Synthesis and cytotoxicity evaluation of biaryl-based chalcones and their potential in TNFα-induced nuclear factor-κB activation inhibition

Article abstract of DOI:10.1016/j.ejmech.2012.02.023

A series of biaryl-based chalcones were designed as a combination of the natural chalcone and biphenyl moieties, and synthesized by two step chemistry involving Knoevenagel reaction and microwave assistant Suzuki coupling. Sulforhodamine B (SRB) assay was performed to evaluate the cell viability inhibitory abilities of these compounds against five cancer cell lines (A549, CNE2, SW480, MCF-7, and HepG2) from different tissues. Their Nuclear Factor-κB (NF-κB) nuclear translocation inhibitory activities were further investigated by High Content Analysis (HCA) based assay. Most of the compounds showed moderate to strong anticancer and NF-κB nuclear translocation inhibition activities and potent compounds were found.

Full text of DOI:10.1016/j.ejmech.2012.02.023

European Journal of Medicinal Chemistry 50 (2012) 393e404
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and cytotoxicity evaluation of biaryl-based chalcones and their
potential in TNF -induced nuclear factor- B activation inhibition
a
k
Yinglin Zuo, Yi Yu, Shuni Wang, Weiyan Shao, Binhua Zhou, Li Lin, Zhuoyu Luo, Ruogu Huang, Jun Du,
*
Xianzhang Bu
School of Pharmaceutical Sciences, Sun Yat-sen University, XinGang Xi Road 135#, GuangZhou 510006, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of biaryl-based chalcones were designed as a combination of the natural chalcone and biphenyl
moieties, and synthesized by two step chemistry involving Knoevenagel reaction and microwave
assistant Suzuki coupling. Sulforhodamine B (SRB) assay was performed to evaluate the cell viability
inhibitory abilities of these compounds against five cancer cell lines (A549, CNE2, SW480, MCF-7, and
Received 10 November 2011
Received in revised form
6 February 2012
Accepted 11 February 2012
Available online 17 February 2012
HepG2) from different tissues. Their Nuclear Factor-kB (NF-kB) nuclear translocation inhibitory activities
were further investigated by High Content Analysis (HCA) based assay. Most of the compounds showed
moderate to strong anticancer and NF-
compounds were found.
k
B
nuclear translocation inhibition activities and potent
Keywords:
Biphenyl chalcones
Cytotoxicity
Ó 2012 Elsevier Masson SAS. All rights reserved.
NF-kB inhibition
High content analysis
1. Introduction
activity in T24 and HT-1376 cells [8]. Many natural chalcones which
were reported exhibiting anticancer activity, such as butein (2) [25],
cardamonin (3) [26], isoliquiritigenin (4) [27], Licochalcone A (5)
Natural occurring or synthetic chalcones (1, 3-diary-2-propene-
ones) have been found exhibiting various biological activities,
especially in anti-inflammatory and anticancer [1e8]. Large
numbers of efforts have been made to elucidate the mechanisms of
chalcone-based compounds for their anticancer activities.
Although interference of microtubule formation [6,7,9,10] was
suggested to be one mechanism for the anticancer activity of
[28] and Xanthohumol (6) [29], were proven to be potent NF-
kB
inhibitors though I kinase (IKK ) blockage and/or other bio-
kB
a
b
b
logical processes in various cell lines. Some synthetic analogue of
chalcone, for example MX781 (7) which is characterized by a large
substituted group on the m- position of one aromatic ring of
chalcone, was also reported with potent IKK inhibitory activity
b
chalcones, their potential of inhibiting Nuclear Factor-
kB (NF-kB)
and induce significant apoptosis [29]. The NF-kB inhibitory prop-
activation pathway, which was thought to play an important role in
the process leading from inflammation to carcinogenesis [11e13],
erties of these compounds are considered at least partially other
explanations for their anticancer activities due to the close linkage
between inflammation and tumorigenesis [11,12,30]. The devel-
opment of highly active and clinically promising chalcone-based
therapeutic anticancer agents would be promising way for
chemotherapy of malignant tumor. Nevertheless, investigations
attracted much attention [14,15]. Typically, NF-
most of inflammation response; recent advances have revealed
important roles of NF- B signaling in oncogenesis. NF- B is
commonly overexpressed and constitutively activated in different
types of tumors [16e18]. Constitutive activation of NF- B promotes
kB is involved in
k
k
k
focused on both NF-
chalcone derivatives remain rarely reported.
We have focused on the NF- B inhibitors for anticancer agents
kB inhibitory and anticancer activities of novel
tumor proliferation, invasion and metastasis [19,20], allows the
malignant cells to escape apoptosis, and therefore contributes to
the radiation and chemotherapeutic resistance and leads to failure
of therapy [21e24].
k
discovery for years, in our previous work [31], we found 4-
arylidene curcumin analogues exhibiting potent anticancer activi-
The chalcone core (1, Fig. 1) was found to inhibit the NF-
k
B
ties, and mechanism studies revealed that the NF-kB inhibition
related survival system and contributed to its antiproliferative
contributed to their anticancer abilities. We herein report the
synthesis of a series of new biaryl-based chalcones, which were
further investigated on their activity of NF-
cell growth inhibition against a panel of cancer cell lines (A549,
kB inhibition and cancer
* Corresponding author. Tel./fax: þ86 20 39943054.
E-mail address: phsbxzh@mail.sysu.edu.cn (X. Bu).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.02.023

394
Y. Zuo et al. / European Journal of Medicinal Chemistry 50 (2012) 393e404
Fig. 1. Structure of representative chalcone-based NF-kB inhibitors.
CNE2, SW480, MCF-7, HepG2), by high content analysis technology
condensation yield the chalcone intermediates 42e44, followed by
microwave assistant Suzuki coupling with aryl-substituted boronic
acids led to the target products 45e48.
based NF-kB translocation assay coupled with anti-proliferation
studies.
In total 38 compounds were obtained successfully and 33
compounds 12e20, 22e41, 45e48 were identified as new
compounds.
2. Results and discussion
2.1. Chemistry
2.2. Biological evaluation
The biaryl-based chalcones were designed as a combination of
typical chalcone moiety with a biphenyl moiety. The biphenyl
moiety occurred in many natural products (eg. 8e10, Fig. 2) and
were found exhibiting a wide variety of biological activities,
including anticancer [32e35], antiangiogenic [32,34] and antiviral
[36] etc. Furthermore, different substitutions were adopted to
expand the structure diversity in current work.
Biaryl-based chalcones 12e20 were synthesized according to
the sequence of reactions as illustrated in Scheme 1. Microwave
assistant Suzuki coupling of (3-fluorophenyl) boronic acid with 1-
(3-bromophenyl) ethanone led to the biphenyl intermediate 11,
followed by chlorotrimethylsilane (TMSCl) catalyzed knoevenagel
condensation to yield the target products. B ring aryl-substituted
chalcones 22 and 23 were obtained by similar procedures
(Scheme 2).
For the synthesis of biaryl-based chalcones 25e35, the reaction
sequences illustrated in Scheme 3 were taken up. Interestingly, by
using 6 equiv. KOH as catalyst, all the acetyl groups were success-
fully removed at knoevenagel condensation step in synthesis of 25
and 28e35 except that in 27 synthesis. We found large amount of
products precipitated during synthesis of the precursor of 27
(compound 26), distinguished from others. The precipitate of 26
may prevent the deprotection of acetyl group in the following step.
The remove of acetyl group in 26 was achieved by dissolved the
product in a mixture of EtOH and H2O under 70 ꢀC with NaOH as
catalyst, yield 27. For the synthesis of 37e41, similar reaction
procedures were used (Scheme 4).
2.2.1. Antiproliferative activity against five human cancer cell lines
After obtain the proposed compounds, all final compounds
12e20, 22e23, 25e35, 37e41, 45e48 along with chalcone inter-
mediates 42e44 were first tested for their antiproliferative activi-
ties against five tumor cell lines (human lung carcinoma cell line,
A549; human nasopharyngeal carcinoma (NPC) cell line, CNE2;
human colon cell line, SW480; human breast adenocarcinoma cell
line, MCF-7; human hepatoma cell line, HepG2) by measuring the
amount of total cell protein with the sulforhodamine B (SRB) assay.
For comparison, doseeresponse experiments were carried out to
obtain IC50
values for each compound, cell viability were measured
and calculated after incubated the compounds with different cells
for 48 h. As summarized in Table 1, most of the tested compounds
show moderate to potent antiproliferative activities against tar-
geted cell lines. Generally, compounds with electron withdraw
group F, Cl or Br on aromatic B ring (ring A, B and C are defined in
Scheme 1) of the aryl-substituted chalcones (12e13, 19e20, 22,
33e34) exhibit relative lower activities than the electron donation
group OH or OCH3 substituted analogs with several exceptions. By
contrast, the 30- position F substituted on C ring of biaryl moiety
show relative higher activities than the 40- position F substituted
analogs except the analogs with halogen substitution on B ring; for
example, 45e46 have lower activities against all cancer cell lines
than that of 15e16, indicating the importance of F substitution
position on ring C. Furthermore, 30,40-dimethoxy substitution on
the C ring is more potent than 40-F substitution by comparing the
data of 28e30 with 38e40 respectively. On the other hand,
although the amino group substitution on the A ring of chalcone
increased the activities slightly by comparing the activity of 25, 27
with that of 45, 46 respectively, the effects of amino group substi-
tution seems not so significant since the other amino group
substituted compounds have no obvious increased cytotoxicity in
general, this conclusion can also be supported by the cytotoxicity
data of 26 and 27, the acylation of amino group on 27 does not effect
its activity apparently.
Biaryl-based chalcones 45e48 were synthesized by reactions
illustrated in Scheme 5. A NaOH (aq) catalyzed knoevenagel
Noticeably, compounds with p- position OCH3 substitution on
aromatic B ring generally have higher activities than others, and an
additional m-position OH substitution on B ring significantly
increase their activities, compounds 35 and 47 show strongest
Fig. 2. Structure of representative biphenyl-based natural products.

Y. Zuo et al. / European Journal of Medicinal Chemistry 50 (2012) 393e404
395
Scheme 1. Reagents and conditions: (a) PdCl2(dppf), 2 M (aq) K2CO3, dioxane, microwave heating, 150 ꢀC, 20 min; (b) TMSCl, DMF, 100 ꢀC, 20 h.
cytotoxicity against A549 cells comparing that of 25, 27e34 and
12e20 respectively, the most potent compound 47 (IC50 ¼ 0.50 M)
show more than 10 times potent than the precursor chalcone 44
M). Furthermore, compound 38 has good activity
against A549, MCF-7 and HepG2, and 15 and 16 showed strong
inhibition activities toward all cell lines, especially for CNE2 cell line
more than 50% tested compounds are good consistent with their
m
NF-
k
B inhibitory properties, indicating a close correlation of the
B inhibitory activity and cytotoxicity. The apparent inconsis-
NF-k
(IC50 ¼ 5.88
m
tence revealed by the rest compounds is most probably due to
a multi-targeting effect of tested compounds on the overall growth
suppression phenotype; their inhibition of other targets in addition
with IC50 values 0.74
mM and 0.77
m
M respectively.
to NF-kB could be also response for the suppression of cell growth.
Furthermore, the cytotoxicity varied along with the cancer cell
type. It is reasonable that the efficacy of the test compounds on cell
survival is also determined by cell’s genetic backgrounds. How
these novel chalcone analogs inhibit cancer cell growth remains to
be established, which requires extensive research in the future.
2.2.2. Inhibition of TNF
NF- B is a transcription factor that is activated in response to
certain stimulations, such as TNF , and is associated with the
activation of many cellular defense genes [37]. Normally, NF- B is in
a-induced nuclear translocation of NF-kB
k
a
k
the cytoplasm and it should be activated and translocated into the
nucleus to induce specific gene expression; to monitor the activa-
tion status of NF-
used to visualize the dynamic movement of the NF-
k
B, a high content analysis (HCA) based assay was
B p65 subunit
3. Conclusions
k
between the cytoplasm and nucleus under various conditions.
A549 cells in a 384-well plate format were treated with tested
In summary, a series of new biaryl-based chalcone derivatives
have been discovered as potential anticancer agents. Although
some biaryl-chalcones and their biological activities [38e41] have
been reported, their anticancer activities were rarely studied. Many
reports have revealed the close correlations of inflammation with
carcinogenesis; our work found that most of the biary-based
compounds before TNF
translocation of NF- B p65 subunit, an automated fluorescence
imaging system for high content analysis was employed to monitor
the cytoplasm/nucleus localization of NF- B in response to TNF
a was added to stimulate the nucleus
k
k
a.
IC50 values of tested compounds were summarized in Table 2, As
shown in Table 2, most of the tested compounds (12e14, 16e19, 23,
26, 28e32, 37e41, 47) show strong to moderate inhibitory activities
chalcone derivatives exhibit significant NF-
and cytotoxicity to a panel of cancer cell lines. Based on our
investigation, the NF- B inhibition might be one of potential
kB inhibitory activity
k
(IC50 ¼ 1.70
m
Me35.28
mM) to TNFa induced NF-kB activation while
mechanisms for their anticancer activities though the detail
mechanism remains to be discovered. Remarkably, Human NPC is
referred to as Cantonese cancer, extremely occurred in Guangdong
province accounting for 18% of all cancers in China [42,43]. It occurs
in about 25 cases per 100,000 people in this region, 25 times higher
than the rest of the world [43]. Our study found that 15 and 16
exhibit potent inhibitory activities toward CNE2 cell growth with
some extend of selectivity to other cell lines, suggesting that 15 and
16 could be served as leads for novel anti-NPC drug discovery;
furthermore, several compounds such as 35, 38, 47 and 48, were
found to be potent leads against different cancer cell line. Overall,
our findings in this work offered a good start point and the novel
potent biaryl-based chalcones may represent new opportunities for
anticancer drug development, such works are scheduled on our
works.
others (15, 20, 22, 25, 27, 33e34, 42e46, 48) present no obvious
activities (IC50 > 50
m
M). The C ring 30- F substituted analogs show
relative higher activities than the 40- F substituted analogs with
several exceptions (15 and 20), this phenomena seems generally to
be consistent with their cytotoxicity; However, unlike their cyto-
toxicity, most of the amino substituted compounds 25e34 and
37e41 exhibiting good activities in NF-
33e34. Representative images from the most potent compound 38
M) were shown in Fig. 3, these images clearly showed
kB inhibition except 25 and
(IC50 ¼ 1.70
m
that the nucleus translocation of NF-
kB was blocked after addition
of 38.
It should be pointed out that the NF-
assay was carried out on A549 based model, significantly, data in
Table 1 and Table 2 suggested that A549 growth suppression of
k
B activation inhibition
Scheme 2. Reagents and conditions: (a) PdCl2(dppf), 2 M (aq) K2CO3, dioxane, microwave heating, 150 ꢀC, 20 min; (b) TMSCl, DMF, 100 ꢀC, 20 h.

396
Y. Zuo et al. / European Journal of Medicinal Chemistry 50 (2012) 393e404
Scheme 3. Reagents and conditions: (a) PdCl2(dppf), 2 M (aq) K2CO3, dioxane, microwave heating, 150 ꢀC, 20 min; (b) KOH, EtOH, rt; (c) NaOH, EtOH/H2O, 70 ꢀC, 8 h.
4. Experiments
percentage peak area of the analyzed compound, retention times
(tR) were calculated in minutes. A list of all purities is given in the
Supporting Information, Table S1. High resolution mass spectra
(HRMS) were recorded on Shimadzu LCMS-IT-TOF.
4.1. General
All commercial reagents and solvents were purchased from
vendors and were used without further purification or distillation.
Microwave reactions were performed in a Biotage Initiator 2.5
microwave reactor. Reactions were monitored by TLC on a glass
plate coated with silica gel with fluorescent indicator (GF254).
Column chromatography was performed on silica gel (200e300
mesh). 1H NMR and 13C NMR spectra were recorded using TMS as
an internal standard with Burker BioSpin Ultrashield 400 NMR
system or Varian INOVA 500NB. The Purities of compounds used for
biological evaluation (>95%) were determined on a DIONEX Ulti-
mate 3000 HPLC System (Chromeleon SR9 Build 2673); column,
4.2. General procedure for the preparation of 11, 21, 24 and 36
The procedure is exemplified by the preparation of 11.
4.2.1. 1-(30-Fluoro-[1,10-biphenyl]-3-yl)ethanone (11)
A previously described Suzuki-Miyaura coupling condition [44]
was used with slight modification. A mixture of 1-(3-bromophenyl)
ethanone (133 mL, 199 mg, 1.0 mmol), (3-fluorophenyl)boronic acid
(182 mg, 1.3 mmol), dichloro(1,10-bis(diphenylphosphino)ferro-
cene)palladium(Ⅱ)-dichloromethane adduct (50 mg, 0.06 mmol),
2M(aq) K2CO3(1.5 ml), and 1,4-dioxane (1.5 ml) was heated in
a sealed vial in a microwave reactor at 150 ꢀC for 20 min. After
cooling, 10 ml water was added, and the mixture was extracted
with EtOAc (10 ml) by three times. The combined organic layer was
washed until neutral and dried over anhydrous sodium sulfate.
After removal of the solvent in vacuum, the crude product was
purified by column chromatography to yield light yellow liquid
AcclaimÒ120C18, 5
mm, 4.6 ꢁ 250 mm; flow rate, 1 ml/min; samples
were eluted with a gradient from certain concentration of A to 95% A
over 30 min, whereas the solvent A was CH3CN in double-deionized
H2O with 0.1% trifluoroacetic acid (TFA), using UV monitor at
254 nm for detection. For compounds 16e18, start from 70% A; for
compounds 12e15, 19 and 20, start from 80% A; for compounds 22,
23 and 42e44, start from 60% A; for compounds 25e35, 37e41 and
45e48, start from 40% A. Compounds purities were calculated as the
150 mg (70.02%); 1H NMR (500 MHz, CDCl3)
d
8.15 (t, J ¼ 1.8 Hz, 1H),
Scheme 4. Reagents and conditions: (a) PdCl2(dppf), 2 M (aq) K2CO3, dioxane, microwave heating, 150 ꢀC, 20 min; (b) KOH, EtOH, rt.

Y. Zuo et al. / European Journal of Medicinal Chemistry 50 (2012) 393e404
397
Scheme 5. Reagents and conditions: (a) 6 M NaOH (aq), EtOH, rt; (b) PdCl2(dppf), 2 M (aq) K2CO3, dioxane, microwave heating, 150 ꢀC, 20 min.
7.94 (ddd, J ¼ 7.8, 1.6, 1.2 Hz, 1H), 7.75 (ddd, J ¼ 7.7, 2.0, 1.1 Hz, 1H),
7.53 (t, J ¼ 7.7 Hz, 1H), 7.44e7.36 (m, 2H), 7.30 (ddd, J ¼ 10.1, 2.7,
1.5 Hz, 1H), 7.10e7.03 (m, 1H), 2.65 (s, 3H); 13C NMR (100 MHz,
4.2.2. 40-Fluoro-[1,10-biphenyl]-3-carbaldehyde (21)
Yellow oil, 80.72%; 1H NMR (400 MHz, CDCl3)
d
10.08 (s, 1H),
8.05 (s, 1H), 7.85 (d, J ¼ 7.6 Hz, 1H), 7.81 (d, J ¼ 7.8 Hz, 1H), 7.64e7.56
CDCl3)
d
197.89,164.34,161.89,142.28,142.21,140.23,140.20,137.57,
(m, 3H), 7.20e7.12 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
192.18,
131.51, 130.43, 130.35, 129.12, 127.72, 126.68, 122.74, 122.72, 114.63,
114.42, 114.05, 113.83, 26.58; HRMS calcd for C14H11OF [M þ Na]þ:
237.0692, found 237.0692.
164.06, 161.60, 141.08, 136.96, 135.80, 135.77, 132.80, 129.54, 128.80,
128.72, 127.77, 116.01, 115.79; HRMS calcd for C13H9OF [M þ H]þ:
201.0716, found 201.0718.
Table 1
Antiproliferative activity of the target compounds against five cancer cell linesa.
Compound
Human cancer cell lines, IC50
A549
(mM)
CNE2
SW480
MCF-7
HepG2
12
13
14
15
16
17
18
19
20
22
23
25
26
27
28
29
30
31
32
33
34
35
37
38
39
40
41
42
43
44
45
46
47
48
15.44 ꢂ 0.45
9.12 ꢂ 0.19
15.51 ꢂ 0.73
2.44 ꢂ 0.27
1.94 ꢂ 0.16
8.90 ꢂ 0.09
9.90 ꢂ 0.47
12.44 ꢂ 1.47
19.83 ꢂ 1.86
12.23 ꢂ 1.10
8.36 ꢂ 0.15
4.31 ꢂ 0.14
7.38 ꢂ 0.09
8.63 ꢂ 0.16
14.37 ꢂ 0.38
7.04 ꢂ 0.09
13.34 ꢂ 1.10
12.23 ꢂ 0.97
6.07 ꢂ 0.09
24.52 ꢂ 0.21
>50
0.94 ꢂ 0.04
18.00 ꢂ 0.48
2.21 ꢂ 0.02
6.20 ꢂ 0.76
6.54 ꢂ 0.05
4.62 ꢂ 0.09
34.21 ꢂ 2.46
9.43 ꢂ 1.06
5.88 ꢂ 0.25
11.23 ꢂ 0.46
11.78 ꢂ 0.65
0.50 ꢂ 0.08
2.06 ꢂ 0.16
9.06 ꢂ 0.51
6.55 ꢂ 0.59
10.40 ꢂ 0.87
0.74 ꢂ 0.10
0.77 ꢂ 0.14
10.00 ꢂ 1.27
5.69 ꢂ 0.08
8.91 ꢂ 0.16
10.45 ꢂ 0.66
7.39 ꢂ 1.22
5.51 ꢂ 0.14
1.60 ꢂ 0.04
2.74 ꢂ 0.03
3.51 ꢂ 0.40
6.29 ꢂ 0.65
6.71 ꢂ 0.38
11.32 ꢂ 2.79
5.75 ꢂ 0.57
4.60 ꢂ 0.83
18.09 ꢂ 3.44
25.50 ꢂ 3.98
NA
7.93 ꢂ 1.18
8.34 ꢂ 1.65
6.59 ꢂ 0.84
6.60 ꢂ 0.57
4.33 ꢂ 0.75
NA
NA
NA
5.55 ꢂ 0.01
5.55 ꢂ 0.01
NA
16.85 ꢂ 0.23
8.61 ꢂ 0.41
16.64 ꢂ 0.07
4.51 ꢂ 0.80
2.97 ꢂ 1.03
13.50 ꢂ 0.88
6.74 ꢂ 0.49
14.79 ꢂ 1.20
18.19 ꢂ 1.27
13.54 ꢂ 2.92
12.02 ꢂ 0.98
7.23 ꢂ 0.42
5.35 ꢂ 0.82
6.64 ꢂ 1.20
12.38 ꢂ 0.30
7.83 ꢂ 0.68
12.5 ꢂ 0.50
8.35 ꢂ 1.09
6.12 ꢂ 0.22
31.70 ꢂ 0.76
22.86 ꢂ 5.15
NA
14.7 ꢂ 0.70
9.30 ꢂ 1.97
6.49 ꢂ 0.73
8.33 ꢂ 0.53
5.63 ꢂ 0.03
NA
NA
NA
8.35 ꢂ 0.08
6.49 ꢂ 0.21
NA
18.15 ꢂ 0.27
12.65 ꢂ 1.34
18.92 ꢂ 0.13
3.08 ꢂ 0.06
4.62 ꢂ 1.19
11.67 ꢂ 0.82
14.20 ꢂ 1.00
19.98 ꢂ 0.62
18.32 ꢂ 0.78
14.12 ꢂ 1.14
10.83 ꢂ 1.60
7.58 ꢂ 2.58
15.01 ꢂ 1.94
14.96 ꢂ 2.71
10.82 ꢂ 2.78
8.92 ꢂ 2.52
13.29 ꢂ 3.77
10.53 ꢂ 3.23
9.03 ꢂ 0.30
18.27 ꢂ 2.04
40.51 ꢂ 9.49
NA
10.41 ꢂ 0.23
6.98 ꢂ 0.94
15.36 ꢂ 1.43
1.72 ꢂ 0.48
1.17 ꢂ 0.08
9.20 ꢂ 2.77
6.83 ꢂ 0.84
12.83 ꢂ 2.72
9.92 ꢂ 0.59
12.30 ꢂ 4.39
5.12 ꢂ 0.11
3.75 ꢂ 1.02
5.63 ꢂ 0.74
3.78 ꢂ 0.36
7.74 ꢂ 1.12
4.01 ꢂ 0.70
7.37 ꢂ 0.71
4.30 ꢂ 0.32
4.21 ꢂ 0.15
11.70 ꢂ 1.52
4.73 ꢂ 0.03
NA
8.96 ꢂ 0.54
2.13 ꢂ 0.12
2.10 ꢂ 0.07
5.36 ꢂ 0.06
2.68 ꢂ 1.16
NA
NA
NA
5.65 ꢂ 0.04
5.37 ꢂ 0.34
NA
19.44 ꢂ 0.37
6.49 ꢂ 0.43
6.33 ꢂ 0.34
10.22 ꢂ 0.52
6.58 ꢂ 0.46
NA
NA
NA
16.35 ꢂ 0.34
11.55 ꢂ 0.47
NA
NA
NA
NA
NA
NA: Not tested.
a
Data shown are the average values from at least two independent experiments with standard error (SE).

398
Y. Zuo et al. / European Journal of Medicinal Chemistry 50 (2012) 393e404
Table 2
122.99, 122.42, 114.89, 114.68, 114.39, 114.17; HRMS calcd for
B activation/translocationa.
M) Compound IC50 M)
C21H14OFCl [M þ Na]þ: 359.0615, found 359.0610.
Inhibition activity of target compounds on NF-
k
Compound IC50
(
m
M)
Compound IC50
>50
2.65 ꢂ 0.41 39
>50 40
(
m
(m
4.3.2. (E)-3-(3-Bromophenyl)-1-(30-fluoro-[1,10-biphenyl]-3-yl)
prop-2-en-1-one (13)
12
13
14
15
16
17
18
19
20
22
23
24.39 ꢂ 6.65 25
11.21 ꢂ 1.53 26
35.28 ꢂ 5.43 27
38
1.70 ꢂ 0.35
3.19 ꢂ 1.00
11.90 ꢂ 3.24
5.44 ꢂ 2.12
>50
Light yellow power, 82.15%; HPLC tR ¼ 13.91 min; 1H NMR
>50
28
7.99 ꢂ 1.35 41
10.29 ꢂ 5.50 42
13.81 ꢂ 3.89 43
6.83 ꢂ 2.35 44
11.62 ꢂ 2.88 45
(500 MHz, CDCl3)
d
8.20 (t, J ¼ 1.6 Hz, 1H), 8.01 (ddd, J ¼ 7.7, 1.7,
33.44 ꢂ 7.28 29
24.05 ꢂ 3.63 30
12.87 ꢂ 0.10 31
13.65 ꢂ 0.32 32
1.1 Hz, 1H), 7.82e7.80 (m, 1H), 7.80 (ddd, J ¼ 7.7, 1.8, 1.1 Hz, 1H), 7.76
(d, J ¼ 15.7 Hz, 1H), 7.60 (td, J ¼ 7.7, 0.4 Hz, 1H), 7.58e7.55 (m, 2H),
7.54 (d, J ¼ 15.7 Hz, 1H), 7.47e7.41 (m, 2H), 7.35 (ddd, J ¼ 10.4, 2.8,
1.4 Hz, 1H), 7.31 (t, J ¼ 7.9 Hz, 1H), 7.12e7.07 (m, 1H); 13C NMR
>50
>50
>50
>50
>50
33
34
>50
>50
46
47
>50
9.59 ꢂ 2.88
(100 MHz, CDCl3)
d 189.86, 164.54, 162.10, 143.41, 142.52, 142.45,
12.41 ꢂ 2.33 37
21.26 ꢂ 4.91 48
>50
140.70, 140.68, 138.64, 137.01, 133.46, 131.66, 131.02, 130.62, 130.59,
130.53, 129.37, 127.98, 127.40, 127.22, 123.22, 123.18, 123.02, 122.99,
114.89, 114.68, 114.38, 114.16; HRMS calcd for C21H14OFBr
[M þ Na]þ: 403.0110, found 403.0104.
a
Data shown are the average values from two independent experiments with
standard error (SE).
4.2.3. N-(5-Acetyl-40-fluoro-[1,10-biphenyl]-2-yl)acetamide (24)
4.3.3. (E)-1-(30-Fluoro-[1,10-biphenyl]-3-yl)-3-(2-methoxyphenyl)
prop-2-en-1-one (14)
White power, 89.65%; 1H NMR (400 MHz, CDCl3)
d 8.48 (d,
J ¼ 8.4 Hz, 1H), 7.96 (dd, J ¼ 8.6, 2.1 Hz, 1H), 7.82 (d, J ¼ 2.1 Hz, 1H),
Yellow oil, 33.13%; HPLC tR ¼ 10.88 min; 1H NMR (500 MHz,
7.40e7.32 (m, 2H), 7.25e7.13 (m, 3H), 2.59 (s, 3H), 2.06 (s, 3H); 13C
CDCl3)
d
8.21 (t, J ¼ 1.6 Hz, 1H), 8.16 (d, J ¼ 15.9 Hz, 1H), 8.01 (ddd,
NMR (100 MHz, CDCl3)
d 196.94, 168.45, 164.09, 161.62, 139.32,
J ¼ 7.7, 1.7, 1.2 Hz, 1H), 7.78 (ddd, J ¼ 7.7, 1.9, 1.1 Hz, 1H), 7.66 (dd,
J ¼ 7.7, 1.7 Hz, 1H), 7.62 (d, J ¼ 15.9 Hz, 1H), 7.58 (td, J ¼ 7.7, 0.4 Hz,
1H), 7.45e7.42 (m, 2H), 7.40 (ddd, J ¼ 8.4, 7.4, 1.7 Hz, 1H), 7.37e7.34
(m, 1H), 7.11e7.05 (m, 1H), 7.01 (td, J ¼ 7.4, 0.6 Hz, 1H), 6.96 (d,
133.13, 133.09, 132.82, 131.17, 131.09, 130.71, 130.34, 129.35, 120.59,
116.64, 116.42, 26.50, 24.81; HRMS calcd for C16H14NO2F [M þ Na]þ:
294.0906, found 294.0899.
J ¼ 8.3 Hz, 1H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 191.13,
4.2.4. N-(5-Acetyl-30,40-dimethoxy-[1,10-biphenyl]-2-yl)acetamide
164.52, 162.08, 158.90, 142.71, 142.64, 140.90, 140.41, 140.39, 139.23,
132.01, 131.13, 130.54, 130.46, 129.25, 129.22, 128.00, 127.30, 123.91,
122.97, 122.94, 122.92, 120.87, 114.73, 114.52, 114.31, 114.09, 111.34,
55.62; HRMS calcd for C22H17O2F [M þ Na]þ: 355.1110, found
355.1108.
(36)
White power, 88.20%; 1H NMR (400 MHz, CDCl3)
d 8.51 (d,
J ¼ 8.5 Hz, 1H), 7.94 (dd, J ¼ 8.6, 2.1 Hz, 1H), 7.85 (d, J ¼ 2.1 Hz, 1H),
7.43 (s,1H), 7.00 (d, J ¼ 8.2 Hz,1H), 6.92 (dd, J ¼ 8.2, 2.0 Hz,1H), 6.85
(d, J ¼ 2.0 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 2.59 (s, 3H), 2.06 (s, 3H);
13C NMR (100 MHz, CDCl3)
d 196.66, 168.28, 149.23, 148.84, 139.22,
4.3.4. (E)-1-(30-Fluoro-[1,10-biphenyl]-3-yl)-3-(4-methoxyphenyl)
prop-2-en-1-one (15)
132.17, 131.23, 129.95, 129.20, 128.46, 121.20, 120.02, 112.06, 111.46,
55.74, 55.64, 26.14, 24.44; HRMS calcd for C18H19NO4
[M ꢃ H]ꢃ:312.1236, found 312.1230.
Yellow power, 65.81%; HPLC tR ¼ 9.41 min; 1H NMR (500 MHz,
CDCl3)
d
8.19 (t, J ¼ 1.7 Hz, 1H), 8.00 (ddd, J ¼ 7.7, 1.7, 1.1 Hz, 1H), 7.83
(d, J ¼ 15.6 Hz, 1H), 7.77 (ddd, J ¼ 7.7, 1.9, 1.1 Hz, 1H), 7.63 (dd, J ¼ 9.1,
2.4 Hz, 2H), 7.58 (t, J ¼ 7.7 Hz, 1H), 7.44 (d, J ¼ 15.6 Hz, 1H),
7.47e7.42 (m, 2H), 7.35 (ddd, J ¼ 10.1, 2.7, 1.3 Hz, 1H), 7.11e7.06 (m,
1H), 6.95 (dd, J ¼ 9.1, 2.4 Hz, 2H), 3.86 (s, 3H); 13C NMR (100 MHz,
4.3. General procedure for the preparation of 12-20, 22 and 23
TMSCl catalyzed Knoevenagel condensations were used [45].
The procedure is exemplified by the preparation of 12. Other
products were synthesized by the corresponding acetophenones
and the corresponding aldehydes.
CDCl3)
d 190.38, 164.53, 162.09, 161.90, 145.17, 142.71, 142.63,
140.52, 139.28, 131.19, 130.56, 130.45, 129.24, 127.88, 127.62, 127.14,
123.01, 122.99, 119.71, 114.77, 114.56, 114.36, 114.14, 55.52; HRMS
calcd for C22H17O2F [M þ H]þ: 333.1291, found 333.1299.
4.3.1. (E)-3-(4-Chlorophenyl)-1-(30-fluoro-[1,10-biphenyl]-3-yl)
prop-2-en-1-one (12)
Intermediate 11 (428.5 mg, 2 mmol), 4-chlorobenzaldehyde
(281.1 mg, 2 mmol) were place in a 40 mL pressure tube and dis-
4.3.5. (E)-3-(3,4-Dimethoxyphenyl)-1-(30-fluoro-[1,10-biphenyl]-3-
yl)prop-2-en-1-one (16)
Yellow oil, 56.35%; HPLC tR ¼ 9.48 min; 1H NMR (500 MHz,
solved in DMF (3 mL). TMSCl (770
m
L, 6 mmol) was added to the
CDCl3)
d
8.19 (t, J ¼ 1.6 Hz,1H), 8.00 (ddd, J ¼ 7.7, 1.6, 1.1 Hz,1H), 7.80
solution. The tube was thoroughly sealed and heated at 100 ꢀC for
20 h on a Carousel 12 PlusÔ reaction station (Radleys Discovery
Technologies). After cooling, the tube was opened and 15 mL water
was added. Then the mixture was extracted with EtOAc (15 ml) by
three times, the combined organic layer was washed with water
(10 mL) by two times and dried over anhydrous sodium sulfate.
After removal of the solvent in vacuum, the crude product was
purified by column chromatography to yield light yellow power,
471 mg (69.94%); HPLC tR ¼ 13.01 min; 1H NMR (500 MHz, CDCl3)
(d, J ¼ 15.6 Hz, 1H), 7.77 (ddd, J ¼ 7.7, 1.9, 1.1 Hz, 1H), 7.58 (td, J ¼ 7.7,
0.4 Hz, 1H), 7.47e7.42 (m, 2H), 7.41 (d, J ¼ 15.6 Hz, 1H), 7.37e7.32
(m, 1H), 7.26 (dd, J ¼ 8.4, 2.0 Hz, 1H), 7.17 (d, J ¼ 2.0 Hz, 1H),
7.11e7.05 (m, 1H), 6.91 (d, J ¼ 8.4 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H);
13C NMR (100 MHz, CDCl3)
d 190.25, 164.39, 161.94, 151.54, 149.24,
145.38, 142.52, 142.44, 140.35, 140.32, 139.11, 131.06, 130.45, 130.36,
129.10, 127.77, 127.75, 126.97, 123.26, 122.86, 122.84, 119.83, 114.64,
114.43, 114.19, 113.97, 111.13, 110.28, 55.94, 55.94; HRMS calcd for
C23H19O3F [M þ H]þ: 363.1396, found 363.1396.
d
8.20 (t, J ¼ 1.7 Hz, 1H), 8.01 (ddd, J ¼ 7.7, 1.7, 1.1 Hz, 1H), 7.80 (d,
J ¼ 15.7 Hz, 1H), 7.79 (ddd, J ¼ 7.7, 1.8, 1.1 Hz, 1H), 7.60 (t, J ¼ 7.7 Hz,
1H), 7.60 (dd, J ¼ 8.8, 2.1 Hz, 2H), 7.53 (d, J ¼ 15.7 Hz, 1H), 7.47e7.39
(m, 2H), 7.41 (dd, J ¼ 8.8, 2.1 Hz, 2H), 7.34 (ddd, J ¼ 10.4, 2.6, 1.4 Hz,
4.3.6. (E)-3-(2,3-Dimethoxyphenyl)-1-(30-fluoro-[1,10-biphenyl]-3-
yl)prop-2-en-1-one (17)
Yellow power, 26.38%; HPLC tR ¼ 11.99 min; 1H NMR (500 MHz,
1H), 7.12e7.07 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
190.06, 164.56,
CDCl3)
d
8.20 (t, J ¼ 1.6 Hz, 1H), 8.13 (d, J ¼ 15.9 Hz, 1H), 8.01 (ddd,
162.11, 143.78, 142.58, 142.50, 140.69, 140.67, 138.80, 136.69, 133.40,
131.58, 130.62, 130.54, 129.79, 129.39, 129.36, 127.95, 127.22, 123.02,
J ¼ 7.7, 1.6, 1.1 Hz, 1H), 7.78 (ddd, J ¼ 7.7, 1.8, 1.1 Hz, 1H), 7.62 (d,
J ¼ 15.9 Hz, 1H), 7.59 (t, J ¼ 7.8 Hz, 1H), 7.43 (m, 2H), 7.36e7.32 (m,

Y. Zuo et al. / European Journal of Medicinal Chemistry 50 (2012) 393e404
399
Fig. 3. Inhibition of TNF
vehicle (DMSO) for 2 h, followed by stimulation with TNF
activated and translocated to the nucleus. Preincubation of the cells with increasing concentrations of compound 38 inhibited the TNF
a
induced NF-
k
B activation by biary-based chalcone 38. Example images of NF-
k
B subcellular localization. A549 cells were treated with compounds or
B is located at cytoplasm, upon TNF treatment, NF- B is
-induced NF- B translocation to the nucleus.
a
(10 ng/ml) for 30 min. In the vehicle (DMSO) treatment, NF-
k
a
k
a
k
1H), 7.30 (dd, J ¼ 8.0, 1.2 Hz, 1H), 7.11 (t, J ¼ 8.0 Hz, 1H), 7.09e7.05
(m, 1H), 6.99 (dd, J ¼ 8.0, 1.2 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H); 13C
7.37e7.32 (m, 1H), 7.24 (dd, J ¼ 8.2, 1.9 Hz, 1H), 7.14 (d, J ¼ 1.9 Hz,
1H), 7.11e7.06 (m, 1H), 6.97 (d, J ¼ 8.2 Hz, 1H), 5.97 (s, 1H), 3.97
NMR (100 MHz, CDCl3)
d
190.81, 164.55, 162.10, 153.34, 149.11,
(s, 3H); 13C NMR (100 MHz, CDCl3)
d 190.63, 164.53, 162.09, 148.62,
142.69, 142.61, 140.55, 140.53, 140.21, 139.07, 131.34, 130.59, 130.50,
129.29, 129.12, 128.02, 127.31, 124.35, 123.70, 123.01, 122.98, 119.79,
114.79, 114.59, 114.44, 114.35, 114.13, 61.44, 56.01; HRMS calcd for
C23H19O3F [M þ H]þ: 363.1396, found 363.1400.
147.00, 145.84, 142.68, 142.61, 140.54, 140.52, 139.26, 131.22, 130.57,
130.49, 129.23, 127.90, 127.46, 127.14, 123.59, 123.01, 122.98, 119.72,
115.08, 114.78, 114.57, 114.36, 114.14, 110.35, 56.14; HRMS calcd for
C22H17O3F [M þ H]þ: 349.1240, found 349.1235.
4.3.7. (E)-1-(30-Fluoro-[1,10-biphenyl]-3-yl)-3-(4-hydroxy-3-
methoxyphenyl)prop-2-en-1-one (18)
4.3.8. (E)-3-(2-Bromophenyl)-1-(30-fluoro-[1,10-biphenyl]-3-yl)
prop-2-en-1-one (19)
Yellow oil, 55.03%; HPLC tR ¼ 6.82 min; 1H NMR (500 MHz,
Light yellow power, 42.39%; HPLC tR ¼ 13.52 min; 1H NMR
CDCl3)
d
8.19 (t, J ¼ 1.8 Hz, 1H), 8.00 (ddd, J ¼ 7.7, 1.6, 1.1 Hz, 1H), 7.79
(500 MHz, CDCl3)
8.01 (ddd, J ¼ 7.7, 1.8, 1.1 Hz, 1H), 7.80 (ddd, J ¼ 7.7, 1.8, 1.1 Hz, 1H),
d
8.20 (t, J ¼ 1.7 Hz, 1H), 8.17 (d, J ¼ 15.7 Hz, 1H),
(d, J ¼ 15.6 Hz, 1H), 7.77 (ddd, J ¼ 7.7, 1.6, 1.1 Hz, 1H), 7.58
(t, J ¼ 7.7 Hz, 1H), 7.47e7.42 (m, 2H), 7.40 (d, J ¼ 15.6 Hz, 1H),
7.76 (dd, J ¼ 7.8, 1.6 Hz, 1H), 7.65 (dd, J ¼ 8.0, 1.2 Hz, 1H), 7.60 (t,

400
Y. Zuo et al. / European Journal of Medicinal Chemistry 50 (2012) 393e404
J ¼ 7.7 Hz, 1H), 7.44 (d, J ¼ 15.7 Hz, 1H), 7.46e7.41 (m, 2H), 7.38 (td,
J ¼ 7.8, 1.2 Hz, 1H), 7.37e7.33 (m, 1H), 7.27 (td, J ¼ 7.8, 1.6 Hz, 1H),
130.12, 130.10, 129.00, 128.12, 125.68, 119.70, 116.20, 115.99, 114.72,
114.45, 55.46; HRMS calcd for C22H18NO2F [M ꢃ H]ꢃ: 346.1243,
found 346.1238.
7.12e7.06 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 190.38, 164.51,
162.07, 143.65, 142.51, 142.43, 140.59, 140.57, 138.58, 135.02,
133.66, 131.56, 130.59, 130.50, 129.34, 128.10, 128.02, 127.85,
127.35, 126.04, 125.06, 122.98, 122.96, 114.84, 114.63, 114.33,
114.11; HRMS calcd for C21H14OFBr [M þ Na]þ: 403.0110, found
403.0118.
4.4.2. (E)-N-(5-(3-(3,4-Dimethoxyphenyl)acryloyl)-40-fluoro-[1,10-
biphenyl]-2-yl)acetamide (26)
Yellow power, 79.57%; HPLC tR ¼ 14.71 min; 1H NMR (400 MHz,
CDCl3)
d
8.51 (d, J ¼ 8.3 Hz, 1H), 8.04 (dd, J ¼ 8.6, 2.1 Hz, 1H), 7.90 (d,
J ¼ 2.1 Hz,1H), 7.78 (d, J ¼ 15.6 Hz,1H), 7.42e7.36 (m, 3H), 7.26e7.20
(m, 4H), 7.15 (d, J ¼ 2.0 Hz, 1H), 6.90 (d, J ¼ 8.4 Hz, 1H), 3.95 (s, 3H),
4.3.9. (E)-3-(4-Bromophenyl)-1-(30-fluoro-[1,10-biphenyl]-3-yl)
prop-2-en-1-one (20)
3.93 (s, 3H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 188.97,168.51,
Light yellow power, 69.55%; HPLC tR ¼ 13.93 min; 1H NMR
163.99, 161.52, 151.52, 149.29, 145.02, 138.90, 134.00, 133.19, 133.15,
131.17, 131.09, 130.93, 130.58, 129.22, 127.87, 123.22, 120.68, 119.57,
116.54, 116.32, 111.20, 110.33, 56.03, 56.02, 24.75; HRMS calcd for
C25H22NO4F [M ꢃ H]ꢃ: 418.1455, found 418.1444.
(500 MHz, CDCl3)
d
8.19 (t, J ¼ 1.6 Hz, 1H), 8.00 ((ddd, J ¼ 7.7, 1.7,
1.0 Hz, 1H), 7.79 ((ddd, J ¼ 7.7, 1.7, 1.0 Hz, 1H), 7.78 (d, J ¼ 15.7 Hz,
1H), 7.60 (t, J ¼ 7.7 Hz, 1H), 7.55 (d, J ¼ 15.7 Hz, 1H), 7.58e7.51 (m,
4H), 7.47e7.41 (m, 2H), 7.36e7.32 (m, 1H), 7.12e7.07 (m, 1H); 13C
NMR (100 MHz, CDCl3)
d
190.03, 164.55, 162.10, 143.83, 142.56,
4.4.3. (E)-1-(6-Amino-40-fluoro-[1,10-biphenyl]-3-yl)-3-(2,4-
dimethoxyphenyl)prop-2-en-1-one (28)
142.48, 140.68, 140.66, 138.77, 133.81, 132.35, 131.58, 130.62, 130.53,
129.98, 129.36, 127.94, 127.21, 125.06, 123.01, 122.98, 122.49, 114.88,
114.67, 114.38, 114.16; HRMS calcd for C21H14OFBr [M þ Na]þ:
403.0110, found 403.0124.
Yellow power, 53.25%; HPLC tR ¼ 19.69 min; 1H NMR (400 MHz,
CDCl3)
d
8.05 (d, J ¼ 15.7 Hz, 1H), 7.91 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.84
(d, J ¼ 2.1 Hz, 1H), 7.57 (d, J ¼ 8.6 Hz, 1H), 7.53 (d, J ¼ 15.7 Hz, 1H),
7.47e7.42 (m, 2H), 7.20e7.14 (m, 2H), 6.78 (d, J ¼ 8.4 Hz, 1H), 6.52
(dd, J ¼ 8.5, 2.4 Hz, 1H), 6.47 (d, J ¼ 2.4 Hz, 1H), 4.18 (s, 2H), 3.88 (s,
4.3.10. (E)-3-(40-Fluoro-[1,10-biphenyl]-3-yl)-1-(4-fluorophenyl)
prop-2-en-1-one (22)
3H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 188.64, 163.30,
White power, 35.31%; HPLC tR ¼ 20.45 min; 1H NMR (400 MHz,
162.68,160.85, 160.03, 148.39, 138.63, 134.45, 134.42, 131.60, 130.73,
130.65, 130.18, 129.92, 128.72, 125.26, 119.90, 117.20, 115.92, 115.71,
114.54, 105.39, 98.24, 55.39, 55.31; HRMS calcd for C23H20NO3F
[M ꢃ H]ꢃ: 376.1349, found 376.1341.
CDCl3)
d
8.12e8.03 (m, 2H), 7.87 (d, J ¼ 15.7 Hz, 1H), 7.78 (s, 1H),
7.65e7.52 (m, 5H), 7.50 (t, J ¼ 7.7 Hz, 1H), 7.23e7.12 (m, 4H); 13C
NMR (100 MHz, CDCl3)
d 188.76, 167.00, 164.47, 164.03, 161.58,
144.86, 141.19, 136.61, 136.57, 135.44, 134.57, 134.54, 131.27, 131.18,
129.57, 129.35, 128.90, 128.82, 127.28, 127.20, 122.06, 116.01, 115.97,
115.79, 115.75; HRMS calcd for C21H14OF2 [M þ Na]þ: 343.0910,
found 343.0917.
4.4.4. (E)-1-(6-Amino-40-fluoro-[1,10-biphenyl]-3-yl)-3-(2,5-
dimethoxyphenyl)prop-2-en-1-one (29)
Yellow power, 70.22%; HPLC tR ¼ 19.98 min; 1H NMR (400 MHz,
CDCl3)
d
8.08 (d, J ¼ 15.8 Hz, 1H), 7.93 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.86
4.3.11. (E)-3-(40-Fluoro-[1,10-biphenyl]-3-yl)-1-(4-hydroxyphenyl)
prop-2-en-1-one (23)
(d, J ¼ 2.1 Hz, 1H), 7.58 (d, J ¼ 15.8 Hz, 1H), 7.49e7.42 (m, 2H),
7.22e7.15 (m, 3H), 6.93 (dd, J ¼ 9.0, 3.0 Hz, 1H), 6.88 (d, J ¼ 9.0 Hz,
1H), 6.80 (d, J ¼ 8.4 Hz, 1H), 4.22 (s, 2H), 3.87 (s, 3H), 3.82 (s, 3H);
White power, 37.74%; HPLC tR ¼ 11.68 min; 1H NMR (400 MHz,
Acetone)
d
8.15e8.08 (m, 3H), 7.99 (d, J ¼ 15.6 Hz,1H), 7.86e7.76 (m,
13C NMR (100 MHz, CDCl3)
d 188.75, 163.65, 161.19, 153.63, 153.29,
4H), 7.73e7.67 (m, 1H), 7.55 (t, J ¼ 7.7 Hz, 1H), 7.31e7.20 (m, 2H),
148.37, 138.64, 134.48, 134.45, 131.99, 130.99, 130.91, 130.26, 129.02,
125.69, 125.12, 123.12, 116.68, 116.23, 116.01, 114.71, 113.83, 112.57,
56.26, 55.98; HRMS calcd for C23H20NO3F [M þ Na]þ: 400.1325,
found 400.1320.
7.01e6.95 (m, 2H); 13C NMR (100 MHz, Acetone)
d
188.13, 164.71,
162.80, 162.28, 143.57, 141.47, 137.58, 137.55, 136.92, 131.97, 131.12,
130.34, 129.85, 129.77, 129.41, 128.33, 127.66, 123.41, 116.53, 116.31,
116.21; HRMS calcd for C21H15O2F [M ꢃ H]ꢃ: 317.0978, found
317.0984.
4.4.5. (E)-1-(6-Amino-40-fluoro-[1,10-biphenyl]-3-yl)-3-(2,3-
dimethoxyphenyl)prop-2-en-1-one (30)
4.4. General procedure for the synthesis of 25, 26, 28-35 and 37-41
Yellow power, 73.74%; HPLC tR ¼ 19.31 min; 1H NMR (400 MHz,
CDCl3)
d
8.06 (d, J ¼ 15.8 Hz, 1H), 7.92 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.84
A mixture of the corresponding acetophenone (1 equiv) and
aldehyde (1 equiv) in anhydrous EtOH was stirred at room temper-
ature for 10 min. Then solid KOH (6 equiv) was added. The reaction
mixture was stirred at room temperature until aldehyde was
consumed as monitored by TLC. After that, HCl (10%) was added until
pH 4 was obtained. The mixture was concentrated in vacuum to
remove EtOH, and further extracted with EtOAc. The EtOAc layer was
dried over anhydrous sodium sulfate. After removal of the solvent in
vacuum, the residue was purified by column chromatography to give
corresponding chalcones.
(d, J ¼ 2.1 Hz, 1H), 7.60 (d, J ¼ 15.8 Hz, 1H), 7.48e7.40 (m, 2H), 7.26
(dd, J ¼ 8.0, 1.4 Hz, 1H), 7.21e7.14 (m, 2H), 7.07 (t, J ¼ 8.0 Hz, 1H),
6.94 (dd, J ¼ 8.1, 1.4 Hz, 1H), 6.79 (d, J ¼ 8.4 Hz, 1H), 4.23 (s, 2H), 3.88
(s, 3H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 188.56, 163.61,
161.15, 153.29, 148.82, 148.53, 138.12, 134.42, 134.38, 131.99, 130.94,
130.86, 130.25, 129.58, 128.77, 125.61, 124.24, 123.72, 119.65, 116.20,
115.99, 114.72, 113.90, 61.36, 55.96; HRMS calcd for C23H20NO3F
[M þ Na]þ: 400.1326, found 400.1320.
4.4.6. (E)-1-(6-Amino-40-fluoro-[1,10-biphenyl]-3-yl)-3-(4-
hydroxy-3-methoxyphenyl)prop-2-en-1-one (31)
4.4.1. (E)-1-(6-Amino-40-fluoro-[1,10-biphenyl]-3-yl)-3-(4-
methoxyphenyl)prop-2-en-1-one (25)
Yellow power, 27.13%; HPLC tR ¼ 13.31 min; 1H NMR (400 MHz,
CDCl3)
d
7.92 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.84 (d, J ¼ 2.1 Hz, 1H), 7.75 (d,
Yellow power, 54.15%; HPLC tR ¼ 19.27 min; 1H NMR (400 MHz,
J ¼ 15.5 Hz, 1H), 7.47e7.42 (m, 2H), 7.39 (d, J ¼ 15.5 Hz, 1H), 7.21
(ddd, J ¼ 8.1, 1.9, 0.4 Hz, 1H), 7.20e7.14 (m, 2H), 7.11 (d, J ¼ 1.9 Hz,
1H), 6.94 (d, J ¼ 8.2 Hz, 1H), 6.79 (d, J ¼ 8.4 Hz, 1H), 5.94 (s, 1H), 4.22
CDCl3)
d
7.92 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.84 (d, J ¼ 2.1 Hz, 1H), 7.78 (d,
J ¼ 15.6 Hz, 1H), 7.61e7.56 (m, 2H), 7.47e7.41 (m, 3H), 7.20e7.14
(m, 2H), 6.94e6.89 (m, 2H), 6.79 (d, J ¼ 8.4 Hz, 1H), 4.20 (s, 2H),
(s, 2H), 3.95 (s, 3H); 13C NMR (100 MHz, Acetone)
d 187.41, 164.14,
3.85 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
188.19, 163.64, 161.48,
161.71, 150.64, 149.84, 148.66, 143.69, 136.13, 136.10, 132.36, 131.93,
131.85, 130.75, 128.78, 128.50, 125.59, 124.03, 121.04, 120.05, 116.60,
161.18, 148.40, 143.20, 134.49, 134.45, 131.81, 130.98, 130.90,

Y. Zuo et al. / European Journal of Medicinal Chemistry 50 (2012) 393e404
401
116.39, 116.10, 115.24, 111.89, 56.37; HRMS calcd for C22H18NO3F
4.4.12. (E)-1-(6-Amino-30,40-dimethoxy-[1,10-biphenyl]-3-yl)-3-
[M ꢃ H]ꢃ: 362.1192, found 362.1189.
(2,4-dimethoxyphenyl)prop-2-en-1-one (38)
Yellow power, 56.27%; HPLC tR ¼ 16.34 min; 1H NMR (400 MHz,
4.4.7. (E)-1-(6-Amino-40-fluoro-[1,10-biphenyl]-3-yl)-3-(3,4,5-
trimethoxyphenyl)prop-2-en-1-one (32)
CDCl3)
d
7.92 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.88 (d, J ¼ 2.1 Hz, 1H), 7.76 (d,
J ¼ 15.6 Hz, 1H), 7.64e7.59 (m, 2H), 7.49 (d, J ¼ 15.6 Hz, 1H),
7.12e7.05 (m, 2H), 7.01 (dd, J ¼ 8.2, 1.9 Hz, 1H), 6.98 (d, J ¼ 7.9 Hz,
1H), 6.97 (d, J ¼ 2.1 Hz, 1H), 6.79 (d, J ¼ 8.4 Hz, 1H), 4.31 (s, 2H), 3.94
Yellow power, 31.94%; HPLC tR ¼ 17.48 min; 1H NMR (400 MHz,
CDCl3)
d
7.93 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.84 (d, J ¼ 2.1 Hz, 1H), 7.72 (d,
J ¼ 15.5 Hz, 1H), 7.47e7.42 (m, 2H), 7.41 (d, J ¼ 15.5 Hz, 1H),
(s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz, DMSO)
d 186.11, 164.32,
7.21e7.14 (m, 2H), 6.85 (s, 2H), 6.80 (d, J ¼ 8.4 Hz, 1H), 4.23 (s, 2H),
161.85, 150.61, 148.89, 148.10, 140.47, 131.84, 131.81, 131.66, 131.07,
130.94, 130.85, 129.76, 126.04, 124.91, 122.33, 122.31, 121.02, 115.89,
115.67, 114.03, 112.51, 112.29, 55.58, 55.43; HRMS calcd for
C23H20NO3F [M ꢃ H]ꢃ: 376.1349, found 376.1348.
3.91 (s, 6H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 188.03,
163.64, 161.18, 153.53, 148.58, 143.59, 140.24, 134.36, 134.33, 131.85,
130.98, 130.90, 130.89, 130.24, 128.72, 125.72, 121.25, 116.24, 116.03,
114.64, 105.71, 61.06, 56.35; HRMS calcd for C24H22NO4F [M ꢃ H]ꢃ:
406.1455, found 406.1464.
4.4.13. (E)-1-(6-Amino-30,40-dimethoxy-[1,10-biphenyl]-3-yl)-3-
(2,5-dimethoxyphenyl)prop-2-en-1-one (39)
4.4.8. (E)-1-(6-Amino-40-fluoro-[1,10-biphenyl]-3-yl)-3-(3-fluoro-
4-hydroxyphenyl)prop-2-en-1-one (33)
Yellow power, 53.88%; HPLC tR ¼ 16.70 min; 1H NMR (400 MHz,
CDCl3)
d
8.07 (d, J ¼ 15.8 Hz, 1H), 7.91 (dd, J ¼ 8.3, 2.1 Hz, 1H), 7.88
Yellow power, 43.05%; HPLC tR ¼ 13.84 min; 1H NMR (400 MHz,
(d, J ¼ 2.0 Hz, 1H), 7.59 (d, J ¼ 15.8 Hz, 1H), 7.16 (d, J ¼ 3.0 Hz, 1H),
7.02 (dd, J ¼ 8.2, 1.9 Hz, 1H), 6.97 (d, J ¼ 1.9 Hz, 1H), 6.97 (d,
J ¼ 8.2 Hz, 1H), 6.91 (dd, J ¼ 9.0, 3.0 Hz, 1H), 6.86 (d, J ¼ 9.0 Hz, 1H),
6.78 (d, J ¼ 8.3 Hz, 1H), 4.28 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.85 (s,
DMSO)
d
7.93 (dd, J ¼ 8.6, 2.1 Hz, 1H), 7.83 (d, J ¼ 2.1 Hz, 1H), 7.81
(dd, J ¼ 14.7, 1.8 Hz, 1H), 7.76 (d, J ¼ 15.4 Hz, 1H), 7.54 (d, J ¼ 15.4 Hz,
1H), 7.52e7.46 (m, 2H), 7.44 (dd, J ¼ 8.4, 1.5 Hz, 1H), 7.35e7.27 (m,
2H), 6.96 (t, J ¼ 8.7 Hz, 1H), 6.82 (d, J ¼ 8.6 Hz, 1H), 5.79 (s, 2H); 13C
3H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 188.65,153.52,153.17,
NMR (100 MHz, DMSO)
d
186.11, 162.69, 160.27, 152.49, 150.40,
149.33, 148.64, 148.59, 138.36, 131.76, 131.02, 129.90, 128.66, 126.46,
125.01, 123.04, 121.34, 116.61, 114.45, 113.66, 112.49, 112.31, 111.70,
56.16, 56.01, 56.00, 55.86; HRMS calcd for C25H25NO5 [M ꢃ H]ꢃ:
418.1654, found 418.1644.
150.09, 147.32, 147.20, 141.27, 141.25, 135.01, 134.98, 131.75, 131.06,
130.98, 130.01, 127.05, 126.98, 126.59, 126.57, 126.40, 123.87, 120.29,
117.82, 117.79, 115.82, 115.61, 115.44, 114.31; HRMS calcd for
C21H15NO2F2 [M ꢃ H]ꢃ: 350.0993, found 350.0991.
4.4.14. (E)-1-(6-Amino-30,40-dimethoxy-[1,10-biphenyl]-3-yl)-3-
(2,3-dimethoxyphenyl)prop-2-en-1-one (40)
4.4.9. (E)-1-(6-Amino-40-fluoro-[1,10-biphenyl]-3-yl)-3-(3-bromo-
4-hydroxy-5-methoxyphenyl)prop-2-en-1-one (34)
Yellow power, 55.24%; HPLC tR ¼ 15.97 min; 1H NMR (400 MHz,
Yellow power, 53.25%; HPLC tR
(400 MHz, DMSO)
¼
17.09 min; 1H NMR
9.96 (s, 1H), 7.99 (dd, J ¼ 8.6, 1.8 Hz, 1H), 7.82
CDCl3)
d
8.07 (d, J ¼ 15.8 Hz, 1H), 7.92 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.88
d
(d, J ¼ 2.1 Hz, 1H), 7.61 (d, J ¼ 15.8 Hz, 1H), 7.26 (dd, J ¼ 7.9, 1.2 Hz,
1H), 7.07 (t, J ¼ 8.0 Hz, 1H), 7.01 (dd, J ¼ 8.2, 1.9 Hz, 1H), 6.97 (d,
J ¼ 1.8 Hz, 1H), 6.97 (d, J ¼ 8.2 Hz, 1H), 6.94 (dd, J ¼ 8.2, 1.3 Hz, 1H),
6.78 (d, J ¼ 8.4 Hz, 1H), 4.29 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.88 (s,
(d, J ¼ 1.8 Hz, 1H), 7.81 (d, J ¼ 15.4 Hz, 1H), 7.66 (d, J ¼ 1.3 Hz, 1H),
7.55 (d, J ¼ 15.4 Hz, 1H), 7.52e7.43 (m, 3H), 7.31 (t, J ¼ 8.9 Hz, 2H),
6.83 (d, J ¼ 8.6 Hz, 1H), 5.79 (s, 2H), 3.91 (s, 3H); 13C NMR
(100 MHz, DMSO)
d
186.06, 162.66, 160.24, 150.40, 148.43, 145.72,
3H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 188.49, 153.18,
141.23, 134.96, 134.93, 131.62, 131.02, 130.94, 130.15, 127.61,
126.32, 125.51, 123.94, 120.62, 115.80, 115.59, 114.12, 111.22,
109.60, 56.51; HRMS calcd for C22H17NO3FBr [M ꢃ H]ꢃ: 440.0298,
found 440.0289.
149.32, 148.76, 148.71, 148.58, 137.85, 131.78, 130.96, 129.90, 129.51,
128.46, 126.42, 124.16, 123.66, 121.30, 119.50, 114.46, 113.79, 112.27,
111.69, 61.28, 55.99, 55.97, 55.87; HRMS calcd for C25H25NO5
[M ꢃ H]ꢃ: 418.1654, found 418.1645.
4.4.10. (E)-1-(6-Amino-40-fluoro-[1,10-biphenyl]-3-yl)-3-(3-
hydroxy-4-methoxyphenyl)prop-2-en-1-one (35)
4.4.15. (E)-1-(6-Amino-30,40-dimethoxy-[1,10-biphenyl]-3-yl)-3-
(3,4,5-trimethoxyphenyl)prop-2-en-1-one (41)
Yellow power, 56.88%; HPLC tR ¼ 13.25 min; 1H NMR (400 MHz,
Yellow power, 56.14%; HPLC tR ¼ 14.21 min; 1H NMR (400 MHz,
CDCl3)
d
7.90 (d, J ¼ 8.4 Hz, 1H), 7.82 (s, 1H), 7.71 (d, J ¼ 15.5 Hz, 1H),
CDCl3)
d
7.92 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.88 (d, J ¼ 2.1 Hz, 1H), 7.72 (d,
7.47e7.37 (m, 3H), 7.26e7.23 (m, 1H), 7.16 (t, J ¼ 8.0 Hz, 2H), 7.10 (d,
J ¼ 8.3 Hz, 1H), 6.84 (d, J ¼ 8.2 Hz, 1H), 6.77 (d, J ¼ 8.4 Hz, 1H), 5.71
(s, 1H), 4.21 (s, 2H), 3.91 (s, 3H); 13C NMR (100 MHz, Acetone)
J ¼ 15.5 Hz,1H), 7.43 (d, J ¼ 15.5 Hz,1H), 7.02 (dd, J ¼ 8.2,1.8 Hz,1H),
6.98 (d, J ¼ 8.2 Hz, 1H), 6.97 (d, J ¼ 1.8 Hz, 1H), 6.85 (s, 2H), 6.79 (d,
J ¼ 8.4 Hz,1H), 4.30 (s, 2H), 3.94 (s, 3H), 3.91 (s, 9H), 3.89 (s, 3H); 13C
d
164.13, 161.70, 150.65, 150.40, 147.66, 143.29, 136.11, 136.08,
NMR (100 MHz, CDCl3) d 187.90, 153.37, 149.28, 148.83, 148.57,
132.45, 131.91, 131.83, 130.78, 129.70, 128.76, 125.60, 122.78, 120.72,
116.58, 116.37, 115.31, 114.62, 112.21, 56.27; HRMS calcd for
C22H18NO3F [M þ H]þ: 364.1343, found 364.1344.
143.28, 140.01, 131.59, 130.86, 130.80, 129.86, 128.30, 126.40, 121.27,
121.19, 114.37, 112.26, 111.63, 105.54, 60.90, 56.19, 55.94, 55.92;
HRMS calcd for C26H27NO6 [M ꢃ H]ꢃ: 448.1760, found 448.1751.
4.4.11. (E)-1-(6-Amino-30,40-dimethoxy-[1,10-biphenyl]-3-yl)-3-(4-
fluorophenyl)prop-2-en-1-one (37)
4.5. Synthesis of (E)-1-(6-amino-40-fluoro-[1,10-biphenyl]-3-yl)-3-
(3,4-dimethoxyphenyl)prop-2-en-1-one (27)
Yellow power, 49.38%; HPLC tR ¼ 17.35 min; 1H NMR (400 MHz,
CDCl3)
d
7.92 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.88 (d, J ¼ 2.1 Hz, 1H), 7.76 (d,
To a mixture of 40 ml EtOH and 10 ml H2O, compound 26
(419 mg, 1.0 mmol) and NaOH (80 mg, 2.0 mmol) were added, and
the mixture was refluxed at 70 ꢀC for 8h. Then the mixture was
concentrated in vacuum and extracted with EtOAc. The organic
layer was dried over anhydrous sodium sulfate. After removal of the
solvent in vacuum, the residue was purified by column chroma-
tography to yield yellow power 235.1 mg (62.35%); HPLC
J ¼ 15.6 Hz, 1H), 7.64e7.59 (m, 2H), 7.49 (d, J ¼ 15.6 Hz, 1H),
7.12e7.05 (m, 2H), 7.01 (dd, J ¼ 8.2, 1.9 Hz, 1H), 6.98 (d, J ¼ 7.9 Hz,
1H), 6.97 (d, J ¼ 2.1 Hz, 1H), 6.79 (d, J ¼ 8.4 Hz, 1H), 4.31 (s, 2H), 3.94
(s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz, DMSO)
d 186.11, 164.32,
161.85, 150.61, 148.89, 148.10, 140.47, 131.84, 131.81, 131.66, 131.07,
130.94, 130.85, 129.76, 126.04, 124.91, 122.33, 122.31, 121.02, 115.89,
115.67, 114.03, 112.51, 112.29, 55.58, 55.43; HRMS calcd for
C23H20NO3F [M ꢃ H]ꢃ: 376.1349, found 376.1348.
tR ¼ 16.49 min; 1H NMR (400 MHz, CDCl3)
7.93 (dd, J ¼ 8.4, 2.1 Hz,
d
1H), 7.85 (d, J ¼ 2.1 Hz, 1H), 7.76 (d, J ¼ 15.5 Hz, 1H), 7.47e7.39 (m,

402
Y. Zuo et al. / European Journal of Medicinal Chemistry 50 (2012) 393e404
2H), 7.41 (d, J ¼ 15.7 Hz, 1H), 7.23 (dd, J ¼ 8.4, 1.9 Hz, 1H), 7.21e7.15
(m, 2H), 7.15 (d, J ¼ 1.9 Hz, 1H), 6.89 (d, J ¼ 8.3 Hz, 1H), 6.79 (d,
J ¼ 8.4 Hz, 1H), 4.21 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H); 13C NMR
the crude product was purified by column chromatography to yield
yellow power 233.3 mg (70.23%); HPLC tR ¼ 26.23 min; 1H NMR
(400 MHz, CDCl3)
d
8.17 (t, J ¼ 1.7 Hz,1H), 8.01e7.94 (m, 1H), 7.83 (d,
(100 MHz, CDCl3)
d
188.00, 163.44, 160.99, 151.07, 149.14, 148.48,
J ¼ 15.6 Hz, 1H), 7.77e7.72 (m, 1H), 7.64e7.54 (m, 5H), 7.44 (d,
143.41, 134.33, 134.30, 131.67, 130.83, 130.75, 130.05, 128.62, 128.20,
125.48, 122.77, 119.71, 116.06, 115.85, 114.56, 111.12, 110.26, 55.94,
55.91; HRMS calcd for C23H20NO3F [M ꢃ H]ꢃ: 376.1349, found
376.1340.
J ¼ 15.6 Hz, 1H), 7.20e7.14 (m, 2H), 6.98e6.92 (m, 2H), 3.87 (s, 3H);
13C NMR (100 MHz, CDCl3)
d 190.43, 163.96, 161.84, 161.51, 145.06,
140.67, 139.10, 136.40, 131.02, 130.37, 129.07, 128.88, 128.80, 127.55,
127.26, 126.90, 119.66, 115.89, 115.70, 114.48, 55.37; HRMS calcd for
C22H17O2F [M þ H]þ: 333.1285, found 333.1288.
4.6. Synthesis of chalcones 42e44 by the ClaiseneSchmidt
condensation between acetophenones derivatives and appropriate
aromatic aldehydes
4.7.2. (E)-3-(3,4-Dimethoxyphenyl)-1-(40-fluoro-[1,10-biphenyl]-3-
yl)prop-2-en-1-one (46)
Yellow power, 60.56%; HPLC tR ¼ 23.63 min; 1H NMR (400 MHz,
In general, acetophenone (5 mmol) was added to equimolar of
aromatic aldehyde and dissolved in EtOH. To the solution, 6 M
NaOH (aq) (2 ml) was added and the reaction mixture was stirred at
room temperature until aldehyde was consumed by monitoring
with TLC. Then HCl (10%) was added until pH 4 was obtained. The
mixture was concentrated in vacuum to remove EtOH, and further
extracted with EtOAc. The EtOAc layer was dried over anhydrous
sodium sulfate. After removal of the solvent in vacuum, the crude
product was purified by recrystallization with EtOH to give corre-
sponding chalcones.
CDCl3)
d
8.16 (t, J ¼ 1.8 Hz, 1H), 7.97 (d, J ¼ 7.7 Hz, 1H), 7.80 (d,
J ¼ 15.6 Hz, 1H), 7.77e7.72 (m, 1H), 7.64e7.54 (m, 3H), 7.41 (d,
J ¼ 15.6 Hz, 1H), 7.26 (dd, J ¼ 8.4, 1.8 Hz, 1H), 7.20e7.13 (m, 3H), 6.91
(d, J ¼ 8.3 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d 190.32, 163.90, 161.45, 151.56, 149.29, 145.26, 140.64,
139.07, 136.38, 136.35, 130.96, 129.00, 128.83, 128.75, 127.81, 127.21,
126.84, 123.21, 119.94, 115.86, 115.65, 111.19, 110.38, 55.95, 55.92;
HRMS calcd for C23H19O3F [M þ H]þ: 363.1391, found 363.1379.
4.7.3. (E)-1-(30-Fluoro-[1,10-biphenyl]-3-yl)-3-(3-hydroxy-4-
methoxyphenyl)prop-2-en-1-one (47)
4.6.1. (E)-1-(3-Bromophenyl)-3-(4-methoxyphenyl)prop-2-en-1-
one (42)
Yellow power, 76.58%; HPLC tR ¼ 20.51 min; 1H NMR (400 MHz,
CDCl3)
d
8.20 (s, 1H), 8.00 (d, J ¼ 7.7 Hz, 1H), 7.78 (d, J ¼ 8.4 Hz, 1H),
Light yellow power, 85.69%; HPLC tR ¼ 14.21 min; 1H NMR
7.78 (d, J ¼ 15.5 Hz, 1H), 7.58 (t, J ¼ 7.7 Hz, 1H), 7.47e7.40 (m, 2H),
7.43 (d, J ¼ 15.6 Hz, 1H), 7.35 (d, J ¼ 10.2 Hz, 1H), 7.31 (d, J ¼ 2.0 Hz,
1H), 7.16 (dd, J ¼ 8.3, 2.0 Hz, 1H), 7.09 (ddd, J ¼ 5.9, 4.2, 2.2 Hz, 1H),
6.89 (d, J ¼ 8.3 Hz, 1H), 5.69 (s, 1H), 3.95 (s, 3H); 13C NMR (100 MHz,
(400 MHz, CDCl3)
d
8.13 (t, J ¼ 1.7 Hz,1H), 7.96e7.89 (m,1H), 7.79 (d,
J ¼ 15.6 Hz, 1H), 7.69 (ddd, J ¼ 7.9, 1.9, 1.0 Hz, 1H), 7.61 (d, J ¼ 8.7 Hz,
2H), 7.37 (s, J ¼ 7.9 Hz, 2H), 6.95 (d, J ¼ 8.8 Hz, 2H), 3.86 (s, 3H).
DMSO)
d 188.89, 163.93, 161.51, 150.41, 146.70, 144.82, 141.94,
4.6.2. (E)-1-(3-Bromophenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-
1-one (43)
141.86, 139.35, 138.72, 131.18, 130.93, 130.84, 129.45, 127.90, 127.67,
126.61, 123.11, 122.38, 119.52, 114.97, 114.65, 114.43, 113.91, 113.69,
111.87, 55.67; HRMS calcd for C22H17O3F [M þ H]þ: 349.1234, found
349.1232.
Light yellow power, 89.25%; HPLC tR ¼ 16.08 min; 1H NMR
(400 MHz, CDCl3)
d
8.13 (t, J ¼ 1.8 Hz,1H), 7.95e7.89 (m,1H), 7.77 (d,
J ¼ 15.6 Hz, 1H), 7.70 (ddd, J ¼ 7.9, 1.9, 1.0 Hz, 1H), 7.38 (t, J ¼ 7.9 Hz,
1H), 7.31 (d, J ¼ 15.6 Hz, 1H), 7.24 (dd, J ¼ 8.3, 2.0 Hz, 1H), 7.16 (d,
J ¼ 2.0 Hz, 1H), 6.91 (d, J ¼ 8.3 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H).
4.7.4. (E)-1-(3-(6-Fluoropyridin-3-yl)phenyl)-3-(3-hydroxy-4-
methoxyphenyl)prop-2-en-1-one (48)
Yellow power, 78.23%; HPLC tR ¼ 14.84 min; 1H NMR (400 MHz,
4.6.3. (E)-1-(3-Bromophenyl)-3-(3-hydroxy-4-methoxyphenyl)
prop-2-en-1-one (44)
Acetone)
d
8.62 (s, 1H), 8.43 (s, 1H), 8.35 (td, J ¼ 8.3, 2.4 Hz, 1H), 8.19
(d, J ¼ 7.7 Hz, 1H), 7.96 (d, J ¼ 7.5 Hz, 1H), 7.82 (d, J ¼ 15.4 Hz, 1H),
7.81 (d, J ¼ 9.8 Hz, 1H), 7.76 (d, J ¼ 15.7 Hz, 1H), 7.70 (t, J ¼ 7.6 Hz,
1H), 7.40 (d, J ¼ 1.6 Hz, 1H), 7.28 (d, J ¼ 8.3 Hz, 1H), 7.22 (dd, J ¼ 8.6,
2.8 Hz, 1H), 7.03 (d, J ¼ 8.2 Hz, 1H), 3.92 (s, 3H); 13C NMR (100 MHz,
Yellow power, 85.62%; HPLC tR ¼ 12.88 min; 1H NMR (400 MHz,
CDCl3)
d
8.13 (s, 1H), 7.92 (d, J ¼ 7.7 Hz, 1H), 7.75 (d, J ¼ 15.6 Hz, 1H),
7.70 (d, J ¼ 8.8 Hz, 1H), 7.38 (t, J ¼ 7.8 Hz, 1H), 7.32 (d, J ¼ 15.6 Hz,
1H), 7.29 (d, J ¼ 1.8 Hz, 1H), 7.15 (dd, J ¼ 8.3, 1.7 Hz, 1H), 6.88 (d,
J ¼ 8.3 Hz, 1H), 5.67 (s, 1H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3)
Acetone)
d 189.57, 151.03, 147.83, 147.00, 146.85, 145.63, 141.34,
141.26, 140.35, 138.08, 131.90, 130.41, 129.28, 128.86, 127.78, 123.48,
120.52, 114.83, 112.27, 110.50, 110.12; HRMS calcd for C21H16NO3F
[M þ H]þ: 350.1187, found 350.1194.
d
189.00, 149.28, 146.05, 145.80, 140.26, 135.45, 131.45, 130.20,
128.24, 126.96, 123.02, 122.96, 119.50, 113.32, 110.73, 56.07; HRMS
calcd for C16H13O3Br [M þ H]þ: 333.0121, found 333.0117.
4.8. Cell culture
4.7. General procedure for synthesis of 45-48
Cells (human lung carcinoma cell line, A549; human nasopha-
ryngeal carcinoma cell line, CNE2; human colon cell line, SW480;
human breast adenocarcinoma cell line, MCF-7; human hepatoma
cell line, HepG2.) were grown in tissue culture flasks in complete
growth medium (RPMI-1640 medium with 2 mM glutamine, pH
The procedure is exemplified by the synthesis of 45.
4.7.1. (E)-1-(40-Fluoro-[1,10-biphenyl]-3-yl)-3-(4-methoxyphenyl)
prop-2-en-1-one (45)
A mixture of 42 (317 mg, 1.0 mmol), (4-fluorophenyl)boronic
7.4, supplemented with 10% fetal bovine serum, 100 mg/ml strep-
acid (182 mg, 1.3 mmol), dichloro(1,10-bis(diphenylphosphino)
tomycin and 100 units/ml penicillin) in a carbon dioxide incubator
ferrocene)palladium(Ⅱ)-dichloromethane
adduct
(50
mg,
(37 ꢀC, 5% CO2, 90% Relative Humidity).
0.06 mmol), 2 M (aq) K2CO3 (2.0 ml), and 1,4-dioxane (2.0 ml) was
heated in a sealed vial in a microwave reactor at 150 ꢀC for 20 min.
After cooling, HCl (10%) was added until pH 4 was obtained and the
mixture was extracted with EtOAc (10 ml) by three times. The
combined EtOAc layer was washed until neutral and dried over
anhydrous sodium sulfate. After removal of the solvent in vacuum,
4.9. In vitro cytotoxicity assay
Cytotoxicity study was determined using 96-well tissue culture
plates. Sulforhodamine B (SRB) assay [46,47] was performed to
evaluate cell viability. It measures cellular protein content to

Y. Zuo et al. / European Journal of Medicinal Chemistry 50 (2012) 393e404
403
determine cell density. Compounds stock solutions (10 mM) were
subtracting background (no TNF
a
). The IC50 of test compounds in
serially diluted with DMSO, and then various concentrations of
compounds in DMSO were further diluted with complete growth
medium to obtain working solutions. The final DMSO concentration
was 0.5%. Cells were plated at 5000 cells/well. The cells were
allowed to grow in carbon dioxide incubator (37 ꢀC, 5% CO2, 90%
RH) for 24 h. Then test compounds in complete growth medium
this NF-kB translocation assay stands for the concentration of
a compound required to induce 50% inhibition. All data are average
values from duplicate samples, and the experiments were repeated
twice.
Acknowledgements
(100
further incubated for 48 h. The cell growth was stopped by gently
layering trichloroacetic acid (50%, 50 L) on top of the medium in all
mL) were added to the wells in triplicate. The plates were
We are indebted to the National High-tech R&D 863 Program
(No. 2008AA02Z304), National Nature Science Foundation of China
(No. 30973619; No. 81172931) and the Fundamental Research
Funds for the Central Universities (No. 09ykpy66) of China for
financial support of this study.
m
the wells. The plates were incubated at 4 ꢀC for 1 h to fix the cells
attached to the bottom of the wells. The liquid of all the wells was
gently pipetted out and discarded. The plates were washed five
times with distilled water and air-dried. The plates were stained
with SRB dye (0.4% in 1% acetic acid, 100
were washed five times with 1% acetic acid and then air-dried. The
adsorbed dye was dissolved in Tris base solution (150 L,10 mM, pH
mL) for 30 min. The plates
Appendix. Supplementary material
m
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.ejmech.2012.02.023.
10.4) and plates were gently shaken for 1 h on an orbital shaker. The
optical density (OD) was recorded on a TECAN infiniteÒ M200 pro
multimode reader at 515 nm. The cell growth was determined by
subtracting mean OD value of respective blank from the mean OD
value of experimental set. Percent growth in presence of test
compounds was calculated considering the growth in absence of
any test compounds as 100%. Plot % control of cell viability against
the test compound concentration by plot concentrations on a log
scale and fit the data by using nonlinear regression in GraphPad
Prism 5, the absolute IC50 values was obtained from the
doseeresponse curves. All data are average values from triplicate
samples, and the experiments were repeated at least two times.
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