernyukov, A. V.;
Zarubaev, V. V.; Shtro, A. A.; Orshanskaya, Y. R.;
Salakhutdinov, N. F. Chem. Heterocycl. Compd. 2017, 53,
5
-OCH
2
); 3.89 (3H, s, 4'-OCH
3
); 3.87 (3H, s, 7-OCH );
3
3
.68 (1H, m, J = 11.1, J = 7.0, CHOH); 2.88–2.74 (2H, m,
); 2.50–2.37 (2H, m, NCH ); 2.14 (2H, t, J = 10.0,
); 1.97–1.87 (4H, m, 2CH ); 1.76 (2H, dt, J = 14.8,
3
64. [Khim. Geterotsikl. Soedin. 2017, 53, 364.] (b) Zhang, S.;
NCH
2
2
Ma, J.; Bao, Y.; Yang, P.; Zhou, L.; Li, K.; Sun, X. Bioorg. Med.
Chem. 2008, 16, 7127. (c) Bonesi, M.; Tundis, R.; Deguin, B.;
Loizzo, M. R.; Menichini, F.; Tillequin, F.; Menichini, F.
Bioorg. Med. Chem. Lett. 2008, 18, 5431. (d) Lozinskii, O. A.;
Shokol, T. V.; Khilya, V. P. Chem. Heterocycl. Compd. 2011,
CH
J = 7.4, CH
2
2
2
); 1.58 (2H, qd, J = 9.8, J = 3.7, CH ).
2
1
3
C NMR spectrum, δ, ppm: 177.4; 163.7; 161.9; 160.5;
1
6
60.2; 159.7; 127.5; 123.8; 114.2; 109.3; 107.6; 96.9; 92.6;
4
7, 1055. [Khim. Geterotsikl. Soedin. 2011, 1283.] (e) Liu, C.
9.1; 58.0; 55.6; 55.4; 51.0; 34.4; 26.9; 23.4. Mass
+
Y.; Dong, L. P.; Wang, S. C.; Wang, Q. A. Mol. Diversity
spectrum (ESI), m/z (Irel, %): 454 [M+H] (100).
2
015, 19, 737. (f) Voskoboynik, O. Y.; Kolomoets, O. S.;
Assay for antiproliferative activity. The antiprolife-
rative activity was evaluated by CCK-8 assay against three
Berest, G. G.; Nosulenko, I. S.; Martynenko, Y. V.;
Kovalenko, S. I. Chem. Heterocycl. Compd. 2017, 53, 256.
[Khim. Geterotsikl. Soedin. 2017, 53, 256.]
9
human cancer cell lines (HeLa, HCC1954, and SK-OV-3).
3
Briefly, cells (5×10 per well in a 96-well plate) were
6. (a) Singh, S.; Ahmad, A.; Raghuvanshi, D. S.; Hasanain, M.;
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treated with different concentrations of compounds 1, 2a–h,
and 3a–h (100, 25, 6.25, 1.56, 0.39, 0.0976, 0.0244, and
0
.0061 μM) for 48 h. Then 5% CCK-8 solution was added
to each well and incubated under conditions of 90%
humidity and 5% CO for another 1–3 h. Color develop-
2
ment was quantified photometrically at 450 nm.). An
absorbance microplate reader (EL×808, Bio-Rad 680) was
used to determine the concentration that killed 50% of cells
7. (a) Nguyen, V. S.; Dong, L. P.; Wang, S. C.; Wang, Q. A.
Eur. J. Org. Chem. 2015, 10, 2297. (b) Nguyen, V. S.; Shi, L.;
Luan, F. J.; Wang, Q. A. Acta. Biochim. Pol. 2015, 62, 547.
(
IC50). 10 μl of 1% sodium dodecyl sulfate (SDS) (dis-
(
c) Nguyen, V. S.; Shi, L.; Wang, S. C.; Wang, Q. A. Anti-
solving 0.1 g of SDS in phosphate buffer saline (PBS) to
prepare 10 ml of solution) or 10 μl of 0.1 mol/l acid, such
as hydrochloric acid was added to stop the color reaction.
The data represent the means of at least three separate
experiments.
Cancer. Agent. Med. Chem. 2017, 17, 137.
Wu, Z.; Cai, S. L.; Fan, W. J.; Wang, Q. A. Chinese J. Org.
Chem. 2012, 32, 1296.
8
.
9. Xuan, L. N.; Wang, P.; Zhang, K.; Shi, Y. P.; Liu, Y. M.;
Zhu, T.; Cheng, B. Q. Med. Chem. Res. 2015, 24, 543.
8
75