Stereoselective synthesis and anti-proliferative effects on prostate cancer evaluation of 5-substituted-3,4-diphenylfuran-2-ones

Article abstract of DOI:10.1016/j.ejmech.2013.04.062

Series of 5-substituted-3,4-diphenylfuran-2-ones were stereoselectively prepared. Their potential anti-proliferative effects on prostate cancer and some of their cyclooxygenases (COXs) inhibitory activities were evaluated. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position and ortho-position of the C-3 phenyl ring and 5-substituted modification of the central furanone, showed that 3-(2-chloro-phenyl)-4-(4-methanesulfonyl-phenyl)-5-(1-methoxy-ethyl) -5H-furan-2-one (13p) was the most potent compound and could effectively reduce the proliferation of prostate cancer cells (PC3 cell IC₅₀ = 20 μM; PC3 PCDNA cell IC₅₀ = 5 μM; PC3 SKP2 cell IC₅₀ = 5 μM; DU145 cell IC₅₀ = 25 μM). The cell cycle analysis for 13p in DU145 indicated that 13p may induce G1 phase arrest.

Full text of DOI:10.1016/j.ejmech.2013.04.062

European Journal of Medicinal Chemistry 65 (2013) 323e336
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Stereoselective synthesis and anti-proliferative effects on prostate
cancer evaluation of 5-substituted-3,4-diphenylfuran-2-ones
,
b
b
c
b
Gai-Zhi Liu a , Hai-Wei Xu , Peng Wang , Zong-Tao Lin , Ying-Chao Duan ,
**
Jia-Xin Zheng b, Hong-Min Liu b
,
*
a School of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan 450046, PR China
b School of Pharmaceutical Science, Zhengzhou University, Ke Xue Da Dao 100, Zhengzhou 450001, PR China
c Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 847 Monroe Avenue, Room 328, Memphis,
TN 38163, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Series of 5-substituted-3,4-diphenylfuran-2-ones were stereoselectively prepared. Their potential anti-
proliferative effects on prostate cancer and some of their cyclooxygenases (COXs) inhibitory activities
were evaluated. Structureeactivity relationship (SAR) data, acquired by substituent modification at the
para-position and ortho-position of the C-3 phenyl ring and 5-substituted modification of the central
furanone, showed that 3-(2-chloro-phenyl)-4-(4-methanesulfonyl-phenyl)-5-(1-methoxy-ethyl)-5H-
furan-2-one (13p) was the most potent compound and could effectively reduce the proliferation of
Received 26 January 2013
Received in revised form
10 April 2013
Accepted 28 April 2013
Available online 14 May 2013
prostate cancer cells (PC3 cell IC50 ¼ 20
m
M; PC3 PCDNA cell IC50 ¼ 5
m
M; PC3 SKP2 cell IC50 ¼ 5
mM;
Keywords:
Rofecoxib
5-Substituted-3,4-diphenylfuran-2-one
Prostate cancer
DU145 cell IC50 ¼ 25
m
M). The cell cycle analysis for 13p in DU145 indicated that 13p may induce G1
phase arrest.
Ó 2013 Elsevier Masson SAS. All rights reserved.
Anti-proliferative
Cell cycle arrest
1. Introduction
important molecular target for the chemoprevention of prostate
cancer [6e10].
Prostate cancer is a significant public health concern in many
regions of the world [1,2]. Compared to other cancer types,
prostate cancer is the second leading cause of cancer death in
men [3]. Previous literature showed that arachidonic acid (AA)
derived from fatty acid and its metabolite prostaglandin E2
(PGE2) stimulated the growth of PC-3 prostate cancer cells [4,5].
These data suggested that AA and its metabolites contributed
to carcinogenesis and progression of prostate cancer. Cyclo-
oxygenases (COXs) are bifunctional hemoproteins catalyzing the
bisoxygenation of arachidonic acid (AA) to prostaglandin (PG) H2,
which serves as a common precursor for the synthesis of pros-
tanoids, such as PGs, prostacyclins, and thromboxanes (TBXs).
Cyclooxygenase-2 (COX-2), an inducible isoform of COX, has been
observed to be expressed in prostate cancer. A number of pre-
clinical and clinical evidences suggested that COX-2 may be an
Many studies indicated that COX-2 is a bona fide pharmacological
target for anticancer therapy. Epidemiological studies showed that
the using of non-steroidal anti-inflammatory drugs (NSAIDs), pro-
totypic inhibitors of COX, is associated with a reduced risk of several
malignancies, including colorectal cancer [11]. It was also reported
that COX-2 inhibitor Celecoxib could block Akt activation in PC-3
cells through the inhibition of phosphoinositide-dependent ki-
nase-1 (PDK-1) with IC50 of 48 mM [12]. In recent years, significant
achievements have been obtained in drug design regarding selective
COX-2 inhibitors and their potential application for the treatment of
different disease states [13e17]. For example, the treatments of
colon, breast, and prostate cancer have shown promising results
[18,19]. Rofecoxib (4-[4-methylsulphonylphenyl]-3-phenylfuran-
2(5H)-one, 2) is a highly selective inhibitor of COX-2 [20e22]. It was
reported [23] that facile air oxidation of the conjugate base of
rofecoxib is a possible contributor to chronic human toxicity.
Therefore, we synthesized a series of 5-substituted rofecoxib de-
rivatives to avoid the oxidation reaction, and at the same time to
obtain new rofecoxib derivatives with good activity and no or little
side effect. Now, a novel series of rofecoxib derivatives, possessing a
* Corresponding author. Tel./fax: þ86 371 67781739.
** Corresponding author. Tel./fax: þ86 371 65962746.
E-mail addresses: liugaizhi@126.com (G.-Z. Liu), liuhm@zzu.edu.cn (H.-M. Liu).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.04.062

324
G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
Fig. 1. Representative examples of selective COX-2 inhibitors.
Fig. 3. The NOE spectra of compound 12a.
Fig. 2. 5-Substituted-3-phenylfuran-4-(4-methanesulfonylphenyl)-2-ones.
central furan-2-one ring are shown as selective COX-2 inhibitors,
which exhibits good anti-proliferative effects on prostate cancer
activity profiles. Diarylheterocycles, and other central ring phar-
macophore templates, have been extensively studied as cyclo-
oxygenase inhibitors [24] (Fig. 1). SAR studies have shown that for
optimum COX-2 selectivity and inhibitory potency, a SO2Me or
SO2NH2 substituent at the para-position of a phenyl ring, and that
the presence of a p-F substituent on the nonsulfonyl vicinal phenyl
ring improved the in vivo activity [25,26].
Based on the above researches and our previous work on the syn-
thesis and bioactivities of
g-alkylidene butenolides [27e31], a series of
new 5-substituted-3-phenylfuran-4-(4-methanesulfonylphenyl)-2-
ones (Fig. 2) as rofecoxib derivatives were designed and synthesized
in the present work. Their prostatic hyperplasia inhibitory activities, the
Scheme 1. Synthesis of the 5-substituted-3-phenylfuran-4-(4-methanesulfonylphenyl)-2-ones (12, 13, 14). Reagents and conditions (i) CH3COCl, AlCl3, CH2Cl2, 97%; (ii) 30% H2O2,
CH3COOH, 99%; (iii) Br2, CH3COOH, 86%; (iv) R-PhCH2COONa, DMF; (v) (Me2CH)2NH, DMF, 70%; (vi) CH3OH, NH2CH2CH2NH2, reflux 70%e100%.

G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
325
Table 1
Inhibitory results of 5-substituted-3-phenylfuran-4-(4-methanesulfonyl phenyl)-2-ones derivative against prostate cancer cell lines. Bold represents the corresponding
compounds of those data show good activity, of which the IC50 values less than 50 mM.
Compound
R
R1
R2
PC-3PCDNA
PC-3 SKP2
PC-3
DU145
IC50 (mM)
IC50
(
m
M)a
IC50
(m
M)
IC50
(
m
M)
2
H
H
H
H
H
H
H
H
>50
>90
>90
>80
>90
>100
>125
25.88 2.08
25.24 2.27
>50
>50
>90
>100
>90
>100
>100
200
Ntc
Nt
Nt
Nt
200
Nt
Nt
Nt
Nt
12a
12b
12c
12d
12e
12f
12g
12h
12i
H
H
H
H
H
H
H
H
Ph
m-NO2Ph
o-MeOPh
3,4,5-triMeOPh
Furoyl
m-MeOep-OHPh
p-OHPh
p-BrPh
Nt
Nt
25.47 1.63b
>50
>50
>50
>50
>50
>50
Nt
>50
>50
>50
Nt
H
H
H
p-ClPh
12j
12k
12l
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH]C(CH3)CH2CH2CH]C(CH3)2
p-N(CH3)2Ph
3,4-(CH2eOeCH2)Ph
p-MeOPh
>50
>50
37.21 2.38
>50
>50
>50
37.09 2.06
>50
>50
>50
25.46 2.30
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
40.52 2.65
5.17 0.78
>50
>50
>50
>50
18.24 1.92
>50
>50
>50
25.86 1.97
>50
>50
>50
>50
>50
>50
50.63 3.15
>50
>50
>50
20.33 2.45
>50
5.48 0.91
>50
45.75 2.04
>50
>50
25.14 2.16
>50
>50
>50
>50
30.11 2.38
>50
>50
>50
Nt
Nt
>50
Nt
Nt
Nt
>50
Nt
>50
Nt
>50
Nt
Nt
>50
Nt
Nt
Nt
Nt
>50
Nt
Nt
Nt
Nt
Nt
>50
Nt
Nt
Nt
>50
Nt
>50
Nt
>50
Nt
Nt
>50
Nt
Nt
Nt
Nt
>50
Nt
Nt
Nt
12m
12n
12o
12p
11a
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
13l
13m
13n
13o
13p
13q
11b
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
14l
a-C10H7Ph
CH3
OCH3
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
H
Ph
m-NO2Ph
o-MeOPh
3,4,5-triMeOPh
Furoyl
m-MeOep-OHPh
p-OHPh
p-BrPh
p-ClPh
p-FPh
p-N(CH3)2Ph
3,4-(CH2eOeCH2)Ph
p-MeOPh
a-C10H7Ph
CH3
OCH3
o-ClPh
15.37 1.04
5.09 0.80
>50
>50
>50
>50
>50
20 ꢀ 1.17
25 ꢀ 2.08
Nt
Nt
Nt
Nt
Nt
>50
>50
Nt
>50
>50
Nt
Nt
Nt
>50
Nt
Nt
>50
Nt
>50
Nt
Nt
Nt
Nt
>50
>50
Nt
>50
>50
Nt
Nt
Nt
>50
Nt
Nt
>50
Nt
>50
Nt
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
H
Ph
m-NO2Ph
o-MeOPh
3,4,5-triMeOPh
Furoyl
m-MeO-p-OHPh
p-OHPh
p-BrPh
p-ClPh
p-FPh
>50
25.13 1.39
25.44 2.16
>50
10.69 1.41
25.71 2.16
>50
>50
>50
47.17 2.04
>50
>50
25.37 2.27
>50
>50
>50
27.07 ꢀ 4.21
p-N(CH3)2Ph
3,4-(CH2eOeCH2)Ph
p-MeOPh
>50
>50
20.04 2.21
>50
36.42 3.77
>50
14m
14n
14o
14p
14q
5-Fu
a-C10H7Ph
CH3
OCH3
o-ClPh
31.44 ꢀ 2.37
Nt
Nt
a
Inhibitory activity was assayed by exposure for 72 h to substances and expressed as concentration required to inhibit prostate cancer cell proliferation by 50% (IC50).
b
c
Data are presented as the means ꢀ SDs of three independent experiments for those IC50 values less than 50
mM.
Nt: no test.

326
G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
mechanisms of this inhibition effect, and some of their COX inhibitory
activities were evaluated and presented.
butenolides 12, 13 and 14 are relatively stable and not very sensitive
to organic bases. This might be due to conjugation of two benzene
substituents and with the 5-alkylidene substituents in the target
compounds. When paraformaldehyde was used as aldehyde source,
2. Results and discussion
12p, 13p and 14p were obtained respectively instead of g-alkyli-
dene-butenolides. Most of the reaction products precipitated in
good yields and high stereoselectivity.
2.1. Chemistry
The NMR spectra data showed that single isomers of 12, 13 and
14 were formed. In the NOE spectrum of 12a (Fig. 3), the correlation
between signals of H-6 (dH 5.90) and phenyl H-2, H-6 (dH 7.80) and
4-methylsulfanylphenyl H-2, H-6 (dH 7.60) showed the geometry of
The title 5-substituted-3-phenylfuran-4-(4-methanesulfonylphen
yl)-2-ones (Fig. 2), possessing a central five-membered lactone ring
with a 5-substitution, were prepared by condensation of rofecoxib (2)
anditsanalogs11(a,b)withaliphaticoraromaticaldehydes orketones
as illustrated in Scheme 1. Rofecoxib 2 and the two new derivatives
11(a,b) were obtained by the simple synthetic method in good yields.
Thioanisole (6) was reacted with acetyl chloride by a FriedeleCrafts
acylation to give compound 7. Compound 8 was obtained almost
quantitatively by hydrogen peroxide oxidation of compound 7. Com-
pound 9 was obtained by compound 8 after reaction with bromine in
ice acetic acid with 86% yield. Then analogs 11(a,b) were prepared
using a one-pot reaction, starting with condensation of compound 9
and sodium phenylacetate. The reaction was monitored by TLC until
completion. Finally, with no further treatment of the reaction, cycli-
zation of intermediate 10 is catalyzed by diisopropylamine to produce
11(a,b) with approximate 70% yield.
double bond (D
5,6) in 12a was Z isomer. Similarly, all of the other
synthetic compounds 12, 13 and 14 were confirmed to have Z
configuration.
In order to understand its high enantioselectivity, theoretical
calculations were carried out for a simple model reaction of rofe-
coxib with benzaldehyde (All calculations were implemented in the
Gaussian 03 program). Due to the potential chiral carbonyl C atom
of PhCHO, the nucleophile (anion) can attack the carbonyl C atom
either from Re or Si side. Transition structures in the stereo-
controlling CeC bond formation were studied using HartreeeFock
(HF) method at 6-31G (d) level and the calculated results were in
agreement with experimental results. The calculated barrier en-
ergies were 7.8 kJ/mol and 8.6 kJ/mol respectively for cis- and trans-
products respectively. Obviously, the barrier energies for cis- is
lower than that for trans-. This is in great agreement with the
experimental results. And the Transition State Structures showed
that the cleavage of OH is trans-cleavage which is in agreement
with the proposed mechanism.
Rofecoxib derivatives 12,13 and 14 were synthesized by reacting
2 and 11(a,b) with various aldehydes or ketones using our previ-
ously reported procedure [28] (Scheme 1 and Table 1). Based on our
previous studies, most of the compounds containing five-
membered lactone are sensitive to strong bases and/or high tem-
perature. However, 2 and 11(a,b), and their target
g-alkylidene
Fig. 4. Effect of compound 13p on the cell cycle distribution of DU145 cells. Cells were treated with different concentrations (0, 5, 15, 20
mM) for 12 h. Then the cells were fixed and
stained with PI to analyze DNA content by flow cytometry. The experiments were performed three times, and a representative experiment is shown.

G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
327
2.2. Evaluation of biological activities
were 40.91%, 42.22%, 60.0% and 64.51%, respectively (Fig. 4). The
results suggested that 13p caused a clear G0/G1 arrest pattern in a
concentration dependent manner.
2.2.1. Prostatic hyperplasia inhibitory activities
Rofecoxib
(2)
and
5-substituted-3-phenylfuran-4-(4-
methanesulfonyl phenyl)-2-ones derivatives 12, 13 and 14 were
screened in vitro for anti-proliferative effects (IC50 values) against
prostate cancer cell line PC3 and its transfected cell lines (PC3
PCDNA and PC3 SKP2) and the second prostate cancer cell line
DU145. The well-known anticancer drug 5-fluorouracil was used as
positive control. All compounds were conducted the MTT assay on
PC3 PCDNA and PC3 SKP2 cell lines. Only the active compounds
were further conducted by the MTT assays on DU145 and PC3 cells.
The results are summarized in Table 1. It can be observed from
Table 1 that 12l, 12p, 13c, 13o, 13p, 14c, 14g, and 14n reduced cell
proliferation in both PC3 transfected cells (PC3 PCDNA and PC3
2.2.3. Effect of 13p on apoptosis of DU145 cells
Further experiments were carried out to determine whether
this anti-proliferative effect of 13p on DU145 cells viability was
closely associated with apoptotic cell death. Morphological analysis
following DAPI staining was performed to analyze the cells with
nuclear chromatin condensation and apoptotic bodies. Cells treated
with 13p displayed chromosomal condensation and formation of
apoptotic bodies (Fig. 5).
2.2.4. Cyclooxygenase inhibitory activities
Some of their in vitro ability to inhibit the COX-1 and/or COX-2
was evaluated (Table 2). The in vitro activity results were reported
SKP2) by 50% at concentrations less than 50
12g, 12h, 13a, 13f, 13k, 14d, 14f and 14p had IC50s much less than
50 M for one of the PC3 transfected cell lines.
According to Table 1, 13p was the most potent compound with
mM. In addition, 12f,
as a percentage of inhibition of the enzymes at 10 mM for most
m
compounds, several active compounds’ and rofecoxib’s activity
results were reported as IC50 values. Most of them exhibited good
COX-2 inhibitory activities. In this preliminary study toward new
potential COX-2 inhibitor compounds as novel drug candidates for
prostatic hyperplasia inhibitory activities, it was well established
that 5-substituted-3-phenyl-furan-4-(4-methanesulfonylphenyl)-
2-ones was a good template for anti-proliferative effects on pros-
tate cancer.
good IC50 values against PC3 PCDNA and PC3 SKP2 cell lines, and it
is much better than the well-known anticancer drug 5-fluorouracil.
The MTT assays conducted on the effective compounds on DU145
and PC3 cells indicated that 13p was the sole compound that
consistently had an IC50 value below 50
with an IC50 of 20 M in PC3 cell and 25
IC50 for 13p is significantly less than the IC50 of rofecoxib (2) (PC3
cell IC50 z 200 M; DU145 cell IC50 z 200 M).
mM, reducing cell viability
m
mM in DU145 cell. Also, the
m
m
2.3. Structure activity relationship
2.2.2. Cell cycle analysis
Three series of compounds 12aep, 13aeq and 14aeq were
screened for prostatic hyperplasia inhibitory activities. Compounds
12l, 12p, 13c, 13o, 13p, 14c, 14g, and 14n exhibited good anti-
proliferative effects against both PC3 PCDNA and PC3 SKP2 cell
lines, whereas compounds 12f, 12g, 12h, 13a, 13f, 13k, 14d, 14f and
Many anticancer drugs interact with cells leading to cell growth
arrest. To determine whether the anticancer effects of compound
13p was caused by cell cycle accumulated at a certain phase, the
effects of different concentrations of compound 13p on cell cycle
progression were examined with DU145 cell line. After treatment
14p had IC50s much lower than 50 mM for one of the PC3 transfected
with compound 13p at various concentrations (0, 5, 15 and 20
mM)
cell lines. The above effective compounds on DU145 and PC3 cells
for 12 h, it was observed that the percentage of cells in G0/G1 phase
indicated that 13p was the only compound that consistently had an
Fig. 5. Compound 13p treatment induces apoptosis in DU145 cells. Cells were seeded at 2 ꢁ 104 cells per 60-mm plate, incubated for 24 h and treated with the indicated con-
centration of 13p for 48 h. Stained nuclei with DAPI solution were then photographed with a fluorescent microscope using a blue filter (original magnification 400ꢁ).

328
G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
Table 2
cell cycle analysis for the active compound 13p in DU145 indicated
that 13p may induce G1 arrest.
In vitro inhibition of COX-1/COX-2 by some of the 5-substituted-3-phenylfuran-4-
(4-methanesulfonyl phenyl)-2-ones derivatives.
Compound
COX-2 inhibition
COX-1 inhibition
4. Experimental protocols
a
b
a
b
%
IC50
(m
M)
%
IC50
3.1
(mM)
4.1. General methods
2 (Rofecoxib)
12b
12c
22.15 ꢀ 4.33c
Ni
72.57 ꢀ 6.69
36.6 ꢀ 7.91
14.4 ꢀ 2.79
Ni
24.6 ꢀ 6.54
16.66 ꢀ 8.19
Ni
0.5
3.0
Nid
Ni
Melting points were determined on a Beijing Keyi XT5 apparatus
and are uncorrected. IR spectra were recorded as KBr pellets on a
Thermo Nicolet (IR200) Spectrometer. 1H and 13C NMR spectra
were recorded on a Bruker DPX-400 spectrometer at 400 and
100 MHz with TMS as internal standard. Mass spectra were taken
by Waters Q-Tof micro mass spectrometer.
71.02 ꢀ 11.18
12f
Nte
12g
12h
12l
12m
12e
Nt
Nt
Nt
65.89 ꢀ 8.79
8.2
Ni
12i
Ni
14.6 ꢀ 2.07
11a
13a
13b
13c
13f
13g
13i
13k
13m
13o
13p
11b
14b
14c
14d
14f
14g
14k
14i
7.97 ꢀ 5.68
59.1 ꢀ 5.68
59.22 ꢀ 11.20
44.24 ꢀ 5.61
14.87 ꢀ 3.11
2.27 ꢀ 0.53
32.68 ꢀ 6.54
4.49 ꢀ 1.40
Ni
24.14 ꢀ 1.62
43.32 ꢀ 5.46
66.92 ꢀ 8.61
Ni
45.59 ꢀ 5.79
20.8 ꢀ 2.07
43.6 ꢀ 3.12
19.5 ꢀ 3.85
Ni
Ni
Ni
Ni
Ni
Nt
4.1.1. 4-(Methylthio)acetophenone (7)
7.3
7.1
14.6
To a cold (ꢂ5 ꢃC) solution of AlCl3 (6.5 g, 0.049 mol) in CHCl3
(50 mL) was added acetyl chloride (205 mL, 2.88 mol) while cooling
to maintain the temperature at ꢂ5 ꢃC. Thioanisole 6 (5.08 g,
0.041 mol) dissolved in CHCl3 (20 mL) was then dropwise added
with cooling to maintain the temperature below 5 ꢃC, the ice bath
was then removed, and the mixture was stirred for 1.5 h until finish.
Ice H2O (100 mL) was slowly added, the mixture was well stirred,
dropwise added chlorohydric acid, and the layers were separated.
The organic layer was washed with H2O (2 ꢁ 100 mL), sat. NaHCO3
(2 ꢁ 100 mL), then brine and dried (Na2SO4). The solvent was
evaporated and the residue was recrystallized in alcohol. The solid
was filtered and air-dried to afford 6.66 g (98%) of 7 as a white
needle crystal. Mp 80e82 ꢃC; 1H NMR (400 MHz, CDCl3, TMS):
7.01 ꢀ 0.50
Ni
Nt
Nt
Ni
Nt
61.21 ꢀ 6.54
8.5
18.59 ꢀ 4.35
12.1
9.2
Nt
28.5 ꢀ 9.88
Ni
Ni
Nt
Nt
Nt
Nt
Ni
13.9
17.6
d
7.91 (d, J ¼ 1.44 Hz, 2H, HePh), 7.25 (d, J ¼ 8.52 Hz, 2H, HePh),
2.56 (s, 3H, CH3), 2.51 (s, 3H, CH3).
14m
14n
14p
10.23 ꢀ 3.41
Nt
Nt
32.43 ꢀ 6.79
4.1.2. 4-(Methylsulfonyl)acetophenone (8)
a
To a solution of 4-(methylthio)acetophenone (7, 5.5 g, 33 mmol)
in glacial acetic acid (15 mL) was added 30% H2O2 (8.5 mL,
82.5 mmol), 98% H2SO4 (1 mL, 5.5 mmol) was then added in drop
with cooling to maintain the temperature at 0 ꢃC, the mixture was
well stirred over 30 min. The mixture was further stirred at 70 ꢃC
for 1.5 h, ice H2O (100 mL) was slowly added, the mixture was well
stirred, then filtered and the filtrate was washed with H2O
(100 mL), and the filtrate was dried under vacuum to give 4-
(methylsulfonyl)acetophenone 8 (6.5 g, 99%). Mp 124e125 ꢃC; 1H
Data are indicated as percentage of inhibition at 10
m
M ꢀ SEM (n ¼ 3).
Values are mean values of two determinations acquired using an ovine COX-1/
COX-2 assay kit, where the deviation from the mean is <10% of the mean value.
b
c
Rofecoxib was tested at 0.1
Ni: no inhibition at the corresponding concentration.
Nt: not tested.
m
M ꢀ SEM (n ¼ 3).
d
e
IC50 value below 50
than the IC50 of rofecoxib (2) (PC3 cell IC50 z 200
IC50 z 200 M). After looking at the structures of these compounds
mM, and the IC50 for 13p is significantly less
mM; DU145 cell
m
NMR (400 MHz, CDCl3, TMS):
(d, J ¼ 8.52 Hz, 2H, HePh), 3.09 (s, 3H, CH3), 2.68 (s, 3H, CH3).
d
8.13 (d, J ¼ 8.48 Hz, 2H, HePh), 8.05
showing good prostatic hyperplasia inhibitory activity, we can
conclude that rofecoxib derivatives 5-substituted-3-phenylfuran-
4-(4-methanesulfonylphenyl)-2-ones possess sites for interaction
with the targeted prostate cancer cells. Compounds 12f, 13f, 14f;
12p, 13p, 14p; 13c, 14c, 12g and 14g possess good prostatic hyper-
plasia inhibitory activity. It may due to their 5-phenyl with
electron-donating substituents which can effectively interact with
the targets both from electronic and stereochemical aspects.
4.1.3. 2-Bromo-1-(4-(methylsulfonyl)phenyl)ethanone (9)
To a solution of 4-(methylsulfonyl)acetophenone (8, 2.0 g,
0.01 mol) in glacial acetic acid (10 mL) at r.t. was added 48% HBr a
drop, well stirred over 5 min, followed by a solution of bromine
(0.5 mL, 0.01 mol) dissolved in 5 mL glacial acetic acid was added in
drop about 0.5 mL, the solution was orange yellow, raise the tem-
perature to 58 ꢃC, after 0.5 h the solution changed to white. Then it
was cooled to 25 ꢃC and the remaining bromine and glacial acid
solution was added in drop. The mixture was stirred for 2 h, after
completion of the reaction, ice H2O (100 mL) was added and solid
precipitated then filtered and the filtrate was dried under vacuum
to give 2.35 g of 5 (85%). Mp 129e131 ꢃC; 1H NMR (400 MHz, CDCl3,
3. Conclusion
The biological evaluation for this novel class of 5-substituted-3-
phenylfuran-4-(4-methanesulfonylphenyl)-2-ones have shown
that (i) a five-membered lactone (furan-2-one) ring serves as a
suitable central ring template to design rofecoxib derivatives as
COX-2 inhibitors, which can effectively reduce prostate cancer cell
proliferation; (ii) the presence of a p-fluoro and/or o-chlorine
substituent on the C-4 phenyl ring improved in vitro prostatic hy-
perplasia inhibitory activities for this class of compounds; (iii) ac-
cording to the structureeactivity relationships, compounds (12, 13,
14)f, (12, 13, 14)p; (13, 14)c and (12, 14)g are good modification to
rofecoxib for prostatic hyperplasia inhibitory activity; and (iv) the
TMS):
d 8.19 (m, 2H, HePh), 8.10 (m, 2H, HePh), 4.48 (s, 2H, CH2),
3.12 (s, 3H, CH3).
4.1.4. General procedure for the synthesis of rofecoxib (2) and its
analogs (11a,b)
50% NaOH (0.8 mL, 15 mmol) was slowly added with stirring to a
solution of phenyl acetic acid (2.0 g, 15 mmol) or 2-
chlorophenylacetic acid (2.0 g, 12 mmol) or 4-fluorophenylacetic
acid (2.0 g, 13 mmol) in DMF (60 mL). Stirring was continued for

G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
329
1 h at r.t., and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone (9,
3.45 g, 12.5 mmol) was added. The mixture was stirred for another
1 h, followed by diisopropylamine (3.8 mL) was slowly added.
Stirring was continued for 4 h at 60 ꢃC, and the mixture was acid-
ified with 2 N HCl (a color change from dark brown to light yellow
was observed). Then, ice and H2O (50 mL) were added and the
stirring continued for a few minutes. The precipitate was filtered
and rinsed with H2O. The crude wet solid was dried under vacuum
to give 2 (3.56 g, 76%). Mp 208e209 ꢃC (lit. 212e214 ꢃC) [22]; IR
(KBr): 1747 (C]O),1149 (CeO),1309 (eCH3),1600,1620,1580 (C]C,
TMS): d 167.96 (C2]O),147.94,147.52,141.59,136.28,132.80,130.73,
130.34, 129.50, 129.35, 129.17, 128.90, 128.64, 128.46, 128.18, 126.38,
113.62 (C6), 44.35 (SCH3); C24H18O4S; HR-MS (ESI) m/z: found
[M þ H]þ 403.0999 (calcd. 403.1004).
4.1.5.2. (5Z)-5-(3-Nitrobenzylidene)-4-(4-(methylsulfonyl)phenyl)-
3-phenylfuran-2(5H)-one (12b). This product was obtained as a
yellow crystal in 90% yield. Mp 289e291 ꢃC; IR (KBr)
n
: 1780 (C]O),
1630 (C]C, Ph),1354 (eCH3), 1165 (CeO), 1525 (NO2), 3020 (eArH),
775, 691 (C]H, Ph) cmꢂ1; 1H NMR (400 MHz, CDCl3, TMS):
8.44
d
Ph), 3018 (eArH), 774, 693 (C]H, Ph) cmꢂ1
CDCl3, TMS):
;
1H NMR (400 MHz,
(s, 1H, 3-nitrobenzylidene, H-2), 8.30 (d, J ¼ 7.9 Hz, 1H, 3-
nitrobenzylidene, H-4), 8.18 (d, J ¼ 7.8 Hz, 1H, 3-nitrobenzylidene,
H-6), 8.11 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.64
(m, 1H, 3-nitrobenzylidene, H-5), 7.60 (d, J ¼ 8.2 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.35 (m, 5H, phenyl), 5.93 (s, 1H,
]C6H), 3.19 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d
7.91 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-3,
H-5), 7.51 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.40
(m, 5H, Hephenyl), 5.20 (s, 2H, CH2), 3.08 (s, 3H, SCH3); 13C NMR
(100.6 MHz, CDCl3, TMS):
d 172.58 (C2]O), 153.48, 141.78, 136.16,
129.44, 129.08, 128.94, 128.45, 128.04, 70.34 (C5), 44.22 (SCH3);
C
17H14O4S; HR-MS (ESI) m/z: found [M þ H]þ 315.0674 (calcd.
d 167.25 (C2]O), 149.35, 148.50, 147.42 (C5), 141.96, 135.75, 134.42,
315.0691).
130.28, 130.00, 129.87, 129.25, 128.80, 128.44, 127.97, 127.74, 125.04,
123.53, 110.25, 44.39 (SCH3); C24H17NO6S; HR-MS (ESI) m/z: found
[M þ H]þ 448.0836 (calcd. 448.0855).
11a (2.52 g, 72%). Mp 193e195 ꢃC; IR (KBr): 1741 (C]O), 1150
(CeO), 1308 (eCH3), 1600, 1620, 1580 (C]C, Ph), 3018 (eArH), 774,
693 (C]H, Ph) cmꢂ1 1H NMR (400 MHz, CDCl3, TMS):
7.92 (d,
;
d
J ¼ 8.3 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.51 (m, 1H, 2-
chlorophenyl), 7.42 (d, J ¼ 8.3 Hz, 2H, 4-methylsulfanyl-phenyl,
H-2, H-6), 7.40 (m, 2H, 2-chlorophenyl), 7.31 (m, 1H, 2-
chlorophenyl), 5.36 (d, J ¼ 18.2 Hz, 2H, CH2), 3.05 (s, 3H, SCH3);
4.1.5.3. (5Z)-5-(2-Methoxybenzylidene)-4-(4-(methylsulfonyl)
phenyl)-3-phenylfuran-2(5H)-one (12c). This product was obtained
as a yellow crystal in 92% yield. Mp 253e255 ꢃC; IR (KBr)
n
: 1780
(C]O), 1483, 1464, 1592 (C]C, Ph), 1311 (eCH3), 1247 (eOCH3),
1152 (CeO), 3020 (eArH), 775, 694 (C]H, Ph) cmꢂ1 1H NMR
(400 MHz, CDCl3, TMS):
13C NMR (100.6 MHz, CDCl3, TMS):
d
167.80 (C2]O), 155.36, 142.26,
;
135.65, 133.52, 131.09, 130.91, 130.36, 129.01, 128.14, 127.91, 127.58
70.39 (C5), 44.29 (SCH3); C17H13ClO4S; HR-MS (ESI) m/z: found
[M þ H]þ 349.0299 (calcd. 349.0301).
d
8.31 (m,1H, HePh), 8.06 (d, J ¼ 8.3 Hz, 2H,
4-methylsulfanylphenyl, H-3, H-5), 7.60 (d, J ¼ 8.3 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.33 (m, 5H, phenyl), 7.26e6.87
(m, 3H, HePh), 6.50 (s, 1H, ]C6H), 3.80 (s, 3H, OCH3), 3.17 (s, 3H,
11b (2.62 g, 73%). Mp 304e306 ꢃC; IR (KBr): 1753 (C]O),1151 (Ce
O), 1302 (eCH3), 1620, 1580, 1424 (C]C, Ph), 3018 (eArH), 706, 682
SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d 168.25 (C2]O), 157.62,
(C]H, Ph) cmꢂ1
;
1H NMR (400 MHz, CDCl3, TMS):
d
7.96 (d,
148.26, 147.22 (C5), 141.42, 136.47, 131.66, 131.05, 130.49, 129.84,
129.57, 129.24, 129.10, 128.72, 128.62, 128.07, 125.97, 121.83, 121.18,
110.50, 107.71, 55.63, 44.39 (SCH3); C25H20O5S; HR-MS (ESI) m/z:
found [M þ H]þ 433.1101 (calcd. 433.1110).
J ¼ 8.3 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.51 (d, J ¼ 8.3 Hz,
2H, 4-methylsulfanylphenyl, H-2, H-6), 7.40 (m, 2H, 4-fluorophenyl),
7.10 (m, 2H, 4-fluorophenyl), 5.19 (s, 2H, CH2), 3.09 (s, 3H, SCH3); 13
C
NMR (100.6 MHz, CDCl3, TMS):
d 172.40 (C2]O), 164.53, 162.04,
153.47, 142.13, 136.15, 131.26, 131.18, 129.57, 128.45, 128.29, 127.99,
125.06, 116.35, 116.13, 70.41 (C5), 44.29 (SCH3); C17H13FO4S; HR-MS
(ESI) m/z: found [M þ H]þ 333.0586 (calcd. 333.0597).
4.1.5.4. (5Z)-5-(3,4,5-Trimethoxybenzylidene)-4-(4-(methylsulfonyl)
phenyl)-3-phenylfuran-2(5H)-one (12d). This product was obtained
as a yellow crystal in 90% yield. Mp 239e241 ꢃC; IR (KBr)
n
: 1780
(C]O), 1640, 1577, 1504, 1449 (C]C, Ph), 1310 (eCH3), 1256 (e
OCH3), 1124 (CeO), 3020 (eArH), 778, 663 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
8.08 (d, J ¼ 8.2 Hz, 2H, 4-
4.1.5. General procedure for the synthesis of 5-alkylidene
substituted-3-phenylfuran-4-(4-methanesulfonyl phenyl)-2-ones
(12aep), (13aeq) and (14aeq)
;
d
methylsulfanylphenyl, H-3, H-5), 7.58 (d, J ¼ 8.2 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.33 (m, 5H, phenyleH), 7.04 (s,
2H, Ph), 5.78 (s, 1H, ]C6H), 3.91 (s, 6H, OCH3), 3.90 (s, 3H, OCH3),
Compound 2a or 11a or 11b (0.01 mol) and anhydrous sodium
carbonate (0.01 mol) were dissolved in methanol solution, then the
corresponding aldehyde or ketone (0.012 mol) was added. The
mixture was stirred at 65 ꢃC for 3e8 h and the reaction was
monitored by TLC until completion. Most of the target product can
be precipitated from the reaction system. Filtration and drying was
done to give a series of target compounds 12, 13 and 14. When the
ketone was acetone the target product cannot be precipitated from
reaction system. The reaction solution was evaporated under
reduced pressure to steam out of most of the methanol, the reaction
mixture was washed with water and ethyl acetate, dried and pu-
rified by column chromatography.
3.18 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d 168.23 (C2]
O), 153.73, 148.37, 147.43, 141.98, 139.96, 136.82, 130.78, 129.73,
129.58, 129.08, 128.98, 128.78, 128.62, 126.24, 114.14, 108.37, 101.65,
61.46 (OCH3), 56.69 (OCH3), 44.73 (SCH3); C27H24O7S; HR-MS (ESI)
m/z: found [M þ H]þ 493.1314 (calcd. 493.1321).
4.1.5.5. (5Z)-5-((Furan-2-yl)methylene)-4-(4-(methylsulfonyl)
phenyl)-3-phenylfuran-2(5H)-one (12e). This product was obtained
as a yellow crystal in 88% yield. Mp 229e231 ꢃC; IR (KBr)
n
: 1770
(C]O), 1647, 1466 (C]C, Ph), 1315 (eCH3), 1157 (CeO), 3050 (e
ArH), 773, 693 (C]H, Ph) cmꢂ1 1H NMR (400 MHz, CDCl3, TMS):
;
4.1.5.1. (5Z)-5-Benzylidene-4-(4-(methylsulfonyl)phenyl)-3-
phenylfuran-2(5H)-one (12a). This product was obtained as a yel-
d
8.06 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.57 (d,
J ¼ 8.2 Hz, 2H, 4-methylsulfanyl-phenyl, H-2, H-6), 7.52 (d,
J ¼ 1.2 Hz, 1H, furaneH), 7.34 (m, 5H, phenyleH), 7.15 (d, J ¼ 3.5 Hz,
1H, furaneH), 6.58 (m, 1H, furaneH), 5.96 (s, 1H, ]C6H), 3.16 (s, 3H,
low crystal in 90% yield. Mp 259e261 ꢃC; IR (KBr)
n
: 1780 (C]O),
1600, 1460 (C]C, Ph), 1310 (eCH3), 1148 (CeO), 3020 (eArH), 2910
(eCHe), 779, 695 (C]H, Ph) cmꢂ1 1H NMR (400 MHz, CDCl3,
TMS):
;
SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d 167.60 (C2]O), 149.16,
d
8.07 (d, J ¼ 8.1 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5),
146.80 (C5), 145.52, 144.56, 141.59, 136.02, 130.22, 129.35, 129.10,
128.67, 128.53, 128.26, 126.08, 115.81, 113.36, 101.89 (C6), 44.40
(SCH3); C22H16O5S; HR-MS (ESI) m/z: found [M þ H]þ 393.0766
(calcd. 393.0797).
7.79 (d, J ¼ 7.5 Hz, 2H, phenyleH), 7.58 (d, J ¼ 8.1 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.34 (overlap, 8H, phenyleH),
5.90 (s, 1H, ]C6H), 3.17 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3,

330
G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
4.1.5.6. (5Z)-5-(4-Hydroxy-3-methoxybenzylidene)-4-(4-(methyl-
(overlap, 5H, phenyleH), 6.63 (d, J ¼ 11.8 Hz, 1H, ]C6H), 6.01 (dd,
J ¼ 11.8 Hz, J ¼ 4.4 Hz, 1H, ]C7H), 5.16 (t, J ¼ 6.4 Hz, 1H, CH]C
(CH3)2), 3.22 (s, 3H, SCH3), 2.25 (m, 4H, CH2), 1.87 (s, 3H, CH3), 1.87
(s, 3H, CH3), 1.70 (s, 3H, CH3); 13C NMR (100.6 MHz, CDCl3, TMS):
sulfonyl)phenyl)-3-phenylfuran-2(5H)-one (12f). This product was
obtained as a yellow crystal in 90% yield. Mp 270e271 ꢃC; IR (KBr)
n:
3478 (eOH),1770 (C]O), 1572, 1560, 1517 (C]C, Ph), 1317 (eCH3),
1266 (eOCH3), 1147 (CeO), 777, 663 (C]H, Ph) cmꢂ1 1H NMR
(400 MHz, CDCl3, TMS): 8.06 (d, 8.2 Hz, 2H, 4-
;
d 167.70 (C2]O), 149.39, 146.45, 141.45, 136.54, 132.46, 130.25,
d
J
¼
129.15, 129.09, 128.90, 128.56, 128.50, 128.10, 126.04, 123.18, 123.09,
111.00 (C6), 44.37 (SCH3), 40.67 (CH3), 26.49 (CH3), 25.72 (CH3),
17.76 (CH2), 17.61 (CH2); C27H28O4S; HR-MS (ESI) m/z: found
[M þ H]þ 449.1745 (calcd. 449.1787).
methylsulfanylphenyl, H-3, H-5), 7.58 (d, J ¼ 8.2 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.47 (d, J ¼ 1.3 Hz, 1H, HePh),
7.30 (m, 5H, phenyleH), 7.22 (d, J ¼ 1.3 Hz, 1H, HePh), 6.92 (d,
J ¼ 8.3 Hz, 1H, HePh), 6.22 (s, 1H, OH), 5.82 (s, 1H, ]C6H), 3.97 (s,
3H, OCH3), 3.17 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
4.1.5.11. (5Z)-5-(4-(Dimethylamino)benzylidene)-4-(4-(methyl-
d
168.11 (C2]O), 148.05, 147.55, 146.88, 145.90, 141.43, 136.55,
sulfonyl)phenyl)-3-phenylfuran-2(5H)-one (12k). This product was
130.38, 129.12, 128.74, 128.62, 128.14, 125.54, 125.08, 114.87, 114.19,
112.42, 56.14, 44.37 (SCH3); C25H20O6S; HR-MS (ESI) m/z: found
[M þ H]þ 449.1042 (calcd. 449.1059).
obtained as a red crystal in 95% yield. Mp 244e246 ꢃC; IR (KBr)
n:
1770 (C]O), 1590, 1578, 1530 (C]C, Ph), 1314 (eCH3), 1371 (CeN),
1164 (CeO), 779, 663 (C]H, Ph) cmꢂ1 1H NMR (400 MHz, CDCl3,
TMS):
;
d
8.04 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5),
4.1.5.7. (5Z)-5-(4-Hydroxybenzylidene)-4-(4-(methylsulfonyl)
7.71 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanyl-phenyl, H-2, H-6), 7.57 (d,
J ¼ 8.8 Hz, 2H, HePh), 7.33 (m, 5H, phenyleH), 6.68 (d, J ¼ 8.8 Hz,
2H, HePh), 5.84 (s, 1H, ]C6H), 3.16 (s, 3H, SCH3), 3.06 (s, 6H, CH3);
phenyl)-3-phenylfuran-2(5H)-one (12g). This product was obtained
as a yellow crystal in 84% yield. Mp 287e289 ꢃC; IR (KBr)
n
: 3371 (e
OH), 1780 (C]O), 1595, 1581, 1511, 1436 (C]C, Ph), 1304 (eCH3),
1170 (CeO), 2960 (eCHe), 778, 693 (C]H, Ph) cmꢂ1 1H NMR
(400 MHz, CDCl3, TMS): 8.07 (d, 8.3 Hz, 2H, 4-
13C NMR (100.6 MHz, CDCl3, TMS):
d 168.60 (C2]O), 147.95, 144.57,
;
141.18, 137.07, 132.72, 130.44, 129.27, 128.66, 128.52, 128.02, 123.40,
115.21, 111.94 (C6), 44.40 (SCH3), 40.10 (NCH3); C26H23NO4S; HR-MS
(ESI) m/z: found [M þ H]þ 446.1421 (calcd. 446.1426).
d
J
¼
methylsulfanylphenyl, H-3, H-5), 7.71 (d, J ¼ 8.7 Hz, 2H, HePh),
7.61 (d, J ¼ 8.3 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.29 (m,
5H, phenyleH), 6.90 (d, J ¼ 8.7 Hz, 2H, HePh), 5.85 (s, 1H, ]C6H),
4.1.5.12. (5Z)-5-((Benzo[d][1,3]dioxol-5-yl)methylene)-4-(4-(methyl-
3.17 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d
168.70 (C2]
sulfonyl)phenyl)-3-phenylfuran-2(5H)-one (12l). This product was
O), 157.73, 148.22, 144.34, 138.11, 137.62, 132.63, 128.7, 128.2, 127.8,
126.4, 122.4, 115.8, 100.6, 44.3. C24H18O5S; HR-MS (ESI) m/z: found
[M þ H]þ 419.0941 (calcd. 419.0953).
obtained as a yellow crystal in 91% yield. Mp 261e263 ꢃC; IR (KBr)
n:
1750 (C]O), 1610 (C]C, Ph), 1309 (eCH3), 1163 (CeO), 1232 (e
OCH2e), 3020 (eArH), 774, 693 (C]H, Ph) cmꢂ1 1H NMR
(400 MHz, CDCl3, TMS): 8.06 (d, 8.2 Hz, 2H, 4-
;
d
J
¼
4.1.5.8. (5Z)-5-(4-Fluorobenzylidene)-4-(4-(methylsulfonyl)phenyl)-
methylsulfanylphenyl, H-3, H-5), 7.57 (d, J ¼ 8.2 Hz, 2H, 4-
methylsulfanyl-phenyl, H-2, H-6), 7.54 (s, 1H, substituent phenyl,
H-2), 7.35 (m, 5H, Hephenyl), 7.12 (d, J ¼ 8.2 Hz, 1H, substituent
phenyl, H-5), 6.82 (d, J ¼ 8.2 Hz, 1H, substituent phenyl, H-6), 6.03
(s, 2H, CH2), 5.81 (s, 1H, ]C6H), 3.17 (s, 3H, SCH3); 13C NMR
3-phenylfuran-2(5H)-one (12h). This product was obtained as a
yellow crystal in 86% yield. Mp 301e303 ꢃC; IR (KBr)
n: 1780 (C]O),
1620, 1580, 1482, 1395 (C]C, Ph), 1315 (eCH3), 1149 (CeO), 3020 (e
ArH), 2910 (eCHe), 772, 690 (C]H, Ph) cmꢂ1; 1H NMR (400 MHz,
CDCl3, TMS):
d
8.09 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-3,
(100.6 MHz, CDCl3, TMS): d 168.03 (C2]O), 148.95, 148.40, 147.91,
146.17 (C5), 141.46, 136.42, 130.36, 129.19, 129.12, 128.63, 128.17,
H-5), 7.70 (d, J ¼ 8.0 Hz, 2H, Ph), 7.64 (d, J ¼ 8.4 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.53 (d, J ¼ 8.0 Hz, 2H, Ph), 7.34
(m, 5H, phenyleH), 5.94 (s, 1H, ]C6H), 3.21 (s, 3H, SCH3); 13C NMR
127.23, 126.52, 125.48, 113.75, 110.00, 108.65, 101.65, 44.37 (SCH3);
C
25H18O6S; HR-MS (ESI) m/z: found [M þ H]þ 447.0898 (calcd.
(100.6 MHz, CDCl3, TMS):
d
167.59 (C2]O), 148.40, 148.02, 141.90,
447.0902).
135.57, 132.20, 132.10, 132.04, 130.40, 129.43, 129.25, 128.65, 128.56,
128.19, 126.51, 123.42, 112.12 (C6), 44.22 (SCH3); C24H17BrO4S; HR-
MS (ESI) m/z: found [M þ H]þ 481.0102 (calcd. 481.0109).
4.1.5.13. (5Z)-5-(4-Methoxybenzylidene)-4-(4-(methylsulfonyl)
phenyl)-3-phenylfuran-2(5H)-one (12m). This product was ob-
tained as a yellow crystal in 90% yield. Mp 268e270 ꢃC; IR (KBr)
n:
4.1.5.9. (5Z)-5-(4-Chlorobenzylidene)-4-(4-(methylsulfonyl)phenyl)-
1780 (C]O), 1599, 1567, 1510 (C]C, Ph), 1330 (eCH3), 1253 (e
OCH3), 1178 (CeO), 3020 (eArH), 769, 693 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
8.06 (d, J ¼ 8.2 Hz, 2H, 4-
3-phenylfuran-2(5H)-one (12i). This product was obtained as a
;
yellow crystal in 85% yield. Mp 307e308 ꢃC; IR (KBr)
n
: 1780 (C]O),
d
1637, 1583, 1488, 1406 (C]C, Ph), 1310 (eCH3), 1149 (CeO), 3020 (e
methylsulfanylphenyl, H-3, H-5), 7.77 (d, J ¼ 8.8 Hz, 2H, HePh),
7.58 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.33 (m,
5H, phenyleH), 6.93 (d, J ¼ 8.8 Hz, 2H, HePh), 5.86 (s, 1H, ]C6H),
3.85 (s, 3H, OCH3), 3.17 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3,
ArH), 2910 (eCHe), 776, 695 (C]H, Ph) cmꢂ1; 1H NMR (400 MHz,
CDCl3, TMS):
d
8.09 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-3,
H-5), 7.75 (d, J ¼ 8.6 Hz, 2H, HePh), 7.64 (d, J ¼ 8.2 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.35 (overlap, 7H, HePh), 5.92
(s, 1H, ]C6H), 3.20 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
TMS):
d 168.24 (C2]O), 160.68, 148.01, 146.04, 141.41, 136.53,
132.58, 130.37, 129.12, 128.71, 128.61, 128.15, 125.22, 114.45, 113.74
(C6), 55.40 (OCH3), 44.37 (SCH3); C25H20O5S; HR-MS (ESI) m/z:
found [M þ H]þ 433.1107 (calcd. 433.1110).
d
167.63 (C2]O), 148.03, 147.68, 141.58, 135.65, 134.98, 131.81,
131.57, 131.37, 130.24, 129.34, 129.07, 128.97, 128.55, 128.26, 128.17,
126.38, 112.06 (C6), 44.19 (SCH3); C24H17ClO4S; HR-MS (ESI) m/z:
found [M þ H]þ 437.0611 (calcd. 437.0614).
4.1.5.14. (5Z)-4-(4-(Methylsulfonyl)phenyl)-5-((naphthalen-1-yl)
methylene)-3-phenylfuran-2(5H)-one (12n). This product was ob-
4.1.5.10. (5Z)-5-((Z/E)-3,7-Dimethylocta-2,6-dienylidene)-4-(4-
(methylsulfonyl)phenyl)-3-phenylfuran-2(5H)-one (12j). This prod-
uct was obtained as a yellow crystal in 80% yield. Mp 114e116 ꢃC; IR
tained as a yellow crystal in 88% yield. Mp 236e238 ꢃC; IR (KBr)
n:
1790 (C]O), 1620, 1583, 1452, 1400 (C]C, Ph), 1310 (eCH3), 1148
(CeO), 3020 (eArH), 2950 (eCHe), 772, 690 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
8.40 (d, J ¼ 7.60 Hz, 1H, HeAr), 8.14
(d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.88 (m, 2H,
HeAr), 7.82 (m, 1H, HePh), 7.69 (d, 8.4 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6),7.60 (m, 1H, HePh), 7.40 (m, 2H,
;
(KBr)
O), 2950 (eCHe), 775, 694 (C]H, Ph) cmꢂ1
CDCl3, TMS):
8.11 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-3,
H-5), 7.62 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.38
n
: 1780 (C]O), 1625, 1602 (C]C, Ph), 1313 (eCH3), 1155 (Ce
d
;
1H NMR (400 MHz,
d
J
¼

G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
331
HePh), 7.38 (m, 2H, HePh), 7.34 (m, 3H, HePh), 6.72 (s, 1H, ]C6H),
3.20 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
168.11 (C2]
O), 148.50, 147.85, 141.79, 136.43, 133.69, 131.58, 130.44, 130.15,
129.98, 129.43, 129.27, 129.17, 128.70, 128.62, 128.52, 128.31, 126.99,
126.76, 126.09, 125.87, 122.69, 109.47 (C6), 44.40 (SCH3); C28H20O4S;
HR-MS (ESI) m/z: found [M þ H]þ 453.1158 (calcd. 453.1161).
1780 (C]O),1610, 1595, 1487, 1465 (C]C, Ph), 1321 (eCH3), 1237 (e
OCH3), 1151 (CeO), 3020 (eArH), 756, 648 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
8.33 (d, J ¼ 7.2 Hz, 1H, HePh), 7.98
d
;
d
(d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.52 (d,
J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.41e7.23 (m, 6H,
phenyl), 7.08 (m, 1H, phenyl), 6.91 (d, J ¼ 8.3 Hz, 1H, HePh), 6.68 (s,
1H, ]C6H), 3.82 (s, 3H, OCH3), 3.11 (s, 3H, SCH3); 13C NMR
4.1.5.15. 4-(4-(Methylsulfonyl)phenyl)-3-phenyl-5-(propan-2-
(100.6 MHz, CDCl3, TMS): d 167.46 (C2]O), 157.76, 151.60, 146.70,
ylidene)furan-2(5H)-one (12o). This product was obtained as yel-
141.43, 135.89, 133.87, 131.76, 131.67, 131.34, 130.64, 130.11, 130.06,
128.22, 127.80, 127.08, 125.76, 121.62, 121.18, 110.52, 108.65, 55.65
(OCH3), 44.31 (SCH3); C25H19ClO5S; HR-MS (ESI) m/z: found
[M þ H]þ 467.0713 (calcd. 467.0720).
low oil in 70% yield. IR (KBr)
(C]C, Ph), 1312 (eCH3), 1156 (CeO), 2960 (eCHe), 772, 694 (C]H,
Ph) cmꢂ1; 1H NMR (400 MHz, CDCl3, TMS):
n: 1780 (C]O), 1653, 1600, 1580, 1440
d
8.03 (d, J ¼ 8.2 Hz, 2H,
4-methylsulfanylphenyl, H-3, H-5), 7.53 (d, J ¼ 8.2 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.23 (s, 5H, phenyleH), 3.12 (s,
3H, SCH3), 2.11 (m, 3H, CH3), 1.44 (s, 3H, CH3); 13C NMR (100.6 MHz,
4.1.5.20. (Z)-5-(3,4,5-Trimethoxybenzylidene)-3-(2-chlorophenyl)-4-
(4-(methylsulfonyl)phenyl)furan-2(5H)-one (13d). This product was
CDCl3, TMS):
d
167.70 (C2]O), 146.26, 143.37, 141.16, 139.31, 129.89,
obtained as a yellow crystal in 88% yield. Mp 261e263 ꢃC; IR (KBr)
n:
129.06, 128.91, 128.63, 128.39, 128.12, 128.09, 126.16, 44.43 (SCH3),
21.24 (CH3), 19.52 (CH3); C20H18O4S; HR-MS (ESI) m/z: found
[M þ H]þ 355.1000 (calcd. 355.1004).
1780 (C]O), 1640, 1575, 1504, 1449, 1414 (C]C, Ph), 1323 (eCH3),
1251 (eOCH3), 1122 (CeO), 3020 (eArH), 778, 663 (C]H, Ph) cmꢂ1
1H NMR (400 MHz, CDCl3, TMS):
methylsulfanylphenyl, H-3, H-5), 7.51 (d, J ¼ 8.3 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.42e7.21 (m, 4H, 2-
chlorophenyl), 7.08 (s, 2H, Ph), 5.97 (s, 1H, ]C6H), 3.92 (s, 6H,
OCH3), 3.91 (s, 3H, OCH3), 3.12 (s, 3H, SCH3); 13C NMR (100.6 MHz,
;
d
8.00 (d, J ¼ 8.3 Hz, 2H, 4-
4.1.5.16. 5-Methoxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-
phenylfuran-2(5H)-one (12p). This product was obtained as yellow
oil in 63% yield. IR (KBr)
CDCl3, TMS):
n ;
: 1784 (C]O) cmꢂ1 1H NMR (400 MHz,
7.92 (d, J ¼ 8.8 Hz, 2H, 4-methylsulfanylphenyl, H-3,
d
CDCl3, TMS): d 168.23 (C2]O), 153.35,151.44, 146.50, 141.62, 135.75,
133.87, 131.63, 130.73, 130.14, 129.98, 128.15, 128.06, 127.91, 127.10,
H-5), 7.65 (d, J ¼ 8.8 Hz, 2H, 4-methylsulfanyl-phenyl, H-2, H-6),
7.39e7.27 (m, 5H, phenyleH), 3.46 (s, 3H, SCH3), 3.09 (s, 3H, OCH3),
125.83, 114.62, 108.14, 61.06 (OCH3), 56.29 (OCH3), 44.26 (SCH3);
1.67 (s, 3H, CH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d
168.82 (C2]
C
27H23ClO7S; HR-MS (ESI) m/z: found [M þ H]þ 528.1001 (calcd.
O), 153.32, 141.75, 135.88, 131.23, 129.81, 129.63, 129.43, 128.92,
128.56, 127.87, 107.44, 50.82, 44.24, 23.21; C19H18O5S; HR-MS (ESI)
m/z: found [M þ H]þ 359.0950 (calcd. 359.0953).
528.1010).
4.1.5.21. (Z)-3-(2-Chlorophenyl)-5-(furan-2-ylmethylene)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (13e). This product was
obtained as a yellow crystal in 89% yield. Mp 207e209 ꢃC; IR (KBr)
4.1.5.17. (Z)-5-Benzylidene-3-(2-chlorophenyl)-4-(4-(methylsulfonyl)
phenyl)furan-2(5H)-one (13a). This product was obtained as a yel-
n
: 1770 (C]O), 1646, 1616, 1474 (C]C, Ph), 1307 (eCH3), 1148 (Ce
O), 3050 (eArH), 776, 694 (C]H, Ph) cmꢂ1 1H NMR (400 MHz,
CDCl3, TMS):
low crystal in 93% yield. Mp 168e170 ꢃC; IR (KBr)
n
: 1764 (C]O),
;
1630, 1620, 1460 (C]C, Ph), 1314 (eCH3), 1147 (CeO), 3020 (eArH),
d
7.98 (d, J ¼ 8.3 Hz, 2H, 4-methylsulfanylphenyl, H-3,
2910 (eCHe), 753, 695 (C]H, Ph) cmꢂ1; 1H NMR (400 MHz, CDCl3,
H-5), 7.55 (d, J ¼ 1.2 Hz, 1H, furaneH), 7.49 (d, J ¼ 8.2 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.39e7.19 (m, 5H, AreH), 6.61
(m, 1H, furaneH), 6.16 (s, 1H, ]C6H), 3.10 (s, 3H, SCH3); 13C NMR
(100.6 MHz, CDCl3, TMS):
144.83, 141.65, 135.46, 133.80, 131.63, 130.75, 130.17, 129.79, 127.9,
TMS):
d
8.00 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5),
7.85 (d, J ¼ 7.2 Hz, 2H, phenyleH), 7.52 (d, J ¼ 8.2 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.43e7.24 (m, 7H, phenyleH),
6.09 (s, 1H, ]C6H), 3.11 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3,
d 166.82 (C2]O), 150.31, 149.03, 144.96,
TMS):
d
167.19 (C2]O), 151.46, 147.03, 141.63, 135.66, 133.82, 132.63,
127.11, 125.98, 116.32, 113.44, 102.79 (C6), 44.35 (SCH3);
C
427.0407).
131.61, 130.92, 130.77, 130.14, 129.97, 129.80, 128.97, 127.92, 127.11,
126.37, 114.59 (C6), 44.32 (SCH3); C24H17ClO4S; HR-MS (ESI) m/z:
found [M þ H]þ 437.0611 (calcd. 437.0614).
22H15ClO5S; HR-MS (ESI) m/z: found [M þ H]þ 427.0403 (calcd.
4.1.5.22. (Z)-5-(4-Hydroxy-3-methoxybenzylidene)-3-(2-chlorophenyl)-
4.1.5.18. (Z)-5-(3-Nitrobenzylidene)-3-(2-chlorophenyl)-4-(4-(meth-
4-(4-(methylsulfonyl)phenyl)furan-2(5H)-one (13f). This product was
ylsulfonyl)phenyl)furan-2(5H)-one (13b). This product was ob-
obtained as a yellow crystal in 90% yield. Mp 218e220 ꢃC; IR (KBr)
n:
tained as a yellow crystal in 89% yield. Mp 130e132 ꢃC; IR (KBr)
n
:
3480 (eOH), 1770 (C]O), 1591, 1514, 1450, 1430 (C]C, Ph), 1360 (e
1780 (C]O), 1630 (C]C, Ph), 1311 (eCH3), 1154 (CeO), 1533 (NO2),
1349 (CeN), 3020 (eArH), 780, 669 (C]H, Ph) cmꢂ1 1H NMR
(400 MHz, CDCl3, TMS): 8.49 (s, 1H, 3-nitrobenzylidene, H-2), 8.33
(d, J ¼ 7.8 Hz,1H, 3-nitrobenzylidene, H-4), 8.22 (d, J ¼ 8.2 Hz,1H, 3-
nitrobenzylidene, H-6), 8.03 (d, 8.2 Hz, 2H, 4-
CH3), 1287 (eOCH3), 1141 (CeO), 777, 663 (C]H, Ph) cmꢂ1; 1H NMR
;
(400 MHz, CDCl3, TMS):
d
7.99 (d,
J
¼
8.2 Hz, 2H, 4-
d
methylsulfanylphenyl, H-3, H-5), 7.53 (s, 1H, phenyleH), 7.50 (d,
J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.41e7.21 (m, 5H,
phenyleH), 6.95 (d, J ¼ 8.3 Hz, 1H, HePh), 6.01 (s, 1H, ]C6H), 5.4e5.8
(br,1H, OH), 3.99 (s, 3H, OCH3), 3.11 (s, 3H, SCH3); 13C NMR (100.6 MHz,
J
¼
methylsulfanylphenyl, H-3, H-5), 7.66 (m, 1H, 3-nitrobenzylidene,
H-5), 7.53 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6),
CDCl3, TMS): d 167.29 (C2]O), 151.47, 147.67, 146.84, 145.43, 141.50,
7.44e7.22 (m, 4H, phenyl), 6.13 (s, 1H, ]C6H), 3.12 (s, 3H, SCH3); 13
C
135.91, 133.89, 131.68, 130.61, 130.11, 129.98, 128.23, 127.91, 127.86,
127.07, 126.04, 125.44, 125.07, 115.06, 114.81, 112.42, 56.17 (OCH3),
44.31 (SCH3); C25H19ClO6S; HR-MS (ESI) m/z: found [M þ H]þ
483.0664 (calcd. 483.0669).
NMR (100.6 MHz, CDCl3, TMS):
d 166.38 (C2]O),151.11, 148.84,
148.55, 142.04, 135.90, 135.07, 134.24, 133.76, 131.49, 131.11, 130.25,
130.05, 129.90, 128.13, 127.85, 127.48, 127.21, 125.22, 123.79, 111.17,
44.33 (SCH3); C24H16ClNO6S; HR-MS (ESI) m/z: found [M þ H]þ
482.0456 (calcd. 482.0465).
4.1.5.23. (Z)-5-(4-Hydroxybenzylidene)-3-(2-chlorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (13g). This product was
obtained as a yellow crystal in 86% yield. Mp 198e200 ꢃC; IR (KBr)
4.1.5.19. (Z)-5-(2-Methoxybenzylidene)-3-(2-chlorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (13c). This product was
n
: 3285 (eOH), 1780 (C]O), 1602, 1580, 1480, 1442 (C]C, Ph), 1313
obtained as a yellow crystal in 90% yield. Mp 211e212 ꢃC; IR (KBr)
n
:
(eCH3), 1160 (CeO), 2960 (eCHe), 763, 650 (C]H, Ph) cmꢂ1 1H
;

332
G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
NMR (400 MHz, CDCl3, TMS):
d
7.99 (d, J ¼ 8.2 Hz, 2H, 4-
O), 151.20, 151.11, 143.98, 141.19, 136.45, 133.96, 132.91, 131.83,
methylsulfanylphenyl, H-3, H-5), 7.78 (d, J ¼ 8.6 Hz, 2H, 4-
hydroxyphenyl), 7.51 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl,
H-2, H-6), 7.47e7.21 (m, 4H, phenyleH), 6.91 (d, J ¼ 8.6 Hz, 2H, 4-
hydroxyphenyl), 5.34 (s, 1H, ]C6H), 3.11 (s, 3H, SCH3); 13C NMR
131.67, 131.64, 130.25, 130.00, 128.73, 127.70, 127.02, 126.95, 123.10,
120.74, 116.14, 111.88, 110.90, 44.32 (SCH3), 40.03 (NCH3), 39.99
(NCH3); C26H22ClNO4S; HR-MS (ESI) m/z: found [M þ H]þ 480.1027
(calcd. 480.1036).
(100.6 MHz, CDCl3, TMS):
d 168.49 (C2]O), 157.01, 148.25, 138.41,
137.66, 135.34, 131.27, 129.47, 128.87, 128.24, 127.89, 127.87, 127.79,
126.85, 122.47, 115.86, 100.69, 44.30. C24H17ClO5S; HR-MS (ESI) m/z:
found [M þ H]þ 453.0557 (calcd. 453.0563).
4.1.5.28. (Z)-3-(2-Chlorophenyl)-5-((1,3-dihydroisobenzofuran-5-yl)
methylene)-4-(4-(methylsulfonyl)phenyl) furan-2(5H)-one (13l).
This product was obtained as a yellow crystal in 87% yield. Mp 164e
166 ꢃC; IR (KBr)
n
: 1760 (C]O), 1610, 1594, 1502, 1448 (C]C, Ph),
1307 (eCH3), 1147 (CeO), 1260 (eOCH2e), 3020 (eArH), 774, 695
(C]H, Ph) cmꢂ1 1H NMR (400 MHz, CDCl3, TMS):
8.00 (d,
4.1.5.24. (Z)-5-(4-Bromobenzylidene)-3-(2-chlorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (13h). This product was
;
d
obtained as a yellow crystal in 85% yield. Mp 194e196 ꢃC; IR (KBr)
n
:
J ¼ 8.3 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.59 (d, J ¼ 1.6 Hz,
2H, HePh), 7.52 (d, J ¼ 8.3 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-
6), 7.41e7.19 (m, 5H, phenyleH), 6.87 (d, J ¼ 8.1 Hz, 2H, HePh), 6.06
(s, 2H, OCH2O), 6.02 (s, 1H, ]C6H), 3.12 (s, 3H, SCH3), 3.06 (s, 6H,
1780 (C]O),1632, 1580, 1481, 1397 (C]C, Ph), 1309 (eCH3), 1147
(CeO), 3020 (eArH), 2910 (eCHe), 768, 690 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
8.00 (d, J ¼ 8.2 Hz, 2H, 4-
methylsulfanylphenyl, H-3, H-5), 7.71 (d, J ¼ 8.5 Hz, 2H, Ph), 7.56
(d, 8.5 Hz, 2H, Ph), 7.51 (d, 8.2 Hz, 2H, 4-
;
d
CH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d 167.21 (C2]O), 151.38,
J
¼
J
¼
149.21, 148.48, 145.72, 141.58, 135.83, 133.88, 131.67, 130.66, 130.13,
129.97, 129.60, 128.15, 127.88, 127.09, 126.93, 126.80, 125.43, 114.67,
110.15, 108.70, 101.71, 44.33 (SCH3); C26H19ClO5S; HR-MS (ESI) m/z:
found [M þ H]þ 479.0716 (calcd. 479.0720).
methylsulfanylphenyl, H-2, H-6), 7.42e7.21 (m, 4H, phenyleH),
6.01 (s, 1H, ]C6H), 3.11 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3,
TMS): d 166.85 (C2]O), 151.34, 147.47, 141.84, 135.46, 133.81, 132.21,
132.18, 131.59, 131.56, 130.86, 130.17, 129.94, 127.95, 127.87, 127.12,
126.79, 124.21, 113.07 (C6), 44.30 (SCH3); C24H16BrClO4S; HR-MS
(ESI) m/z: found [M þ H]þ 514.9713 (calcd. 514.9719).
4.1.5.29. (Z)-5-(4-Methoxybenzylidene)-3-(2-chlorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (13m). This product was
obtained as a yellow crystal in 90% yield. Mp 200e202 ꢃC; IR (KBr)
4.1.5.25. (Z)-5-(4-Chlorobenzylidene)-3-(2-chlorophenyl)-4-(4-
n
: 1780 (C]O), 1592, 1580, 1508 (C]C, Ph), 1303 (eCH3), 1263 (e
OCH3),1159 (CeO), 3020 (eArH), 773, 649 (C]H, Ph) cmꢂ1; 1H NMR
(400 MHz, CDCl3, TMS): 7.98 (d, 8.3 Hz, 2H, 4-
(methylsulfonyl)phenyl)furan-2(5H)-one (13i). This product was
obtained as a yellow crystal in 85% yield. Mp 173e175 ꢃC; IR (KBr)
n
:
d
J
¼
1780 (C]O), 1637, 1580, 1492, 1400 (C]C, Ph), 1311 (eCH3), 1150
(CeO), 3020 (eArH), 2910 (eCHe), 776, 695 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
8.00 (d, J ¼ 8.2 Hz, 2H, 4-
methylsulfanylphenyl, H-3, H-5), 7.82 (d, J ¼ 8.8 Hz, 2H, HePh),
7.51 (d, J ¼ 8.3 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.41e7.22
(m, 4H, phenyleH), 6.96 (d, J ¼ 8.8 Hz, 2H, HePh), 6.04 (s, 1H, ]
C6H), 3.87 (s, 3H, OCH3), 3.11 (s, 3H, SCH3); 13C NMR (100.6 MHz,
CDCl3, TMS): d 167.41 (C2]O), 160.93, 151.44, 145.58, 141.53, 135.94,
133.89, 132.79, 131.69, 130.60, 130.11, 129.97, 128.24, 127.86, 127.06,
125.56, 125.18, 114.65, 114.53, 55.42 (OCH3), 44.33 (SCH3);
C
467.0720).
;
d
methylsulfanylphenyl, H-3, H-5), 7.78 (d, J ¼ 8.5 Hz, 2H, HePh),
7.51 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.41 (d,
J ¼ 8.5 Hz, 2H, HePh), 7.42e7.22 (m, 4H, 2-chlorophenyl), 6.04 (s,
1H, ]C6H), 3.11 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d
166.94 (C2]O), 151.32, 147.30, 141.74, 135.77, 135.49, 133.79,
25H19ClO5S; HR-MS (ESI) m/z: found [M þ H]þ 467.0718 (calcd.
132.01, 131.57, 131.13, 130.87, 130.18, 129.93, 129.26, 127.98, 127.81,
127.14, 126.66, 113.08 (C6), 44.32 (SCH3); C24H16Cl2O4S; HR-MS (ESI)
m/z: found [M þ H]þ 471.0219 (calcd. 471.0225).
4.1.5.30. (Z)-3-(2-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-5-
(naphthalen-1-ylmethylene)furan-2(5H)-one (13n). This product
was obtained as a yellow crystal in 92% yield. Mp 211e213 ꢃC; IR
4.1.5.26. (Z)-5-(4-Fluorobenzylidene)-3-(2-chlorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (13j). This product was
(KBr)
1144 (CeO), 3020 (eArH), 2950 (eCHe), 766, 690 (C]H, Ph) cmꢂ1
1H NMR (400 MHz, CDCl3, TMS):
8.05 (d, J ¼ 8.0 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.88 (m,
3H, HeAr), 7.61 (d, J ¼ 8.0 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-
6), 7.59 (m, 1H, HePh), 7.52 (m, 2H, HePh), 7.43e7.26 (m, 4H, He
Ar), 6.91 (s, 1H, ]C6H), 3.13 (s, 3H, SCH3); 13C NMR (100.6 MHz,
n: 1790 (C]O),1620,1583,1452, 1400 (C]C, Ph),1314 (eCH3),
obtained as a yellow crystal in 88% yield. Mp 257e258 ꢃC; IR (KBr)
n
:
;
1780 (C]O), 1630, 1597, 1506, 1460 (C]C, Ph), 1310 (eCH3), 1149
(CeO), 3020 (eArH), 2910 (eCHe), 768, 690 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
8.00 (d, J ¼ 8.3 Hz, 2H, 4-
d
8.45 (d, J ¼ 7.2 Hz, 1H, HeAr),
;
d
methylsulfanylphenyl, H-3, H-5), 7.84 (d, J ¼ 3.4 Hz, 2H, Ph), 7.51
(d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.40e7.10 (m,
6H, phenyleH), 6.05 (s, 1H, ]C6H), 3.11 (s, 3H, SCH3); 13C NMR
CDCl3, TMS): d 167.29 (C2]O), 151.34, 148.00, 141.85, 135.81, 133.89,
(100.6 MHz, CDCl3, TMS):
d
167.06 (C2]O), 164.56, 162.05, 151.40,
133.71, 131.65, 130.80, 130.41, 130.19, 130.17, 130.03, 129.21, 128.44,
128.03, 127.13, 127.10, 126.66, 126.14, 125.86, 122.67, 110.33 (C6),
44.33 (SCH3); C28H19ClO4S; HR-MS (ESI) m/z: found [M þ H]þ
487.0767 (calcd. 487.0771).
146.71, 141.72, 135.57, 133.82, 132.94, 132.86, 131.59, 130.81, 130.15,
129.93, 128.99, 128.96, 127.94, 127.11, 126.31, 116.30, 116.08, 113.24
(C6), 44.30 (SCH3); C24H16ClFO4S; HR-MS (ESI) m/z: found [M þ H]þ
455.0517 (calcd. 455.0520).
4.1.5.31. 3-(2-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-5-
4.1.5.27. (Z)-5-(4-(Dimethylamino)benzylidene)-3-(2-chlorophenyl)-
4-(4-(methylsulfonyl)phenyl)furan-2(5H)-one (13k). This product
was obtained as a red crystal in 87% yield. Mp 250e252 ꢃC; IR (KBr)
(propan-2-ylidene)furan-2(5H)-one (13o). This product was ob-
tained as a yellow oil in 73% yield. IR (KBr)
1559, 1423 (C]C, Ph), 1312 (eCH3), 1153 (CeO), 2960 (eCHe), 774,
682 (C]H, Ph) cmꢂ1 1H NMR (400 MHz, CDCl3, TMS):
7.92 (d,
n: 1770 (C]O), 1596,
n
: 1770 (C]O), 1578, 1557, 1526, 1420 (C]C, Ph), 1310 (eCH3), 1370
(CeN), 1160 (CeO), 770, 665 (C]H, Ph) cmꢂ1 1H NMR (400 MHz,
CDCl3, TMS):
;
d
;
J ¼ 8.0 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.47 (d, J ¼ 8.0 Hz,
2H, 4-methylsulfanylphenyl, H-2, H-6), 7.25 (m, 1H, phenyleH), 7.16
(m, 1H, phenyleH), 7.04 (m, 1H, phenyleH), 3.05 (s, 3H, SCH3), 2.11
(m, 3H, CH3), 1.52 (s, 3H, CH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d
7.96 (d, J ¼ 8.3 Hz, 2H, 4-methylsulfanylphenyl, H-3,
H-5), 7.76 (d, J ¼ 8.9 Hz, 2H, HePh), 7.50 (d, J ¼ 8.3 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.37e7.23 (m, 4H, phenyleH),
6.70 (d, J ¼ 8.9 Hz, 2H, HePh), 6.02 (s, 1H, ]C6H), 3.10 (s, 3H, SCH3),
d
167.71 (C2]O), 149.96, 143.40, 141.07, 138.08, 133.89, 131.51,
3.06 (s, 6H, CH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d 167.81 (C2]
130.40, 130.32, 129.66, 129.23, 128.35, 127.74, 127.54, 126.81, 44.83

G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
333
(SCH3), 21.06 (CH3), 19.73 (CH3); C20H17ClO4S; HR-MS (ESI) m/z:
found [M þ H]þ 389.0612 (calcd. 389.0614).
obtained as a yellow crystal in 88% yield. Mp 259e260 ꢃC; IR (KBr)
: 1751 (C]O), 1596, 1560, 1424 (C]C, Ph), 1309 (eCH3), 1230 (e
OCH3), 1151 (CeO), 3020 (eArH), 706, 682 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
8.30 (dd, J ¼ 8.0 Hz, J ¼ 1.6 Hz, 1H,
HePh), 8.08 (t, J ¼ 8.4 Hz, J ¼ 6.8 Hz, 2H, 4-methylsulfanyl-phenyl,
H-3, H-5), 7.60 (dd, 6.8 Hz, 4.2 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.35 (m, 3H, phenyl), 7.06e6.97
(m, 3H, HePh), 6.88 (d, J ¼ 8.0 Hz, 1H, HePh), 6.49 (s, 1H, ]C6H),
3.80 (s, 3H, OCH3), 3.17 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3,
n
;
4.1.5.32. 3-(2-Chlorophenyl)-5-methoxy-5-methyl-4-(4-(methyl-
d
sulfonyl)phenyl)furan-2(5H)-one (13p). This product was obtained
as yellow oil in 60% yield. IR (KBr)
(400 MHz, CDCl3, TMS):
n
: 1781 (C]O) cmꢂ1
;
1H NMR
J
¼
J
¼
d
7.95 (d, J ¼ 8.4 Hz, 1H), 7.89 (d, J ¼ 8.4 Hz,
1H), 7.62 (d, J ¼ 8.4 Hz, 1H), 7.61e7.40 (br, 4H, phenyleH), 3.47 (s,
3H, SCH3), 3.08 (s, 3H, OCH3),1.75 (s, 3H, CH3); 13C NMR (100.6 MHz,
CDCl3, TMS):
d
166.83 (C2]O), 153.78, 149.37, 141.77, 131.23, 129.81,
TMS): d 168.15 (C2]O), 157.67, 148.05, 147.11, 141.65, 136.31, 131.64,
129.63, 129.43, 128.92, 128.56, 127.87, 108.25, 98.62, 51.23, 50.73,
44.26, 44.20, 29.66, 24.34; C19H18ClO5S; HR-MS (ESI) m/z: found
[M þ H]þ 393.0560 (calcd. 393.0563).
131.24, 131.16, 130.42, 128.17, 124.86, 124.83, 121.78, 121.19, 115.96,
115.75, 110.55, 107.94, 55.64 (OCH3), 44.36 (SCH3); C25H19FO5S; HR-
MS (ESI) m/z: found [M þ H]þ 451.1011 (calcd. 451.1015).
4.1.5.33. (Z)-5-(2-Chlorobenzylidene)-3-(2-chlorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (13q). This product was
obtained as a yellow crystal in 86% yield. Mp 200e202 ꢃC; IR (KBr)
4.1.5.37. (Z)-5-(3,4,5-Trimethoxybenzylidene)-3-(4-fluorophenyl)-4-
(4-(methylsulfonyl)phenyl)furan-2(5H)-one (14d). This product was
obtained as a yellow crystal in 91% yield. Mp 257e259 ꢃC; IR (KBr)
n:
n
: 1777 (C]O), 1596, 1580, 1424 (C]C, Ph), 1314 (eCH3), 1149 (Ce
O), 3020 (eArH), 2910 (eCHe), 769, 682 (C]H, Ph) cmꢂ1; 1H NMR
(400 MHz, CDCl3, TMS):
1764 (C]O),1596,1560,1506,1442 (C]C, Ph),1314 (eCH3),1260 (e
OCH3), 1129 (CeO), 3020 (eArH), 706, 682 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
8.11 (d, J ¼ 8.4 Hz, 2H, 4-
;
d
8.32 (dd, J ¼ 8.0 Hz, J ¼ 1.6 Hz, 1H, Ph),
d
8.11 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.63 (d,
J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.42e7.37 (m, 4H,
phenyleH), 7.30 (m, 1H, phenyleH), 6.99 (m, 1H, phenyleH), 6.44
(s, 1H, ]C6H), 3.16 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
methylsulfanylphenyl, H-3, H-5), 7.59 (d, J ¼ 8.4 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.38 (m, 2H, 4-fluorophenyl, H-
3, H-5), 7.03 (s, 2H, Ph), 7.02 (m, 2H, 4-fluoro-phenyl, H-2, H-6), 5.77
(s, 1H, ]C6H), 3.91 (s, 6H, OCH3), 3.90 (s, 3H, OCH3), 3.18 (s, 3H,
d
167.70 (C2]O), 164.47, 161.97, 148.35, 147.70, 141.98, 135.79,
SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d 167.74 (C2]O), 153.36,
134.65, 131.91, 131.34, 131.26, 130.67, 130.41, 130.36, 129.56, 128.35,
126.44, 124.43, 116.11, 115.89, 108.97, 44.38 (SCH3); C24H16Cl2O4S;
HR-MS (ESI) m/z: found [M þ H]þ 471.0219 (calcd. 471.0225).
147.73, 146.92, 141.84, 139.81, 136.27, 131.19, 131.10, 130.32, 128.30,
128.25, 124.75, 124.72, 116.02, 115.80, 113.90, 108.16, 61.02 (OCH3),
56.31 (OCH3), 44.29 (SCH3); C27H23FO7S; HR-MS (ESI) m/z: found
[M þ H]þ 511.1221 (calcd. 511.1227).
4.1.5.34. (Z)-5-Benzylidene-3-(4-fluorophenyl)-4-(4-(methylsulfonyl)
phenyl)furan-2(5H)-one (14a). This product was obtained as a yel-
4.1.5.38. (Z)-3-(4-Fluorophenyl)-5-(furan-2-ylmethylene)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (14e). This product was
obtained as a yellow crystal in 87% yield. Mp 228e229 ꢃC; IR (KBr)
low crystal in 90% yield. Mp 245e247 ꢃC; IR (KBr)
n: 1765 (C]O),
1596, 1580, 1511, 1423 (C]C, Ph), 1310 (eCH3), 1148 (CeO), 3020 (e
ArH), 2910 (eCHe), 774, 682 (C]H, Ph) cmꢂ1; 1H NMR (400 MHz,
n
: 1749 (C]O), 1596, 1580, 1511, 1423 (C]C, Ph), 1310 (eCH3), 1149
(CeO), 3050 (eArH), 770, 682 (C]H, Ph) cmꢂ1; 1H NMR (400 MHz,
CDCl3, TMS):
CDCl3, TMS):
d
8.10 (dd,
J
¼
6.8 Hz,
J
¼
2.0 Hz, 2H, 4-
methylsulfanylphenyl, H-3, H-5), 7.80 (t, J ¼ 8.8 Hz, J ¼ 1.6 Hz,
2H, 4-fluorophenyl), 7.59 (dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.40 (m, 5H, phenyl), 7.80 (t,
J ¼ 17.6 Hz, J ¼ 8.8 Hz, 2H, 4-fluorophenyl), 5.89 (s, 1H, ]C6H), 3.17
d
8.10 (d, J ¼ 8.0 Hz, 2H, 4-methylsulfanylphenyl, H-3,
H-5), 7.57 (d, J ¼ 8.0 Hz, 2H, 4-methylsulfanyl-phenyl, H-2, H-6),
7.52 (d, J ¼ 1.6 Hz, 1H, furaneH), 7.38 (m, 2H, 4-fluorophenyl, H-3,
H-5), 7.14 (d, J ¼ 3.6 Hz, 1H, furaneH), 6.99 (m, 2H, 4-fluorophenyl,
H-2, H-6), 6.58 (m, 1H, furaneH), 5.95 (s, 1H, ]C6H), 3.16 (s, 3H,
(s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d 167.91 (C2]O),
164.50, 162.97, 147.74, 147.45, 141.85, 136.16, 132.76, 131.24, 131.15,
130.78, 130.31, 129.61, 128.95, 128.33, 125.32, 124.64, 116.04, 115.82,
113.85 (C6), 44.37 (SCH3); C24H17FO4S; HR-MS (ESI) m/z: found
[M þ H]þ 421.0907 (calcd. 421.0910).
SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d 167.51 (C2]O), 149.14,
146.59, 145.46, 144.66, 141.87, 135.88, 131.16, 131.07, 130.18, 128.37,
124.99, 124.75, 124.71, 116.03, 115.94, 115.82, 113.38, 102.03 (C6),
44.38 (SCH3); C22H15FO5S; HR-MS (ESI) m/z: found [M þ H]þ
411.0698 (calcd. 411.0702).
4.1.5.35. (Z)-5-(3-Nitrobenzylidene)-3-(4-fluorophenyl)-4-(4-(meth-
ylsulfonyl)phenyl)furan-2(5H)-one (14b). This product was ob-
4.1.5.39. (Z)-5-(4-Hydroxy-3-methoxybenzylidene)-3-(4-
tained as a yellow crystal in 90% yield. Mp 275e277 ꢃC; IR (KBr)
n
:
fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan-2(5H)-one
This product was obtained as a yellow crystal in 90% yield. Mp 242e
243 ꢃC; IR (KBr)
: 3480 (eOH), 1722 (C]O), 1596, 1560, 1432 (C]C,
Ph), 1302 (eCH3),1242 (eOCH3), 1158 (CeO), 777, 682 (C]H, Ph)
cmꢂ1 1H NMR (400 MHz, CDCl3 and DMSO, TMS):
8.10 (d,
(14f).
1769 (C]O), 1596, 1512, 1423 (C]C, Ph), 1307 (eCH3), 1155 (CeO),
1560 (NO2),1354 (CeN), 3020 (eArH), 706, 682 (C]H, Ph) cmꢂ1; 1H
n
NMR (400 MHz, CDCl3, TMS):
nitrobenzylidene, H-2), 8.28 (d,
nitrobenzylidene, H-4), 8.19 (dd, J ¼ 8.4 Hz, J ¼ 1.6 Hz, 1H, 3-
nitrobenzylidene, H-6), 8.14 (d, 8.0 Hz, 2H, 4-
d
8.44 (d, J ¼ 1.6 Hz, 1H, 3-
J
¼
8.0 Hz, 1H, 3-
;
d
J ¼ 7.6 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.61 (d, J ¼ 7.6 Hz,
2H, 4-methylsulfanylphenyl, H-2, H-6), 7.38 (m, 3H, phenyleH),
7.28 (d, J ¼ 8.0 Hz, 1H, HePh), 7.00 (m, 2H, phenyleH), 6.91 (d,
J ¼ 8.4 Hz, 1H, HePh), 5.85 (s, 1H, ]C6H), 3.93 (s, 3H, OCH3), 3.20 (s,
J
¼
methylsulfanylphenyl, H-3, H-5), 7.63 (m, 1H, 3-nitrobenzylidene,
H-5), 7.60 (d, J ¼ 8.2 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.41
(m, 2H, 4-fluorophenyl), 7.03 (m, 2H, 4-fluorophenyl), 5.92 (s,1H, ]
3H, SCH3); 13C NMR (100.6 MHz, CDCl3 and DMSO, TMS):
d 167.70
C6H), 3.19 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d
167.15
(C2]O), 148.78, 148.14, 147.79, 145.48, 141.66, 136.23, 131.11, 131.03,
130.31, 128.17, 125.54, 125.12, 125.08, 124.86, 123.51, 115.83, 115.60,
114.76, 113.63, 56.04 (OCH3), 44.28 (SCH3); C25H19FO6S; HR-MS
(ESI) m/z: found [M þ H]þ 467.0958 (calcd. 467.0965).
(C2]O),162.20, 149.27,148.56,147.15,142.21, 135.73,135.58, 134.35,
131.36, 131.28, 130.21, 130.00, 128.56, 126.65, 125.05, 124.12, 123.59,
116.22, 116.00, 110.41 (C6), 44.37 (SCH3); C24H16FNO6S; HR-MS (ESI)
m/z: found [M þ H]þ 466.0753 (calcd. 466.0761).
4.1.5.40. (Z)-5-(4-Hydroxybenzylidene)-3-(4-fluorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (14g). This product was
4.1.5.36. (Z)-5-(2-Methoxybenzylidene)-3-(4-fluorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (14c). This product was
obtained as a yellow crystal in 84% yield. Mp 269e271 ꢃC; IR (KBr)
n:

334
G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
3416 (eOH), 1732 (C]O), 1596, 1580, 1432 (C]C, Ph), 1312 (eCH3),
1173 (CeO), 2960 (eCHe), 845, 682 (C]H, Ph) cmꢂ1 1H NMR
(400 MHz, CDCl3 and DMSO, TMS):
8.09 (d, J ¼ 8.0 Hz, 2H, 4-
H-5), 7.72 (d, J ¼ 8.8 Hz, 2H, 4-dimethylaminobenzylidene, H-2, H-
6), 7.58 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.36
(m, 2H, phenyleH), 6.98 (t, J ¼ 17.2 Hz, J ¼ 8.4 Hz, 2H, phenyleH),
6.74 (d, J ¼ 8.8 Hz, 2H, 4-(dimethylamino)benzylidene, H-3, H-5),
5.83 (s, 1H, ]C6H), 3.16 (s, 3H, SCH3), 3.06 (s, 6H, CH3); 13C NMR
;
d
methylsulfanylphenyl, H-3, H-5), 7.67 (d, J ¼ 8.4 Hz, 2H, 4-
hydroxybenzylidene, H-2, H-6), 7.62 (d, J ¼ 8.0 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.36 (m, 2H, 4-fluorophenyl, H-
3, H-5), 7.03 (m, 2H, 4-fluorophenyl, H-2, H-6), 6.87 (d, J ¼ 8.4 Hz,
2H, 4-hydroxybenzylidene, H-3, H-5), 5.89 (s, 1H, ]C6H), 3.20 (s,
(100.6 MHz, CDCl3, TMS):
d 168.13 (C2]O), 148.01, 144.98, 141.50,
136.89, 132.74, 130.99, 130.91, 130.38, 128.13, 125.70, 122.31, 115.82,
115.61, 115.21, 112.32, 111.94 (C6), 44.38 (SCH3), 40.29 (N(CH3)2);
3H, SCH3); 13C NMR (100.6 MHz, CDCl3 and DMSO, TMS):
d
167.80
C
26H22FNO4S; HR-MS (ESI) m/z: found [M þ H]þ 464.1314 (calcd.
(C2]O), 159.41, 141.73, 132.82, 131.16, 131.08, 130.33, 128.16, 124.31,
123.39, 116.25, 115.78, 115.57, 114.65, 44.27 (SCH3); C24H17FO5S; HR-
MS (ESI) m/z: found [M þ H]þ 437.0845 (calcd. 437.0859).
464.1332).
4.1.5.45. (Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-3-(4-
fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan-2(5H)-one
This product was obtained as a yellow crystal in 93% yield. Mp 237e
239 ꢃC; IR (KBr)
: 1757 (C]O), 1596, 1560, 1423 (C]C, Ph), 1300 (e
CH3), 1140 (CeO), 1260 (eOCH2e), 3020 (eArH), 774, 695 (C]H,
Ph) cmꢂ1; 1H NMR (400 MHz, CDCl3, TMS):
(14l).
4.1.5.41. (Z)-5-(4-Bromobenzylidene)-3-(4-fluorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (14h). This product was
n
obtained as a yellow crystal in 87% yield. Mp 271e272 ꢃC; IR (KBr)
n:
1757 (C]O), 1596, 1580, 1423 (C]C, Ph), 1318 (eCH3), 1160 (CeO),
3020 (eArH), 2910 (eCHe), 768, 690 (C]H, Ph) cmꢂ1 1H NMR
(400 MHz, CDCl3, TMS):
8.12 (dd, J ¼ 6.8 Hz, J ¼ 1.6 Hz, 2H, 4-
d
8.10 (d, J ¼ 8.4 Hz, 2H,
;
4-methylsulfanylphenyl, H-3, H-5), 7.60 (d, J ¼ 8.4 Hz, 2H, 4-
methylsulfanylphenyl, H-2, H-6), 7.54 (d, J ¼ 1.6 Hz, 1H, substitu-
ent phenyl, H-2), 7.40 (m, 2H, 4-fluorophenyl), 7.16 (dd, J ¼ 8.0 Hz,
d
methylsulfanylphenyl, H-3, H-5), 7.67 (m, 2H, Ph), 7.61 (dd,
J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.56
(m, 2H, Ph), 7.41 (m, 2H, phenyleH), 7.02 (m, 2H, phenyleH), 5.83
(s, 1H, ]C6H), 3.19 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
J
¼
1.6 Hz, 1H, substituent phenyl, H-5), 7.01 (m, 2H, 4-
fluorophenyl), 6.85 (d, J ¼ 8.0 Hz, 1H, substituent phenyl, H-6),
6.05 (s, 2H, CH2), 5.82 (s, 1H, ]C6H), 3.19 (s, 3H, SCH3); 13C NMR
d
167.62 (C2]O), 147.85, 147.54, 141.98, 135.96, 132.18, 132.03,
(100.6 MHz, CDCl3, TMS): d 167.89 (C2]O), 164.24, 161.75, 149.06,
131.67, 131.24, 131.16, 130.26, 128.37, 125.66, 124.51, 124.01, 116.09,
115.87, 112.35 (C6), 44.34 (SCH3); C24H16BrFO4S; HR-MS (ESI) m/z:
found [M þ H]þ 499.0009 (calcd. 499.0015).
148.46, 147.70, 146.14, 141.79, 136.30, 131.15, 131.06, 130.30, 128.27,
127.21, 126.57, 124.83, 124.80, 124.42, 115.97, 115.76, 113.90, 110.03,
108.67, 101.65, 44.35 (SCH3); C25H17FO6S; HR-MS (ESI) m/z: found
[M þ H]þ 465.0800 (calcd. 45.0808).
4.1.5.42. (Z)-5-(4-Chlorobenzylidene)-3-(4-fluorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (14i). This product was
4.1.5.46. (Z)-5-(4-Methoxybenzylidene)-3-(4-fluorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (14m). This product was
obtained as a yellow crystal in 86% yield. Mp 226e228 ꢃC; IR (KBr)
obtained as a yellow crystal in 86% yield. Mp 272e274 ꢃC; IR (KBr)
n:
1758 (C]O), 1596, 1580, 1511, 1488 (C]C, Ph), 1319 (eCH3), 1151
(CeO), 3020 (eArH), 2910 (eCHe), 776, 695 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
8.12 (d, J ¼ 8.4 Hz, 2H, 4-
;
n
: 1742 (C]O), 1596, 1580, 1510, 1424 (C]C, Ph), 1308 (eCH3), 1254
(eOCH3), 1177 (CeO), 3020 (eArH), 843, 682 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3, TMS):
7.98 (d, J ¼ 8.4 Hz, 2H, 4-
d
;
methylsulfanylphenyl, H-3, H-5), 7.75 (d, J ¼ 8.4 Hz, 2H, 4-
chlorophenyl), 7.61 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-
2, H-6), 7.40 (m, 4H, HePh), 7.01 (m, 2H, 4-fluorophenyl), 5.85 (s,
1H, ]C6H), 3.19 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d
methylsulfanylphenyl, H-3, H-5), 7.81 (d, J ¼ 8.8 Hz, 2H, 4-
methoxyphenyl), 7.50 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl,
H-2, H-6), 7.40 (dd, J ¼ 8.8 Hz, J ¼ 5.2 Hz, 2H, 4-fluorophenyl), 7.02
(t, J ¼ 17.2 Hz, J ¼ 8.8 Hz, 2H, 4-fluorophenyl), 6.96 (d, J ¼ 8.8 Hz, 2H,
4-methoxy-phenyl), 6.04 (s, 1H, ]C6H), 3.86 (s, 3H, OCH3), 3.10 (s,
d
167.64 (C2]O),147.74,147.54,141.97,135.98,135.57,131.85,131.26,
131.24, 131.16, 130.27, 129.22, 128.37, 125.58, 124.51, 124.48, 116.08,
115.86, 112.31 (C6), 44.34 (SCH3); C24H16ClFO4S; HR-MS (ESI) m/z:
found [M þ H]þ 455.0515 (calcd. 455.0520).
3H, SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d 167.37 (C2]O),
160.95, 151.46, 145.61, 141.59, 135.92, 133.91, 132.78, 131.71, 130.59,
130.09, 129.98, 128.28, 127.84, 127.05, 125.59, 125.20, 114.62, 114.54,
55.41 (OCH3), 44.31 (SCH3); C25H19FO5S; HR-MS (ESI) m/z: found
[M þ H]þ 451.1010 (calcd. 451.1015).
4.1.5.43. (Z)-5-(4-Fluorobenzylidene)-3-(4-fluorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (14j). This product was
obtained as a yellow crystal in 85% yield. Mp 291e292 ꢃC; IR (KBr)
n:
1759 (C]O),1596, 1580, 1507, 1422 (C]C, Ph), 1310 (eCH3), 1148
(C]O), 3020 (eArH), 2910 (eCHe), 768, 682 (C]H, Ph) cmꢂ1 1H
NMR (400 MHz, CDCl3 and DMSO, TMS):
8.11 (d, J ¼ 6.8 Hz, 2H, 4-
4.1.5.47. (Z)-3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-5-
(naphthalen-1-ylmethylene)furan-2(5H)-one (14n). This product
was obtained as a yellow crystal in 91% yield. Mp 262e264 ꢃC; IR
;
d
methylsulfanylphenyl, H-3, H-5), 7.85 (m, 2H, Ph), 7.65 (d,
J ¼ 6.8 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.39 (m, 2H, Ph),
7.18 (m, 2H, phenyleH), 7.08 (m, 2H, phenyleH), 6.03 (s, 1H, ]C6H),
3.17 (s, 3H, SCH3); 13C NMR (100.6 MHz, CDCl3 and DMSO, TMS):
(KBr)
1146 (CeO), 3020 (eArH), 2950 (eCHe), 771, 682 (C]H, Ph) cmꢂ1
1H NMR (400 MHz, CDCl3, TMS):
8.15 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5), 7.89 (d,
J ¼ 8.8 Hz, 2H, 4-fluorophenyl), 7.79 (m, 1H, HePh), 7.69 (d,
J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6),7.60 (m, 1H, He
Ph), 7.56 (m, 2H, HePh), 7.40 (m, 2H, HePh), 7.02 (t, J ¼ 17.6 Hz,
J ¼ 8.8 Hz, 2H, 4-fluorophenyl), 6.71 (s, 1H, ]C6H), 3.20 (s, 3H,
n: 1759 (C]O),1596,1580,1509,1423 (C]C, Ph),1309 (eCH3),
;
d
8.38 (d, J ¼ 7.60 Hz, 1H, HeAr),
d
167.69 (C2]O), 148.63, 147.28, 147.26, 142.10, 135.35, 133.00,
132.92, 131.56, 131.47, 130.47, 129.68, 129.65, 128.26, 125.15, 125.12,
124.99, 116.26, 116.05, 115.98, 115.76, 112.39 (C6), 44.11 (SCH3);
C
24H16F2O4S; HR-MS (ESI) m/z: found [M þ H]þ 439.0812 (calcd.
439.0816).
SCH3); 13C NMR (100.6 MHz, CDCl3, TMS):
d 168.05 (C2]O), 14.38,
147.62, 141.98, 136.26, 133.69, 131.57, 131.30, 131.22, 130.37, 130.24,
129.98, 129.18, 128.55, 128.43, 127.02, 126.12, 125.85, 125.64, 122.66,
116.07, 115.85, 109.69, 44.38 (SCH3); C28H19FO4S; HR-MS (ESI) m/z:
found [M þ H]þ 471.1058 (calcd. 471.1066).
4.1.5.44. (Z)-5-(4-(Dimethylamino)benzylidene)-3-(4-fluorophenyl)-
4-(4-(methylsulfonyl)phenyl)furan-2(5H)-one (14k). This product
was obtained as a red crystal in 93% yield. Mp 261e262 ꢃC; IR (KBr)
n
: 1751 (C]O), 1596, 1560, 1423 (C]C, Ph), 1310 (eCH3), 1370 (Ce
N), 1162 (CeO), 842, 682 (C]H, Ph) cmꢂ1 1H NMR (400 MHz,
CDCl3, TMS):
8.13 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-3,
;
4.1.5.48. 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-5-
(propan-2-ylidene)furan-2(5H)-one (14o). This product was
d

G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
335
obtained as a yellow oil in 75% yield. IR (KBr)
1580, 1511, 1423 (C]C, Ph), 1312 (eCH3), 1156 (CeO), 2960 (eCHe),
769, 682 (C]H, Ph) cmꢂ1; 1H NMR (400 MHz, CDCl3, TMS):
8.05
(dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, 4-methylsulfanylphenyl, H-3, H-5),
7.53 (dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-
6), 7.24 (s, 2H, 4-fluorophenyl), 6.91 (s, 2H, 4-fluorophenyl), 3.13 (s,
3H, SCH3), 2.10 (m, 3H, CH3), 1.44 (s, 3H, CH3); 13C NMR (100.6 MHz,
n
: 1748 (C]O), 1596,
violet solution. Then 200
m
L of crystal violet solution from each well
was then transferred to a 96 well plate. The crystal violet concen-
tration could then be determined by spectrometry absorbance at
570 nm wavelength. The relative absorbance detected by the
spectrometer revealed the cell viability. The viability was plotted
and analyzed. MTT assays were conducted for the candidate com-
pounds to determine whether they had IC50s that were less than
d
CDCl3, TMS):
d
167.63 (C2]O), 146.19, 143.27, 141.35, 139.08, 131.05,
50
mM. Additional MTT assays were conducted on the candidate
130.96, 129.81, 128.19, 127.46, 126.60, 125.06, 125.02, 115.65, 115.44,
44.37 (SCH3), 21.21 (CH3), 19.48 (CH3); C20H17FO4S; HR-MS (ESI) m/
z: found [M þ H]þ373.0997 (calcd. 373.0910).
compounds that had approximate IC50s that were less than 50
m
M.
The average 50% inhibitory concentration (IC50) was determined
from the doseeresponse curves according to the inhibition ratio for
each concentration. Each concentration was analyzed in triplicate.
(IC50s was calculated using the software SPSS 16.0).
4.1.5.49. 3-(2-Fluorophenyl)-5-methoxy-5-methyl-4-(4-(methyl-
sulfonyl)phenyl)furan-2(5H)-one (14p). This product was obtained
as yellow oil in 60% yield. IR (KBr)
(400 MHz, CDCl3, TMS):
7.95 (d, J ¼ 8.8 Hz, 2H), 7.65 (d, J ¼ 8.4 Hz,
2H), 7.39 (m, 2H),7.06 (m, 2H), 3.45 (s, 3H, SCH3), 3.10 (s, 3H, OCH3),
1.66 (s, 3H, CH3); 13C NMR (100.6 MHz, CDCl3, TMS):
168.84 (C2]
n
: 1778 (C]O) cmꢂ1
;
1H NMR
4.2.3. Flow cytometric analysis of cell cycle distribution
d
For flow cytometric analysis of DNA content, 5 ꢁ 105 DU145 cells
in exponential growth were treated with different concentrations
of the test compounds for 12 h. After an incubation period, the cells
were collected, centrifuged and fixed with ice-cold ethanol (70%).
The cells were then treated with buffer containing RNAse A and
0.1% Triton X-100 and then stained with PI. Samples were analyzed
on Accuri C6 flow cytometer (Becton, Dickinson). Data obtained
from the flow cytometer was analyzed using the FlowJo software
(Tree Star, Inc., Ashland, OR, USA).
d
O),164.63, 162.14, 153.44, 141.82, 135.72, 131.59, 130.58, 129.57,
128.06, 124.52, 124.49, 116.26, 116.05, 107.55, 50.89, 44.22, 23.02;
C
19H18FO5S; HR-MS (ESI) m/z: found [M þ H]þ 377.0853 (calcd.
377.0859).
4.1.5.50. (Z)-5-(2-Chlorobenzylidene)-3-(4-fluorophenyl)-4-(4-
(methylsulfonyl)phenyl)furan-2(5H)-one (14q). This product was
obtained as a yellow crystal in 89% yield. Mp 204e206 ꢃC; IR (KBr)
4.2.4. Nuclear staining with DAPI
n
: 1765 (C]O), 1596, 1580, 1424 (C]C, Ph), 1305 (eCH3), 1142 (Ce
O), 3020 (eArH), 2910 (eCHe), 769, 682 (C]H, Ph) cmꢂ1; 1H NMR
(400 MHz, CDCl3 and DMSO, TMS):
After treatment of 13P on DU145 cells for 48 h, the cells were
washed twice with PBS and then fixed with 3.7% paraformaldehyde
(Sigma) in PBS for 10 min at room temperature. Fixed cells were
washed with PBS, and stained with 4,6-diamidino-2-phenylindole
(DAPI, Sigma) solution for 10 min at room temperature. The cells
were washed two more times with PBS and analyzed via a fluo-
rescence microscope.
d
8.32 (dd, J ¼ 8.0 Hz, J ¼ 1.6 Hz,
1H, Ph), 8.11 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanyl-phenyl, H-3, H-5),
7.63 (d, J ¼ 8.4 Hz, 2H, 4-methylsulfanylphenyl, H-2, H-6), 7.42e7.38
(m, 4H, Ph), 7.30 (dd, J ¼ 7.6 Hz, J ¼ 1.6 Hz, 1H, Ph), 7.03 (m, 2H,
phenyleH), 6.44 (s, 1H, ]C6H), 3.17 (s, 3H, SCH3); 13C NMR
(100.6 MHz, CDCl3 and DMSO, TMS):
d 167.71 (C2]O), 148.35,
141.98, 135.79, 134.65, 131.91, 131.34, 131.26, 131.04, 130.67, 130.41,
130.37, 130.32, 129.75, 128.35, 127.37, 127.04, 126.01, 116.11, 115.0,
108.9, 44.38 (SCH3); C24H16ClFO4S; HR-MS (ESI) m/z: found
[M þ H]þ 455.0519 (calcd. 455.0520).
4.3. Cyclooxygenase inhibition studies
The ability of the tested compounds to inhibit ovine COX-1 and
COX-2 was determined using an enzyme immunoassay (EIA) kit
(catalog number 560101, Cayman Chemical, Ann Arbor, MI) ac-
cording to the manufacturer’s instructions. Cyclooxygenase cata-
lyzes the first step in the biosynthesis of arachidonic acid (AA) to
PGH2. PGF2, produced from PGH2 by reduction with stannous
chloride, is measured by enzyme immunoassay (ACE competitive
EIA). Stock solutions of test compounds were dissolved in a mini-
mum volume of DMSO. Briefly, to a series of supplied reaction
4.2. General procedure for prostatic hyperplasia inhibitory activity
assay [2,12,32e34]
4.2.1. Cell culture
Two different prostate cancer cell lines were cultured. One
prostate cancer cell line was PC3 and its transfected cell lines (PC3
PCDNA and PC3 SKP2). PC3, PC3 PCDNA, and PC3 SKP2 cells were
cultured in 10 mL RMPI 1640 medium with 10% fetal bovine serum.
buffers (960
2 mM phenol) with either COX-1 or COX-2 (10
presence of heme (10 L) was added 10 L of various concentrations
of test drug solutions (0.001, 0.1, 1, 10, 50, and 100 M in a final
volume of 1 mL). These solutions were incubated for a period of
5 min at 37 ꢃC after which 10
L of AA (100 M) solution was added
and the COX reaction was stopped by the addition of 50 L of 1 M
mL, 0.1 M TriseHCl pH 8.0 containing 5 mM EDTA and
m
L) enzyme in the
Since the transfected cells express resistance to antibiotics, 50
mL of
m
m
G418 antibiotic also was added to the PC3 PCDNA and PC3 SKP2
plates to screen for the transfected cells. The second prostate cancer
cell line was DU145, which were cultured in 10 mL RMPI 1640 with
10% fetal bovine serum.
m
m
m
m
HCl after 2 min. PGF2a, produced from PGH2 by reduction with
stannous chloride, was measured by enzyme immunoassay. This
assay is based on the competition between PGs and a PG acetyl-
cholinesterase conjugate (PG tracer) for a limited amount of PG
antiserum. The amount of PG tracer that is able to bind to the PG
antiserum is inversely proportional to the concentration of PGs in
the wells since the concentration of PG tracer is held constant while
the concentration of PGs varies. This antibody PG complex binds to
a mouse anti-rabbit monoclonal antibody that had been previously
attached to the well. The plate is washed to remove any unbound
reagents and then Ellman’s reagent, which contains the substrate to
acetylcholine esterase, is added to the well. The product of this
enzymatic reaction produces a distinct yellow color that absorbs at
4.2.2. MTT assays
Exponentially growing cells were seeded into 96-well plates at a
concentration of 1 ꢁ 104 cells per well. After 24 h incubation at
37 ꢃC, the culture medium was removed and replaced with fresh
medium containing the candidate compounds in different con-
centrations. The cells were incubated for another 72 h. Afterward,
0.5 mL of MTT assay solution was added to all wells and incubated
for 1e3 h at 37 ꢃC to generate crystal violet. When a sufficient
amount of crystal violet had been generated, the MTTassay solution
was removed. Then 0.5 mL of an MTT dissolve solution consisting of
4% hydrochloric acid in 96% isopropanol were added to the plates
before shaking for 5e10 min (average 7 min) to create the crystal

336
G.-Z. Liu et al. / European Journal of Medicinal Chemistry 65 (2013) 323e336
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412 nm. The intensity of this color, determined spectrophotomet-
rically, is proportional to the amount of PG tracer bound to the well,
which is inversely proportional to the amount of PGs present in the
well during the incubation: Absorbance [Bound PG Tracer] 1/PGs.
Percent inhibition was calculated by the comparison of compound-
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Acknowledgment
[19] Z. Xiang, L. Ho, S. Yemul, Z. Zhao, W. Qing, P. Pompl, K. Kelley, A. Dang,
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We are grateful for the financial support from the Doctoral
Research Foundation of Henan University of Traditional Chinese
Medicine (No. BSJJ2010-03).
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A.W.F. Hutchinson, M.J. Forrest, J.Y. Gauthier, R. Gordon, M. Gresser, J. Guay,
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Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.04.062.
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