Synthesis and antiproliferative activity of aminoalkylated chalcones on three human cancer cells

Article abstract of DOI:10.1007/s00044-017-2120-6

Abstract: Two series of 16 novel aminoalkylated chalcone derivatives 2a–h and 3a–h were synthesized from 2′-hydroxy-3,4,4′,6′-tetramethoxychalcone (1) through extending alkoxy side chain at the 2′-position, and introducting amine hydrogen bond receptor at the end of the side chain. Their in vitro antiproliferative activities were evaluated on a panel of three human cell lines (Hela, HCC1954, and SK-OV-3) by CCK-8 assay. The results showed that all the target compounds, except compound 3e, exhibited moderate to potent antiproliferative activities against these three human cancer cells with the IC₅₀ values of 6.78–64.45 μmol/L, in particular compounds 2g (on Hela cells), 2c (on HCC1954 cells), and 2c, 2d (on SK-OV-3 cells) possess IC₅₀ values below 10 μmol/L. It showed the introduction of aminoalkyl moiety at 2′-O-position of chalcone 1 resulted to produce the desired effect of increasing the antiproliferative activities, and the distance between the amino groups and chalcone moiety plays an important role, the optimal number of methylene units is two-carbon spacer. Graphical abstract: A series of 16 novel aminoalkylated chalcones were synthesized and their antiproliferative acivities on three human cancer cells were evaluated. [InlineMediaObject not available: see fulltext.].

Full text of DOI:10.1007/s00044-017-2120-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-2120-6
ORIGINAL RESEARCH
Synthesis and antiproliferative activity of aminoalkylated
chalcones on three human cancer cells
1 ●
2 ●
1 ●
1
Cui Li Gangqiang Wang Xueli Li Qiuan Wang
Received: 5 July 2017 / Accepted: 14 November 2017
©
Springer Science+Business Media, LLC, part of Springer Nature 2017
Abstract Two series of 16 novel aminoalkylated chalcone
derivatives 2a–h and 3a–h were synthesized from 2′-
hydroxy-3,4,4′,6′-tetramethoxychalcone (1) through extend-
ing alkoxy side chain at the 2′-position, and introducting
amine hydrogen bond receptor at the end of the side chain.
Their in vitro antiproliferative activities were evaluated on a
panel of three human cell lines (Hela, HCC1954, and SK-
OV-3) by CCK-8 assay. The results showed that all the
target compounds, except compound 3e, exhibited moderate
to potent antiproliferative activities against these three human
cancer cells with the IC50 values of 6.78–64.45 μmol/L, in
particular compounds 2g (on Hela cells), 2c (on HCC1954
cells), and 2c, 2d (on SK-OV-3 cells) possess IC50 values
below 10 μmol/L. It showed the introduction of aminoalkyl
moiety at 2′-O-position of chalcone 1 resulted to produce the
desired effect of increasing the antiproliferative activities,
and the distance between the amino groups and chalcone
moiety plays an important role, the optimal number of
methylene units is two-carbon spacer.
Graphical abstract A series of 16 novel aminoalkylated
chalcones were synthesized and their antiproliferative
acivities on three human cancer cells were evaluated.
●
●
Keywords Chalcone Aminoalkylated derivatives
Electronic supplementary material The online version of this article
●
Synthesis Antiproliferative activity
(https://doi.org/10.1007/s00044-017-2120-6) contains supplementary
material, which is available to authorized users.
*
Qiuan Wang
wangqa@hnu.edu.cn
1
2
Introduction
College of Chemistry and Chemical Engineering, Hunan
University, Changsha 410082, China
Chalcones are precursors in the biosynthesis of flavonoids
and occur widely in medicinal plants. Chemically, they
School of Nuclear Technology and Chemistry & Biology, Hubei
University of Science and Technology, Hubei 437100, China

Med Chem Res
consist of two aromatic rings linked by a three-carbon α, β-
unsaturated system. Chalcones have attracted much research
attention because of their biological activity and pharma-
ceutical potential resulting from their antitumor, anti-
inflammatory, antioxidant, and neuroprotective properties
synthesis and biological activity of chalcones with ami-
noalkyl moieties.
2′-Hydroxy-3,4,4′,6′-tetramethoxychalcone (1), a syn-
thetic 2′-hydroxy polymethoxylated chalcone, posses an
appealing pharmacological profile combining high anti-
oxidant, and lipid peroxidation activity with potent soybean
LOX inhibition (Detsi et al. 2009). On the basis of these
results and following our previous work (Huang et al. 2014;
Nguyen et al. 2017; Dong et al. 2015), herein we report the
synthesis of two series of 16 novel aminoalkylated chalcone
derivatives 2a–h and 3a–h from 2′-hydroxy-3,4,4′,6′-tetra-
methoxy chalcone (1) through extending alkoxy side chain
at the 2′-position, and introducing amine hydrogen bond
receptor at the end of the side chain. Their in vitro anti-
proliferative activities against three human cancer cell lines
Hela (cervical carcinoma), HCC1954 (breast cancer), and
SK-OV-3 (ovarian cancer) were evaluated using cell
counting kit-8 (CCK-8) assay.
(
Barbic et al. 2010; Campbell et al. 2016; Blanc et al. 2008;
Abd-Rahman et al. 2014; Li et al. 2017). Among these
properties, antitumor effects were most extensively exam-
ined (Kuppuswami et al. 2015; EI-Melige et al. 2017;
Emami et al. 2016). However, the in vitro efficacy and
mode of action of chalcones are controversial since polar
polyphenols are poorly absorbed, do not conform to the
Lipinski rules (Dominy et al. 2001; Lipinski 2004), and are
rapidly metabolized by liver enzymes in plasma, leading to
insignificant bioavailability (Abay et al. 2015). It thus
remains a challenge to reconcile their poor bioavailability
with putative health effects.
Most drugs contain nitrogen, and the introduction of the
aminoalkyl group into molecules is a general strategy for
improving bioactivity (Bandeira et al. 2016; Bao et al. 2008;
Balakishan et al. 2010). Aminoalkylation of drugs could be
used to increase the hydrophilic properties of drugs through
the introduction of a polar function in their structure (Bonesi
et al. 2008). The solubility in water of a drug could be
further enhanced through the quaternization of the nitrogen
atom in its aminoalkylated derivative and conversion into
an ammonium salt. Little research has been reported on the
Results and discussion
Synthesis of novel aminoalkylated chalcone derivatives
2a–h and 3a–h from 2′-hydroxy-3,4,4′,6′-tetramethoxy
chalcone (1) is shown in Scheme 1. Chalcone 1 was syn-
thesized by aldol condensation of 2-hydroxy-4,6-dimethoxy
acetophene with 3,4-dimethoxy benzaldeyde according to
Scheme 1 Sythesis of aminoalkylated polymethoxychalcone derivatives 2a–h and 3a–h. Reaction conditions: a (CH
3 2 4 2 3
) SO , K CO , acetone,
reflux; b 25% NaOH (aq), C OH, r.t.; c K CO , dibromoalkanes, acetone, reflux; d amines, K CO , KI, CH CN, reflux
H
2 5
2
3
2
3
3

Med Chem Res
Table 1 Half-inhibitory concentrations (IC50 in μmol/L) of
compounds 1, 2a–h, and 3a–h on the human cancer cell lines
derivatives except 3e showed moderate to potent anticancer
activity to tested cell lines with IC50 values ranging from
Compounds
Hela
HCC1954
SK-OV-3
6.78 to 64.45 μmol/L. Therefore, the comparision of these
new synthesized aminoalkylated chalcones with parent
chalcone revealed that the introduction of aminoalkyl
moiety at 2′-O-position of chalcone 1 resulted to produce
the desired effect of increasing the antiproliferative activ-
ities. It was established chalcones with an aminoalkyl
moiety on the aromatic ring exhibit promising in vitro
antiproliferative activity. This supports the hypothesis that
nitrogen-containing chalcones would enhance biological
activity compared to non-nitrogen analogs. A good number
of synthesized derivatives showed remarkable more potency
as compared to positive control cis-Platin, compounds 2a–h
series except 2f were equal or more potent (lower IC50
values) against Hela cells with IC50 values of 8.80–13.43
μmol/L than the positive control cis-Platin (IC50 13.30
μmol/L), compounds 2a–h, 3a, and 3c were equal or more
potent against HCC1954 cells with IC50 values of
6.78–28.98 μmol/L than the positive control cis-Platin
1
>100
>100
>100
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
a
b
c
10.03 ± 0.38
10.44 ± 0.68
12.29 ± 0.89
13.43 ± 1.60
11.62 ± 0.14
22.24 ± 0.25
8.80 ± 0.88
12.7 ± 0.66
29.45 ± 1.33
40.83 ± 1.21
33.45 ± 0.71
37.06 ± 1.50
>100
16.16 ± 0.72
18.85 ± 2.42
6.78 ± 0.43
17.12 ± 0.58
28.98 ± 3.01
23.94 ± 0.49
17.51 ± 2.25
27.29 ± 4.12
26.01 ± 0.94
34.73 ± 0.57
16.37 ± 0.70
28.29 ± 2.37
>100
11.16 ± 1.34
12.01 ± 3.88
8.15 ± 1.24
8.87 ± 0.83
16.87 ± 0.17
19.94 ± 2.37
14.33 ± 0.10
19.16 ± 2.07
45.18 ± 3.78
48.44 ± 0.66
58.52 ± 3.51
49.63 ± 3.68
>100
d
e
f
g
h
a
b
c
d
e
f
46.58 ± 1.01
38.63 ± 1.16
51.79 ± 6.09
13.30 ± 1.93
0.0055 ± 5.2E-07
38.15 ± 1.42
30.59 ± 3.81
46.12 ± 1.87
29.32 ± 2.22
0.009 ± 2.17E-06
40.10 ± 1.84
64.45 ± 3.01
54.18 ± 3.54
18.66 ± 0.46
0.0028 ± 3.36E-08
0.0031 ± 3.13E-08
g
h
a
cis-Platin
a
Paclitaxel
a
Staurosporin
a
0.0112 ± 1.69E-06 0.037 ± 3E-06
(IC50 29.32 μmol/L), and compounds 2a–h series were
equal or more potent against SK-OV-3 cells with IC50
cis-Platin Paclitaxel and Staurosporin were employed as positive
controls
values 8.15–19.16 μmol/L than the positive control cis-
Platin (IC50 18.66 μmol/L). In particular, compound 2g
characterized with pyrrolidinylethoxyl substituent on Hela
cells, compound 2c characterized with diethylaminoethoxyl
substituent on HCC1954 cells, and compounds 2c, 2d
characterized with piperidinylethoxyl substituent on SK-
OV-3 cells showed markedly potency with IC50 value
below 10 μmol/L. Furthermore, we have carried out some
experiments to evaluate the synthesized derivatives’ biolo-
gical activitiy, unfortunately the biological of corresponding
products showed higher IC50 values than Paclitaxel and
Staurosporin.
With the increase of the length of alkyl chain of ami-
noalkylated chalcone from two-carbon to four-carbon
spacer, there is a significant decrease in antiproferative
activities against all the three cancer cells. It showed the
distance between the amino groups and chalcone moiety
plays an important role, the optimal number of methylene
units is two-carbon spacer in our present experiments, and
some aminoalkylated chalcone with two-carbon posses IC50
values of below 10 μmol/L.
the reported procedure (Detsi et al. 2009; Fernandes et al.
014). The coupling constant of 15.5–16.5 H observed of
2
Z
1
HNMR in olefinic protons Hα and Hβ indicates the for-
mation of only the expected E isomer. Compounds 4 and 5
were the key intermediates, they were prepared from alky-
lation of 2′-OH group by using dihaloalkanes via Wil-
liamson ether synthesis (Dong et al. 2010). Thus, 1 was
alkylated with the equivalent amount of potassium carbo-
nate in acetone followed by the addition of excessive
amounts of 1,2-dibromoethane or 1,4-dibromobutane furn-
ished 4 or 5. Subsequently, compounds 4 or 5 was reacted
with two equivalent secondary amines, anhydrous K CO
2
3
and the catalytic amount of KI in CH CN at 60–65 °C. This
3
process produced the desired target aminoalkylated chal-
cones 2a–h and 3a–h in moderate to good yields.
Chalcone 1 and 16 novel aminoalkylated chalcone deri-
vatives 2a–h and 3a–h were investigated for their anti-
proliferative activity employing the CCK-8 assay with cis-
Platin, Paclitaxel and Staurosporin as possitive controls
against three human cancer cell lines (Hela, HCC1954, and
SK-OV-3). Their activities were expressed by the con-
centration of drug inhibiting 50% cell growth (IC ) and
Conclusion
5
0
data are presented in Table 1. The dose-response curves for
CCK-8 assay of compound 2g on Hela cells, compound 2c
on HCC1954 cells, and compounds 2c, 2d on SK-OV-3
cells proliferation are shown in Fig. 1.
In conclusion, two series of 16 novel aminoalkylated
chalcone derivatives 2a–h and 3a–h were synthesized from
2′-hydroxy-3,4,4′,6′-tetramethoxychalcone (1).
A good
As show in Table 1, the parent chalcone 1 did not dis-
played any antiproliferative activity to the three cancer cells
number of synthesized aminoalkylated chalcones exhibit
comparable or higher antiproliferative activities than the
positive control drug cis-Platin, some compounds (2g on
(
IC50 > 100 μmol/L), while all aminoalkylated chalcone

Med Chem Res
Fig. 1 The dose-response
curves of compounds 2g (on
Hela), 2c (on HCC1954), and
The inhibitory effect of 2g
on Hela cell proliferation
The inhibitory effect of 2d
on SK-OV-3 cell proliferation
1
10
100
2
c, 2d (on SK-OV-3) cell
9
0
8
6
4
2
0
0
0
0
0
proliferation
70
50
30
10
10
1
2
3
4
5
-
20
-
1
2
3
4
5
Log compound (μM )
IC = 8.80 μM
Log compound (μM )
50
IC = 8.87 μM
5
0
The inhibitory effect of 2c
on HCC1954 cell proliferation
The inhibitory effect of 2c
on SK-OV-3 cell proliferation
1
10
110
9
7
5
3
1
0
0
0
0
0
9
0
70
50
30
10
-
10
-10
1
2
3
4
5
1
2
3
4
5
Log compound (¦ÌM )
Log compound (μM )
IC = 8.15 μM
IC = 6.78 ¦ÌM
5
0
5
0
Hela cells, 2c on HCC1954 cells, and 2c, 2d on SK-OV-3
cells) possess IC50 values of below 10 μmol/L. It was
established chalcones with an aminoalkyl moiety on the
aromatic ring exhibit promising in vitro antiproliferative
activity. This supports the hypothesis that nitrogen-
containing chalcones would enhance biological activity
compared to non-nitrogen analogs. The distance between
the amino groups and chalcone moiety plays an important
role, the optimal number of methylene units is two-carbon
spacer. The aminoethylated chalcones are a class of
potential antitumor agents and worthy of further
investigation.
were determined by an XRC-1 apparatus and were uncor-
rected. Column chromatography was carried out on silica
gel 200–300 mesh (Qingdao Ocean Chemical Products of
China). Commercially available AR or chemical pure
reagents, and anhydrous solvent removed water and redis-
tilled were employed.
2-Hydroxy-4,6-dimethoxyacetophenone and 2′-hydroxy-
3,4,4′,6′-tetramethoxy chalcone (1) were prepared from
phloroglucinol according to previous methods (Detsi et al.
2009; Chen et al. 2016).
Synthesis of 2′-(2-bromoethoxy)-3,4,4′,6′-tetramethoxy
chalcone (4) and 2′-(2-bromobutoxy)-3,4,4′,6′-tetramethoxy
chalcone (5)
Experimental part
General
1,2-Dibromoehtane or 1,4-dibromobutane (0.18 mL, 2
mmol) was added dropwise to a solution of 2′-hydroxy-
3,4,4′,6′-tetramethoxy chalcone (0.5 g, 1.45 mmol) and
potassium carbonate in dry acetone (50 mL), and the mix-
ture (stirred at ambient temperature beforehand for 1 h) was
refluxed for 24 h. The progress of the reaction was mon-
itored by TLC. After cooling to room temperature, the
mixture was filtered, the solvent was evaporated, and the
residue was purified by silica gel chromatography (petro-
leum ether/ethyl acetate = 3:1, volume ratio) to afford
compound 4 or 5.
1
13
The H NMR and C NMR spectra were recorded using
TMS as the internal standard in CDCl with a Bruker-
3
AV400 spectrometer at 400 and 100 MHz, respectively.
The chemical shifts (δ) were measured by ppm, and cou-
pling constant (J) was calculated in hertz (Hz). Mass spectra
(
MS), high-resolution mass spectrometry (HRMS) were
determined with VG Autospec-3000 or Mat 95 XP spec-
trometer and Micromass ZQ 2000 mass spectrometer
(
Manchester, UK) by the EI or ESI method. Melting points

Med Chem Res
2
′-(2-Bromoethoxy)-3,4,4′,6′-tetramethoxychalcone (4)
156.88, 150.10, 148.12, 143.50, 126.88, 126.24, 121.87,
111.19, 110.03, 108.95, 90.64, 90.08, 66.55, 56.81, 54.93,
1
Yield: 87%, yellow oil. H NMR (400 MHz, CDCl3): 7.21
+
(
d, J = 15.6 Hz, 1H, β-H), 7.03–7.01 (m, 2H, α-H and 2-H),
54.89, 54.86, 54.43, 44.95. MS(EI): m/z 415.20 [M] ,
+
6
1
.83–6.77 (m, 2H, 5-H and 6-H), 6.13 (s, 1H, 5′-H), 6.07 (s,
HRMS(EI): m/z 415.2005 [M] (calcd for C H O N
2
3 29 6
H, 3′-H), 4.19 (t, J = 6.1 Hz, 2H, OCH ), 3.84 (s, 3H, 3-
415.1995).
2
OCH ), 3.82 (s, 3H, 4-OCH ), 3.78 (s, 3H, 4′-OCH ), 3.70
3
3
3
1
3
(
s, 3H, 6′-OCH ), 3.45 (t, J = 6.0 Hz, 2H, CH Br).
C
3
2
2
′-(2-Diethylaminoethoxy)-3,4,4′,6′-tetramethoxychalcone
NMR (100 MHz, CDCl ): δ 193.12, 161.42, 158.08,
1
3
(
2b) Yield: 75%, pale yellow oil. H NMR (400 MHz,
1
1
5
56.25, 150.35, 148.33, 143.96, 127.09, 126.34, 122.28,
11.86, 110.17, 109.15, 91.21, 90.91, 68.04, 55.21, 55.16,
5.10, 54.79, 27.96. MS(EI): m/z 450.07 [M] , HRMS(EI):
CDCl ): δ 7.19 (d, J = 16.1 Hz, 1H, β-H), 7.01 (d, J = 16.3
3
Hz, 1H, α-H), 6.98 (s, 1H, 2-H), 6.78 (d, J = 5.9 Hz, 1H, 5-
H), 6.75 (d, J = 6.2 Hz, 1H, 6-H), 6.10 (s, 2H, 3′-H and 5′-
H), 4.02 (t, J = 5.8 Hz, 2H, OCH ), 3.83 (s, 3H, 3-OCH ),
+
+
m/z 450.0680 [M] (calcd for C H O Br 450.0678).
2
1 23 6
2
3
3
6
.82 (s, 3H, 4-OCH ), 3.77 (s, 3H, 4′-OCH ), 3.68 (s, 3H,
3 3
2
′-(4-Bromobutoxy)-3,4,4′,6′-tetramethoxychalcone (5)
′-OCH ), 2.79 (t, J = 5.7 Hz, 2H, CH N), 2.54 (q, J = 7.1
3
2
1
Yield: 89%, yellow oil. H NMR (400 MHz, CDCl ): δ 7.19
13
3
Hz, 4H, 2NCH ), 0.91 (t, J = 7.1 Hz, 6H, 2CH ). C NMR
2
3
(
d, J = 15.6 Hz, 1H, β-H), 7.01–6.98 (m, 2H, α-H and 2-H),
(100 MHz, CDCl ): δ 193.52, 161.25, 157.66, 156.70,
3
6
1
.81–6.72 (m, 2H, 5-H and 6-H), 6.09 (s, 1H, 5′-H), 6.06 (s,
1
1
5
50.19, 148.18, 143.77, 126.85, 126.22, 121.91, 110.98,
10.05, 109.00, 90.43, 90.22, 66.04, 54.96, 54.92, 54.89,
H, 3′-H), 3.89 (t, J = 5.6 Hz, 2H, OCH ), 3.82 (s, 6H, 3,4-
2
OCH ), 3.77 (s, 3H, 4′-OCH ), 3.6 9 (s, 3H, 6′-OCH ), 3.23
+
3
3
3
4.48, 50.09, 46.40, 10.13. MS(EI): m/z 443.21 [M] ,
1
3
(
t, J = 6.3 Hz, 2H, CH Br), 1.90–1.70 (m, 4H, 2CH ).
C
+
2
2
HRMS(EI): m/z 443.2303 [M] (calcd for C H O N
4
2
5 33 6
NMR (100 MHz, CDCl ): δ 194.33, 162.27, 158.77,
3
43.2308).
1
1
6
57.92, 151.19, 149.21, 144.58, 127.88, 127.30, 122.91,
12.16, 111.07, 109.96, 91.53, 91.03, 77.38, 77.07, 76.75,
7.55, 56.12–55.82, 55.48, 33.51, 29.19, 27.54. MS(EI): m/
2
′-(2-Dipropylaminoethoxy)-3,4,4′,6′-tetramethoxychalcone
1
+
+
(2c) Yield: 63%, yellow oil. H NMR (400 MHz, CDCl ):
3
z 478.10 [M] , HRMS(EI): m/z 478.0997 [M] (calcd for
C H O Br 478.0991).
δ 7.19 (d, J = 16.2 Hz, 1H, β-H), 7.00 (d, J = 16.1 Hz, 1H,
α-H), 6.97 (s, 1H, 2-H), 6.77 (s, 1H, 5-H), 6.74 (d, J = 9.5
Hz, 1H, 6-H), 6.08 (d, J = 4.3 Hz, 2H, 3′-H and 5′-H), 3.92
2
3 27 6
(
t, J = 6.3 Hz, 2H, OCH ), 3.81 (s, 6H, 3, 4-OCH ), 3.76 (s,
2 3
General procedure for the synthesis of aminoalkylated
chalcone derivatives 2a–h and 3a–h
3
2
7
H, 4′-OCH ), 3.67 (s, 3H, 6′-OCH ), 2.67 (t, J = 6.3 Hz,
3 3
H, CH N), 2.33–2.25 (m, 4H, 2NCH ), 1.29 (d, J = 14.8,
2
2
1
3
.4 Hz, 4H, 2CH ), 0.71 (t, J = 7.3 Hz, 6H, 2CH ).
C
2
3
To a suspension of compound 4 or 5 (0.32 mmol) and
NMR (100 MHz, CDCl ): δ 193.26, 161.21, 157.68,
3
anhydrous K CO (0.64 mmol) in CH CN (5 mL), the
2
3
3
1
1
5
57.07, 150.10, 148.15, 143.39, 126.95, 126.29, 121.86,
11.12, 110.05, 108.97, 90.54, 89.97, 66.66, 55.87, 54.92,
4.88, 54.84, 54.41, 51.81, 51.68, 19.42, 10.77. MS(EI): m/
corresponding secondary amine (0.32 mmol) and a catalytic
amount of KI were added, and the resulting mixture was
refluxed for 1 h. After filtering, the resulting filtrate was
evaporated to dryness under reduced pressure. The residue
was suspended in water (20.0 mL), and extracted with
dichloromathane (3 × 25 mL). The combined organic were
evaporated under reduced pressure. The residue was pur-
ified on a silica gel chromatography (petroleum ether/ethyl
acetate = 3:1–1:1 with several drops of triethylamine,
volume ratio) to afford 2a–h or 3a–h.
+
+
z 471.23 [M] , HRMS(EI): m/z 471.2619 [M] (calcd for
C H O N 471.2621).
2
7 37 6
2′-(2-Piperidinylethoxy)-3,4,4′,6′-tetramethoxychalcone
(2d) Yield: 70%, yellow oil. H NMR (400 MHz, CDCl ):
δ 7.17 (d, J = 15.8 Hz, 1H, β-H), 7.01 (d, J = 15.9 Hz, 1H,
α-H), 6.97 (s, 1H, 2-H), 6.76 (m, 1H, 5-H, 6-H), 6.09 (d, J
1
3
=
5.1 Hz, 2H, 3′-H, 5′-H), 4.11 (t, J = 5.0 Hz, 2H, OCH2),
2
′-(2-Dimethylaminoethoxy)-3,4,4′,6′-tetramethoxychal-
3.82 (s, 6H, 3, 4-OCH ), 3.76 (s, 3H, 4′-OCH ), 3.68 (s, 3H,
3
3
1
cone (2a) Yield: 81%, pale yellow oil. HNMR (400
MHz, CDCl ): δ 7.17 (d, J = 15.9 Hz, 1H, β-H), 6.99 (d, J
6′-OCH ), 2.81 (t, J = 5.0 Hz, 2H, CH N), 2.52 (s, 4H,
3 2
1
3
2NCH ), 1.45 (m, 4H, 2CH ), 1.28 (s, 2H, CH ). C NMR
3
2 2 2
=
16.0 Hz, 1H, α-H), 6.97 (s, 1H, 2-H), 6.77 (d, J = 2.6 Hz,
(100 MHz, CDCl ): δ 193.59, 161.30, 157.64, 156.32,
3
1
H, 5-H), 6.74 (d, J = 5.0 Hz, 1H, 6-H), 6.08 (s, 2H, 3′-H
150.25, 148.20, 143.97, 126.73, 126.17, 121.93, 110.86,
110.07, 109.01, 90.38, 90.34, 64.93, 55.63, 54.97, 54.91,
and 5′-H), 3.97 (t, J = 5.8 Hz, 2H, OCH ), 3.80 (s, 6H, 3, 4-
OCH ), 3.75 (s, 3H, 4′-OCH ), 3.67 (s, 3H, 6′-OCH ), 2.55
2
+
54.51, 53.17, 23.56, 22.23. MS(EI): m/z 455.20 [M] ,
3
3
3
1
3
+
(
t, J = 5.8 Hz, 2H, CH N), 2.13 (s, 6H, N(CH ) ).
C
HRMS(EI): m/z 455.2305 [M] (calcd for C H O N
2
3 2
26 33 6
NMR (100 MHz, CDCl ): δ 193.28, 161.23, 157.70,
455.2308).
3

Med Chem Res
2
′-[2-(1-Methylhexahydropyrazinyl)ethoxy]-3,4,4′,6′-tetra-
3.50 (m, 1H, OH), 2.74–2.66 (m, 2H, CH N), 2.64 (t, J =
2
1
methoxychalcone (2e) Yield: 68%, pale yellow oil. H
5.6 Hz, 2H, CH ), 2.13 (t, J = 6.6 Hz, 2H, CH ), 1.96 (s,
2
2
NMR (400 MHz, CDCl ): δ 7.18 (d, J = 15.7 Hz, 1H, β-H),
1H, OH), 1.75–1.63 (m, 2H, CH ), 1.45–1.32 (m, 2H,
3
2
1
3
7
.00 (d, J = 15.8 Hz, 1H, α-H), 6.97 (s, 1H, 2-H), 6.77 (d, J
5.8 Hz, 1H, 5-H), 6.74 (d, J = 7.6 Hz, 1H, 6-H), 6.08 (d,
J = 5.5 Hz, 2H, 3′-H, 5′-H), 4.00 (t, J = 5.6 Hz, 2H, OCH2),
CH2). C NMR (100 MHz, CDCl ): δ 193.66, 161.26,
3
=
157.67, 156.70, 150.22, 148.17, 143.87, 126.80, 126.18,
121.94, 110.97, 110.09, 109.05, 90.53, 90.12, 66.06, 55.64,
54.97, 54.92, 54.91, 54.48, 50.45, 33.10. MS(EI): m/z
3
6
2
.82 (s, 6H, 3, 4-OCH ), 3.76 (s, 3H, 4′-OCH ), 3.68 (s, 3H,
3 3
+
+
′-OCH ), 2.62 (t, J = 5.6 Hz, 2H, CH N), 2.42 (s, 4H,
471.22 [M] , HRMS(EI): m/z 471.2230 [M] (calcd for
3
2
1
3
NCH ), 2.20 (s, 4H, 2CH ), 2.09 (s, 3H, CH ). C NMR
C H O N 471.2257).
26 33 6
2
2
3
(
100 MHz, CDCl ): δ 193.50, 161.19, 157.65, 156.75,
3
1
1
5
50.16, 148.17, 143.72, 126.83, 126.22, 121.89, 111.05,
10.02, 108.96, 90.49, 90.04, 66.30, 55.77, 54.96, 54.90,
4.88, 54.44, 53.90, 52.58, 44.87, 28.66, 13.18. MS(EI): m/
2′-(4-Dimethylaminobutoxy)-3,4,4′,6′-tetramethoxychal-
cone (3a) Yield: 80%, pale yellow oil. H NMR (400
1
MHz, CDCl ): δ 7.19 (d, J = 15.6 Hz, 1H, β-H), 7.00–6.97
3
+
+
z 470.21 [M] , HRMS(EI): m/z 470.2416 [M] (calcd for
C H O N 470.2417).
(m, 2H, α-H, 2-H), 6.77 (d, J = 2.7 Hz, 1H, 5-H), 6.74 (d, J
= 4.6 Hz, 1H, 6-H), 6.06 (s, 2H, 3′-H, 5′-H), 3.86 (t, J =
2
5 34 6 2
6
.1 Hz, 2H, OCH ), 3.80 (s, 6H, 3, 4-OCH ), 3.74 (s, 3H,
2 3
2
′-(2-Morpholinylethoxy)-3,4,4′,6′-tetramethoxychalcone
6′-OCH ), 3.66 (s, 3H, 4′-OCH ), 2.11–2.06 (m, 2H,
3 3
1
(
2f) Yield: 90%, pale yellow oil. H NMR (400 MHz,
NCH ), 2.00 (s, 6H, 2CH ), 1.68–1.53 (m, 2H, CH ),
2 3 2
1
3
CDCl ): δ 7.17 (d, J = 16.0 Hz, 1H, β-H), 7.00 (d, J = 16.1
1.47–1.36 (m, 2H, CH2). C NMR (100 MHz, CDCl ): δ
3
3
Hz, 1H, α-H), 6.97 (s, 1H, 2-H), 6.77 (d, J = 5.7 Hz, 1H, 5-
H), 6.74 (d, J = 7.5 Hz, 1H, 6-H), 6.10 (s, 1H, 3′-H), 6.08
194.35, 162.23, 158.75, 158.17, 151.12, 149.20, 144.38,
128.00, 127.32, 122.89, 111.05, 109.98, 91.54, 90.90,
77.35, 77.04, 76.72, 68.52, 59.07, 56.07–55.79, 55.44,
46.06, 45.10, 26.94, 23.93, 11.18. MS(ESI): m/z 444.10 [M
(
s, 1H, 5′-H), 4.02 (t, J = 5.4 Hz, 2H, OCH ), 3.82 (s, 6H, 3,
2
4
3
2
-OCH ), 3.77 (s, 3H, 4′-OCH ), 3.68 (s, 3H, 6′-OCH ),
3 3 3
+
+
.50–3.44 (m, 4H, 2OCH ), 2.62 (t, J = 5.3 Hz, 2H, CH N),
+H] , HRMS(EI): m/z 443.2302 [M]
(calcd for
2
2
1
3
.42–2.36 (m, 4H, 2NCH2). C NMR (100 MHz, CDCl3):
C H O N 443.2308).
25
33 6
δ 193.54, 161.21, 157.66, 156.64, 150.24, 148.21, 143.85,
1
9
5
26.70, 126.18, 121.85, 111.03, 110.03, 108.91, 90.54,
0.07, 66.35, 65.74, 56.28, 54.95, 54.91, 54.89, 54.46,
2′-(4-Diethylaminobutoxy)-3,4,4′,6′-tetramethoxychalcone
(3b) Yield: 82%, pale yellow oil. H NMR (400 MHz,
1
+
3.13, 28.67, 13.18. MS(EI): m/z 457.21 [M] , HRMS(EI):
CDCl ): δ 7.28 (d, J = 16.0 Hz, 1H, β-H), 7.09–7.06 (m,
3
+
m/z 457.2107 [M] (calcd for C H O N 457.2101).
2H, α-H, 2-H), 6.86 (d, J = 4.0 Hz, 1H, 5-H), 6.83 (d, J =
2
5 31 7
3.6 Hz, 1H, 6-H), 6.16 (s, 2H, 3′-H, 5′-H), 3.96 (t, J = 6.2
2
′-(2-Pyrrolidinylethoxy)-3,4,4′,6′-tetramethoxychalcone
Hz, 2H, OCH ), 3.90 (s, 6H, 3, 4-OCH ), 3.84 (s, 3H, 6′-
OCH ), 3.76 (s, 3H, 4′-OCH ), 2.40 (d, J = 7.1 Hz, 2H,
3 3
2
3
1
(
2g) Yield: 75%, pale yellow oil. H NMR (400 MHz,
CDCl ): δ 7.19 (d, J = 16.0 Hz, 1H, β-H), 7.00 (d, J = 15.9
NCH ), 2.39–2.31 (m, 4H, 2NCH ), 1.69–1.66 (m, 2H,
3
2
2
Hz, 1H, α-H), 6.98 (s, 1H, 2-H), 6.78 (s, 1H, 5-H), 6.75 (d,
J = 7.8 Hz, 1H, 6-H), 6.09 (s, 2H, 3′-H, 5′-H), 4.02 (t, J =
CH ), 1.49–1.46 (m, 2H, CH ), 0.94–0.90 (m, 6H, 2CH ).
2 2 3
1
3
C NMR (100 MHz, CDCl ): δ 194.32, 162.20, 158.69,
3
5
4
.8 Hz, 2H, OCH ), 3.82 (s, 6H, 3, 4-OCH ), 3.76 (s, 3H,
158.16, 151.07, 149.14, 144.34, 127.94, 127.26, 122.88,
112.09, 111.01, 109.87, 91.49, 90.78, 68.61, 56.03–55.74,
55.41, 52.34, 46.55, 27.22, 23.21, 11.55. MS(ESI): m/z
2
3
′-OCH ), 3.68 (s, 3H, 6′-OCH ), 2.73 (t, J = 5.8 Hz, 2H,
3
3
CH N), 2.44 (s, 4H, 2CH ), 1.57 (dd, J = 6.4, 3.1 Hz, 4H,
2
2
1
3
+
+
2
1
1
5
4
CH2). C NMR (100 MHz, CDCl ): δ 194.52, 162.21,
472.30 [M+H] , HRMS(EI): m/z 471.2627 [M] (calcd for
3
58.67, 157.86, 151.11, 149.13, 144.68, 127.88, 127.27,
22.89, 112.07, 111.00, 109.94, 91.47, 91.05, 68.26, 55.95,
5.91, 55.87, 55.45, 54.80, 54.49, 23.41. MS(EI): m/z
C H O N 471.2621).
2
7 37 6
2′-(4-Dipropylaminobutoxy)-3,4,4′,6′-tetramethoxychal-
+
+
1
41.20[M] , HRMS(EI): m/z 441.2159 [M] (calcd for
cone (3c) Yield: 78%, yellow oil. H NMR (400 MHz,
C H O N 441.2151).
CDCl ): δ 7.20 (d, J = 16.1 Hz, 1H, β-H), 7.01–6.98 (m,
2
5
31
6
3
2H, α-H, 2-H), 6.78 (d, J = 4.5 Hz, 1H, 5-H), 6.75 (d, J =
2
′-[2-(4-Hydroxypiperidinyl)ethoxy]-3,4,4′,6′-tetramethox-
2.8 Hz, 1H, 6-H), 6.07 (s, 2H, 3′-H, 5′-H), 3.86 (t, J = 6.2
Hz, 2H, OCH ), 3.81 (s, 6H, 3, 4-OCH ), 3.76 (s, 3H, 6′-
1
ychalcone (2h) Yield: 85%, pale yellow oil. H NMR
2
3
(
(
400 MHz, CDCl ): δ 7.18 (d, J = 15.9 Hz, 1H, β-H), 7.00
d, J = 16.0 Hz, 1H, α-H), 6.98 (s, 1H, 2-H), 6.78 (s, 1H, 5-
OCH ), 3.68 (s, 3H, 4′-OCH ), 2.26 (t, J = 7.3 Hz, 2H,
NCH ), 2.15–2.19 (m, 4H, 2NCH ), 1.61–1.56 (m, 2H,
2 2
3
3 3
H), 6.75 (d, J = 6.4 Hz, 1H, 6-H), 6.08 (d, J = 2.7 Hz, 2H,
CH ), 1.40–1.37 (m, 2H, CH ), 1.30–1.25 (m, 4H, 2CH ),
2 2 2
0.72 (t, J = 7.3 Hz, 6H, 2CH3). C NMR (100 MHz,
1
3
3
′-H, 5′-H), 4.01 (t, J = 5.7 Hz, 2H, OCH ), 3.82 (s, 6H, 3,
2
4
-OCH ), 3.76 (s, 3H, 4′-OCH ), 3.68 (s, 3H, 6′-OCH ),
CDCl ): δ 194.26, 162.21, 158.71, 158.21, 151.06, 149.14,
3
3
3
3

Med Chem Res
1
9
2
44.28, 127.96, 127.28, 122.86, 112.14, 111.01, 109.88,
CDCl ) δ 7.29 (d, J = 15.9 Hz, 1H, β-H), 7.09 (d, J = 12.2
3
1.51, 90.79, 68.69, 56.0–55.72, 55.40, 53.54, 27.13,
Hz, 2H, α-H, 2-H), 6.89–6.82 (m, 2H, 5-H, 6-H), 6.16 (d, J
= 5.6 Hz, 2H, 3′-H, 5′-H), 3.96 (t, J = 6.0 Hz, 2H, OCH2),
3.91 (s, 6H, 3-OCH , 4-OCH ), 3.86 (s, 3H, 6′-OCH ), 3.77
+
3.30, 20.04, 11.89. MS(ESI): m/z 500.20 [M+H] , HRMS
+
(
EI): m/z 499.2870 [M] (calcd for C H O N 499.2934).
2
9
41
6
3
3
3
(
s, 3H, 4′-OCH ), 2.28 (s, 2H, NCH ), 2.25 (d, J = 7.9 Hz,
3 2
2
′-(4-Piperidinylbutoxy)-3,4,4′,6′-tetramethoxychalcone
4H, 2NCH ), 1.76–1.61 (m, 2H, CH ), 1.56 (d, J = 7.1 Hz,
2 2
1
(
3d) Yield: 74%, yellow oil. H NMR (400 MHz, CDCl ):
2H, CH ), 1.52–1.41 (m, 4H, 2CH ), 1.37 (d, J = 4.8 Hz,
2 2
3
1
3
δ 7.29 (d, J = 15.9 Hz, 1H, β-H), 7.10–7.07 (m, 2H, α-H, 2-
H), 6.87 (s, 1H, 5-H), 6.84 (d, J = 6.1 Hz, 1H, 6-H), 6.16 (d,
J = 5.6 Hz, 2H, 3′-H, 5′-H), 3.96 (t, J = 6.0 Hz, 2H, OCH2),
2H, CH2). C NMR (101 MHz, CDCl ) δ 194.32, 162.19,
3
158.56, 157.89, 151.10, 149.12, 144.42, 127.74, 127.13,
122.86, 111.85, 111.02, 109.86, 91.32, 90.79, 68.26, 55.84,
55.36, 53.32, 26.86, 24.58, 23.61, 23.20. MS(ESI): m/z
3
4
2
3
1
1
5
.91 (s, 6H, 3, 4-OCH ), 3.86 (s, 3H, 6′-OCH ), 3.77 (s, 3H,
3 3
+
+
′-OCH ), 2.28 (s, 2H, NCH ), 2.25 (d, J = 7.9 Hz, 4H,
470.30 [M+H] , HRMS(EI): m/z 469.2459 [M] (calcd for
3
2
NCH ), 1.70–1.67 (m, 2H, CH ), 1.57–1.49 (m, 6H,
CH ), 1.37 (s, 2H, CH ). C NMR (100 MHz, CDCl ): δ
62.22, 158.72, 158.13, 151.11, 149.18, 144.52, 127.95,
27.29, 122.93, 111.02, 109.88, 91.44, 90.82, 68.56, 58.83,
6.07–55.79, 55.45, 54.28, 27.24, 25.71, 24.28, 23.21. MS
C H O N 469.2464).
27 35 6
2
2
1
3
2
2
3
2′-[4-(4-Hydroxypiperidinyl)butoxy]-3,4,4′,6′-tetramethox-
1
ychalcone (3h) Yield: 85%, pale yellow oil. H NMR
(400 MHz, CDCl ): δ 7.28 (d, J = 16.6 Hz, 1H, β-H),
3
+
+
(
(
EI): m/z 484.27 [M+H] , HRMS(EI): m/z 483.2615 [M]
calcd for C H O N 483.2621).
7.14–7.02 (m, 2H, α-H, 2-H), 6.87–6.82 (m, 2H, 5, 6-H),
6.16 (d, J = 5.9 Hz, 2H, 3′-H, 5′-H), 3.96 (t, J = 5.6 Hz, 2H,
OCH ), 3.89 (s, 6H, 3, 4-OCH ), 3.85 (s, 3H, 6′-OCH ),
2
8 37 6
2
3
3
2
′-[4-(1-Methylhexahydropyrazinyl)butoxy]-3,4,4′,6′-tetra-
3.77 (s, 3H, 4′-OCH ), 3.66 (s, 1H, OCH), 2.78–2.67 (m,
3
1
methoxychalcone (3e) Yield: 65%, pale yellow oil. H
2H, NCH ), 2.43–2.32 (m, 2H, NCH ), 2.22–2.05 (m, 2H,
2
2
NMR (400 MHz, CDCl ): δ 7.19 (d, J = 16.0 Hz, 1H, β-H),
NCH ), 1.74–1.52 (m, 6H,CH ), 1.30–1.20 (m, 3H, CH ,
2 2 2
3
1
3
7
=
(
.03–6.94 (m, 2H, α-H, 2-H), 6.78 (s, 1H, 5-H), 6.75 (d, J
6.2 Hz, 1H, 6-H), 6.06 (d, J = 4.1 Hz, 2H, 3′, 5′-H), 3.87
t, J = 5.9 Hz, 2H, OCH ), 3.81 (s, 6H, 3, 4-OCH ), 3.76 (s,
OH). C NMR (100 MHz, CDCl ): δ 194.32, 162.19,
3
158.56, 157.89, 151.10, 149.12, 144.42, 127.74, 127.13,
122.86, 111.02, 109.86, 91.32, 90.79, 68.26, 55.84, 55.36,
53.36, 26.86, 24.58, 23.61, 23.20. MS(EI): m/z 499.25
2
3
3
5
2
1
1
5
H, 6′-OCH ), 3.67 (s, 3H, 4′-OCH ), 2.39–2.12 (m, 13H,
3 3
+
+
NCH , NCH ), 1.65–1.55 (m, 2H, CH ), 1.50–1.38 (m,
[M] , HRMS(EI): m/z 499.2565 [M]
(calcd for
2
3
2
1
3
H, CH2). C NMR (100 MHz, CDCl ): δ 194.34, 162.17,
C H O N 499.2570).
28 37 7
3
58.64, 158.05, 151.04, 149.10, 144.38, 127.83, 127.18,
22.88, 111.92, 110.97, 109.74, 91.35, 90.69, 68.41, 57.96,
5.99–55.73, 55.39, 54.92, 52.87, 45.91, 27.06, 23.33. MS
In vitro assay for antiproliferative activity
+
+
(
(
EI): m/z 498.28 [M] , HRMS(EI): m/z 498.2724 [M]
calcd for C H O N 498.2730).
Hela, HCC-1954, and SK-OV-3 cells were all cultured in a
medium supplemented with 10% fetal bovine serum and 1%
penicilin-streptomycin in a humidified atmosphere of 5%
2
8 38 6 2
2
′-(4-Morpholinylbutoxy)-3,4,4′,6′-tetramethoxychalcone
1
(
3f) Yield: 92%, pale yellow oil. H NMR (400 MHz,
CO at 37 °C, respectively, and Hela was maintained in
2
CDCl ): δ 7.27 (d, J = 15.9 Hz, 1H, β-H), 7.11–7.05 (m,
RPMI-L640 medium. While HCC1954 and SK-OV-3 were
maintained in DMEM/F12 medium. 20 mmol/L stock
solution of the tested compounds including control were
prepared with DMSO. The highest DMSO concentration of
medium (0.5%) did not have significant effect on deter-
mined celluar functions.
3
2
H, α-H, 2-H), 6.86 (s, 1H, 5-H), 6.83 (d, J = 8.5 Hz, 1H, 6-
H), 6.15 (d, J = 6.6 Hz, 2H, 3′-H, 5′-H), 3.96 (t, J = 5.9 Hz,
2
H, OCH ), 3.91 (s, 3H, 3-OCH ), 3.90(s, 3H, 4-OCH ),
2 3 3
3
.85 (s, 3H, 6′-OCH ), 3.77 (s, 3H, 4′-OCH ), 3.66–3.57
3
3
(
(
m, 4H, 2OCH ), 2.40–2.24 (m, 6H, 3NCH ), 1.83–1.65
2 2
1
3
m, 2H, CH ), 1.63–1.50 (m, 2H, CH ). C NMR (100
Proliferative of Hela, HCC1954, and SK-OV-3 cells was
evaluated by CCK-8 (Dojindo, Kumamoto, Japan) assay,
according to the manufacture’s instructions. This assay is
based on the cleavage of the tetrazolium Salt WST-8 by
mitochondrial dehydrogenase in viable cells (Chen et al.
2
2
MHz, CDCl ): δ 194.47, 162.23, 158.65, 157.93, 151.15,
3
1
1
5
4
49.16, 144.55, 127.76, 127.16, 122.90, 111.88, 111.01,
09.82, 91.39, 90.78, 68.23, 66.08, 65.03, 57.95, 55.91,
5.43, 52.79, 44.87, 43.65, 26.85, 22.26. MS(EI): m/z
+
+
3
85.23 [M] , HRMS(EI): m/z 485.2408 [M] (calcd for
2015). Briefly, 1 × 10 cells/well were incubated with 45 μL
C H O N 485.2414).
culture medium in 384-well plates. After being adhered to
the well, the cells were treated with 5 μL of tested com-
pounds at different concentrations, and then cultured for 72
h before addition of 5 μL CCK-8 to the culture medium in
2
7 35 7
2
′-(4-Pyrrolidinylbutoxy)-3,4,4′,6′-tetramethoxychalcone
1
(
3g) Yield: 75%, pale yellow oil. H NMR (400 MHz,

Med Chem Res
J Med Chem
forward structure-activity relationship.
1:2307–2310
each well. After 2–4 h incubation at 37 °C, absorbance at
50 nm of each well was measured with a fluorimeter
Novostar, BMG LABTECH, Germany). Each experiment
was reported three times, and the data represented the mean
of all measurements. The IC50 values were calculated using
the Graphpad Prism 5 software.
5
4
(
Campbell A, Do T, Hofmann E, Higginbottom G, Hauser Q, Kline R,
Ma LL, Paula S, Snider L, Webster J (2016) Hydroxylated
chalcones with dual properties: xanthine oxidase inhibitors and
radical scavengers. Bioorg Med Chem 24:578–587
Chen BQ, Liu YM, Shi YP, Wang P, Xuan LN, Zhang K, Zhu T
(
2015) Synthesis and in vitro antiproliferative activity of novel
benzisoselenazolone derivatives. Med Chem Res 24:543–552
Chen H, Lu SH, Shen AJ, Song YL, Tian W, Wang MP, Yang C,
Zhang L, Zhang M, Zheng CH, Zhu J, Zhou YJ (2016) Structural
modification of luteolin from Flos Chrysanthemi leads to
increased tumor cell growth inhibitory activity. Bioorg Med
Chem Lett 26:3464–3467
Acknowledgements We thank the National Natural Science Foun-
dation of China (No. J1210040) and Education Department of Hubei
Province Science and Technology Research Project of China (No.
Q20162803) for the financial support.
Compliance with ethical standards
Detsi A, Hadjipavlou –Litina D, Kontogiorgic CA, Kefalas P, Maj-
dalan M (2009) Natural and synthetic 2′-htdroxy-chalcones and
aurones: synthesis, characterization and evaluation of the anti-
oxidsant and soybean lipoxygenase inhibitory activity. Bioorg
Med Chem 17:8073–8085
Conflict of interest The authors declare that they have no competing
interests.
Dominy BW, Feeney PJ, Lipinski CA, Lombardo F (2001) Experi-
mental and computational approaches to estimate solubility and
permeability in drug discovery and development settings. Adv
Drug Deliv Rev 46:3–25
References
Dong XW, Du LL, Hu YZ, Liu T, Pan ZC, Yang B (2010) Synthesis
of chlorinated flavonoids with anti-inflammatory and pro-
apoptotic activities in human neutrophils. Eur J Med Chem
45:3986–3992
Dong LP, Nguyen VS, Wang QA, Wang SC (2015) The first total
synthesis of sophoflavescenol, flavenochromane C and citrusinol.
Eur J Org Chem 2015(10):2297–2302
Abay ET, Bonnet SL, de Kock C, Kendrekar P, Noreljaleel AEM,
Wilhelm A, van der Wiesner L, Westhuizen JH, Swart KJ (2015)
Syntheses and in vitro antiplasmodial activity of aminoalkylated
chalcones and analogues. J Nat Prod 78:1848–1856
Abd-Rahman N, Mai CW, Kang YB, Pichika MR, Yaeghoobi M
(
2014) Chalcones with electron-withdrawing and electron-
donating substituents: anticancer activity against TRAIL resis-
tant cancer cells, structure-activity relationship analysis and reg-
ulation of apoptotic proteins. Eur J Med Chem 77:378–387
Balakishan G, Kamal A, Janaki RM, Pal-Bhadra M, Ramakrishna G,
Raju P, Viswanath A (2010) Synthesis and anti-cancer activity of
chalcone linked imidazolones. Bioorg Med Chem Lett
EI-Melige S, Kamal AM, Taher AT, Youssef A (2017) Design,
synthesis and cytotoxic activity of certain novel chalcone analo-
gous compounds. Eur J Med Chem 126:52–60
Emami S, Mirzaei H (2016) Recent advances of cytotoxic chalconoids
targeting tubulin polymerization: synthesis and biological activ-
ity. Eur J Med Chem 121:610–639
2
0:4865–4869
Fernandes E, Feritas M, Ribeiro D (2014) Synthesis of chlorinated
flavonoids with anti-inflammatory and pro-apoptotic activities in
human neutrophils. Eur J Med Chem 86:153–164
Huang XQ, Liu HR, Liu XJ, Liu WK, Lou DH, Wang QA (2014)
Synthesis and acetylcholinesterase inhibitory activity of Mannich
base derivatives of flavokawain B. Bioorg Med Chem Lett
24:4749–4753
Kuppuswami BK, Manogaran P, Narasimha KKG, Raghavan S,
Venkatraman G (2015) Synthesis and anticancer activity of
chalcones derived from vanillin and isovanillin. Med Chem Res
24:4157–4165
Lipinski CA (2004) Lead-and drug-like compounds: the rule-of-five
revolution. Drug Discov Today Technol 1(4):337–341
Li Y, Li W, Nguyen VS, Wang QA (2017) Synthesis of citrus poly-
methoxyflavonoids and their antiproliferative activities on Hela
cells. Med Chem Res 26(7):1585–1592
Bandeira Graziele D, Evangelista Fernanda CG, Maralice O, Silva
Marina G (2016) Synthesis and in vitro evaluation of novel
triazole/azide chalcones. Med Chem Res 26:27–43
Bao YM, Li KJ, Ma JG, Sun XD, Yang PW, Zou L, Zhang SX (2008)
Nitrogen-containing flavonoid analogues as CDK1/cyclin B
inhibitors: synthesis, SAR analysis, and biological activity.
Bioorg Med Chem 16(15):7127–7132
Barbic M, Heilmann J, Jurgenliemk G, Vogel S (2010) Synthesis,
cytotoxicity, antioxidative and anti-inflammatory activity of
chalcones and influence of A-ring modifications on the pharma-
cological effect. Eur J Med Chem 45(6):2206–2213
Bonesi M, Deguin B, Loizzo MR, Menichini F, Tillequim F, Tundis R
(
2008) In vitro biological evaluation of novel 7-O-
dialkylaminoalkyl cytotoxic pectolinarigenin derivaties against a
panel of human cancer cell lines. Bioorg Med Chem Lett
1
8:5431–5434
Nguyen VS, Shi L, Wang QA, Wang SC (2017) Synthesis of icaritin
and β-anhydroicaritin Mannich base derivatives and their cyto-
toxic activities on three human cancer cell lines. Anticancer
Agents Med Chem 17(1):137–142
Blanc M, Boccard J, Boumendjel A, Carrupt PA, Choisnard L,
Dumontet C, Geze A, Matera EL, Nicolle E, Wouessidjewe D
(
2008) Antimitotic and antiproliferative activitis of chalcones: