Synthesis of alkylsulfonyl and substituted benzenesulfonyl curcumin mimics as dual antagonist of L-type Ca2+ channel and endothelin A/B2 receptor

Article abstract of DOI:10.1016/j.bmc.2015.09.004

We synthesized a library of curcumin mimics with diverse alkylsulfonyl and substituted benzenesulfonyl modifications through a simple addition reaction of important intermediate, 1-(3-Amino-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-propenone (10), with various sulfonyl chloride reactants and then tested their vasodilatation effect on depolarization (50 mM K⁺)- and endothelin-1 (ET-1)-induced basilar artery contraction. Generally, curcumin mimics with aromatic sulfonyl groups showed stronger vasodilation effect than alkyl sulfonylated curcumin mimics. Among the tested compounds, six curcumin mimics (11g, 11h, 11i, 11j, 11l, and 11s) in a depolarization-induced vasoconstriction and seven compounds (11g, 11h, 11i, 11j, 11l, 11p, and 11s) in an ET-1-induced vasoconstriction showed strong vasodilation effect. Based on their biological properties, synthetic curcumin mimics can act as dual antagonist scaffold of L-type Ca²⁺ channel and endothelin A/B₂ receptor in vascular smooth muscle cells. In particular, compounds 11g and 11s are promising novel drug candidates to treat hypertension related to the overexpression of L-type Ca²⁺ channels and ET peptides/receptors-mediated cardiovascular diseases.

Full text of DOI:10.1016/j.bmc.2015.09.004

Bioorganic & Medicinal Chemistry 23 (2015) 6673–6682
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of alkylsulfonyl and substituted benzenesulfonyl curcumin
mimics as dual antagonist of L-type Ca2+ channel and endothelin A/B2
receptor
Chong-Bin Park a,y, Chan Mug Ahn b,y, Sangtae Oh c, Daeho Kwon d,e, Won-Chul Cho a, Woon-Seob Shin d,e
,
Yuan Cui f, Ye Sol Um f, Byong-Gon Park e,f, , Seokjoon Lee e,g,
⇑
⇑
a Department of Thoracic and Cardiovascular Surgery, Gangneung Asan Hospital, Ulsan University College of Medicine, Gangneung 210-711, Republic of Korea
b Department of Basic Science, Yonsei University Wonju College of Medicine, Wonju 220-701, Republic of Korea
c Department of Basic Science, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea
d Department of Microbiology, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea
e Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea
f Department of Physiology, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea
g Department of Pharmacology, Catholic Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We synthesized a library of curcumin mimics with diverse alkylsulfonyl and substituted benzenesulfonyl
modifications through a simple addition reaction of important intermediate, 1-(3-Amino-phenyl)-3-(4-
hydroxy-3-methoxy-phenyl)-propenone (10), with various sulfonyl chloride reactants and then tested
their vasodilatation effect on depolarization (50 mM K+)- and endothelin-1 (ET-1)-induced basilar artery
contraction. Generally, curcumin mimics with aromatic sulfonyl groups showed stronger vasodilation
effect than alkyl sulfonylated curcumin mimics. Among the tested compounds, six curcumin mimics
(11g, 11h, 11i, 11j, 11l, and 11s) in a depolarization-induced vasoconstriction and seven compounds
(11g, 11h, 11i, 11j, 11l, 11p, and 11s) in an ET-1-induced vasoconstriction showed strong vasodilation
effect. Based on their biological properties, synthetic curcumin mimics can act as dual antagonist scaffold
of L-type Ca2+ channel and endothelin A/B2 receptor in vascular smooth muscle cells. In particular,
compounds 11g and 11s are promising novel drug candidates to treat hypertension related to the
overexpression of L-type Ca2+ channels and ET peptides/receptors-mediated cardiovascular diseases.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 7 August 2015
Revised 3 September 2015
Accepted 4 September 2015
Available online 5 September 2015
Keywords:
Curcumin
Curcumin mimic
Vasodilatation
High potassium ion
Endotheline-1
L-type Ca2+ channel blocker
Endothelin A/B2 receptor antagonist
1. Introduction
NF-
j
B ligand (RANKL).11 Recently, we have expanded the original
4-diethylamino
structure of curcumin mimics to include
a
Curcumin (1) isolated from the root of Curcuma longa L. has
versatile and useful biological properties. It shows anti-inflamma-
tory,1 antioxidant,2 antiviral,3 chemopreventive,4 anti-infective,5
and wound-healing properties.6 Based on its diverse and interest-
ing biological properties, we previously reported the synthesis of
a curcumin mimic library and described the novel biological prop-
erties of each member after first report by Bowen and co-workers.7
For example, the alkyl or aryl amide-linked curcumin mimic library
(2) was shown to inhibit angiogenesis8 and multidrug resistance
(MDR).9,10 Substituted triazolyl curcumin mimics (3 and 4) synthe-
sized through click reaction exhibited strong inhibitory activity
against osteoclastogenesis induced by the receptor activator of
chalcone structure (5) by replacing the methoxy and hydroxyl
groups of curcumin to increase bulkiness and the electronic effect.
As a result, newly synthesized curcumin derivatives (5) show a
sensitization effect to tumor necrosis factor (TNF)-related apopto-
sis-inducing ligand (TRAIL). These observations indicate that
curcumin mimics having 4-diethylamino and substituted triazole
groups are promising TRAIL-sensitizers with the potential for
application in combination chemotherapy of brain tumors.12,13
All members of the synthetic curcumin library reported in our lab-
oratory show low cellular toxicity, whereas curcumin mimics with
substituted benzimidazole groups (6) exhibited strong cytotoxicity
against various cancer cells14 and multidrug-resistant cancer
cells.15 Considering our previous reports on the structure–activity
relationship of diverse curcumin mimic libraries, we conclude that
their diverse biological properties mainly depend on the additional
right-side functionalities. Although the biological properties of
curcumin (1) are very impressive in the field of healthcare food
⇑
Corresponding authors. Tel.: +82 33 649 7471; fax: +82 33 641 1074 (B.-G.P.);
tel.: +82 33 649 7454; fax: +82 33 641 1074 (S.L.).
E-mail addresses: bgpark@cku.ac.kr (B.-G. Park), sjlee@cku.ac.kr (S. Lee).
These authors are equally contributed in this paper.
y
http://dx.doi.org/10.1016/j.bmc.2015.09.004
0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.

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C.-B. Park et al. / Bioorg. Med. Chem. 23 (2015) 6673–6682
supplements, its potency is actually inadequate for use as a clinical
drug. Nevertheless, it is very promising to begin drug discovery
from the structural modification of curcumin (1).
production results in atherosclerosis caused by inflammatory
cytokines released from macrophages,39,40 oxidative stress due to
reactive oxygen species production from VSMCs,41,42 lipid
biosynthesis,43 and hypercholesterolaemia.44 Thus, the inhibitors
of ET-1 synthesis or ETA/ETB2 receptor antagonists are clinically
important to treat or prevent cardiovascular diseases including
atherosclerosis, essential hypertension, pulmonary arterial hyper-
tension (PAH), peripheral (PAD) and coronary artery disease
(CAD), stroke, and diabetic complications of the vasculature.45–47
In the vascular wall, ET receptor type A (ETAR) and type B2 (ETB2R)
are localized in vascular smooth muscle cells and mediates the
major part of the vasoconstrictor effect of ET-1, whereas the ET
receptor type B1 (ETB1R) is localized to the endothelial cells and
mediates vasodilatation via release of nitric oxide (NO).23
Therefore, when considering the clinical usefulness of the
vasodilation effect depending on the mechanism-based vascular
dilation activity, it is more important to discover novel vasodila-
tion drug candidates affecting both depolarization- and ET-1-in-
duced vascular constriction.
As shown in our previous research, the sulfonyl amide linked
curcumin library (7) showed a vasodilation effect on the contrac-
tion of the basilar artery induced by depolarization. Subsequently,
we conducted experiments to determine whether our sulfonyl
curcumin mimics library (7) also dilated constricted vascular tone
induced by ET-1. In this paper, we describe the synthesis of a
sulfonyl amide linked curcumin library (7) including newly
synthesized compounds and show their vasodilation effect on con-
tracted rabbit basilar artery produced via depolarization (50 mM
K+) and ET-1, which means that they can be used as dual antagonist
of L-type Ca2+ channel and ETA/B2R.
Several years ago, we synthesized an alkyl or aryl sulfonyl
amide curcumin mimic library (7) and reported that library mem-
bers exhibit a vasodilatation effect on the depolarization (50 mM
K+)-induced basilar arterial contraction ex vivo.16 Therefore, it
seems reasonable to conclude that the sulfonyl amide linked
curcumin library (7) has a potential to control vascular tone. Con-
sidering this, we extended our research of the basic vasodilation
property of curcumin mimics (7) in order to evaluate the clinical
potential for treating vascular related diseases (Fig. 1).
Vascular tone is mainly dependent on intracellular Ca2+ ([Ca2+]i)
concentration which is increased by L-type Ca2+ channels on the
vascular smooth muscle cell (VSMC) membrane and inositol
1,4,5-trisphosphate (IP3)-mediated Ca2+ release from sarcoplasmic
reticulum (SR) through
G protein-coupled receptor-induced
phospholipase C (PLC) activation.17,18 Physiologically, L-type Ca2+
channels are slowly inactivated during sustained depolarization,
so that the Ca2+ influx is sufficient to mediate the pressure-induced
constriction of resistance vessels and contribute to the dynamic
autoregulation of the systemic and cerebral arteries.19 Therefore,
sustained Ca2+ influx via L-type Ca2+ channels maintains a tonic
level of vascular contraction and provides an excitatory template
for endogenously vasoactive substances.20 However, in hyperten-
sion, the development of anomalous arterial tone is associated
with increased expression of L-type Ca2+ channel
a1C subunits,
which play a critical role in increasing blood pressure and flow.21
Therefore, L-type Ca2+ channel antagonists can be used as anti-hy-
pertensive agents, but can be expected to act only as adjuvants
because the overexpression of L-type Ca2+ channels is not limited
to hypertension.22
2. Results and discussion
2.1. Synthesis
More importantly, endothelial dysfunction is regarded to occur
early during the development of cardiovascular diseases including
severe hypertension, vascular complications associated with dia-
betes mellitus, atherosclerosis, and stroke.23 Reduction in bioavail-
ability of nitric oxide (NO) is considered the key factor of
endothelial dysfunction that causes increased vascular tone, plate-
let aggregation, and inflammation.24 Endothelial dysfunction also
involves biological mediators, including increased endotheline-1
(ET-1) expression and altered expression of ET-1 receptors.25
ET-1 is a vasoactive peptide of 21-amino acids originally isolated
from endothelial cell-conditioned medium26 and is well known
as the most potent vasoconstrictor.27,28 In physiological states,
ET-1 is produced in small amounts predominantly in endothelial
cells (ECs)23 and acts as a vascular regulator, pro-inflammatory
mediator, and mitogen mediated by endothelin receptor type A
(ETAR), type B1 (ETB1R), and type B2 (ETB2R) coupled with G pro-
teins.29,30 ETAR and ETB2R primarily have vasoconstriction and
In our previous report,16 we synthesized 15 sulfonyl curcumin
mimics; however, as shown in Scheme 1, we additionally produced
six compounds to obtain a more detailed structure–activity rela-
tionship. Namely, the important synthetic intermediate, 1-(3-Ami-
nophenyl)-3-(4-hydroxy-3-methoxyphenyl)propenone (10), was
produced from the aldol reaction of 4-hydroxy-3-methoxyben-
zaldehyde (8) with 3-acetylaniline (9) using basic catalyst (40%
KOH) in ethanol at room temperature for 10 h. This amine interme-
diate (10) was reacted with a variety of sulfonyl chlorides in a solu-
tion of dioxane and water (1:1) while stirring for 5–7 h at 0 °C to
yield alkyl- or aryl-substituted sulfonylamide curcumin derivatives
(11a–11u). Newly synthesized compounds created for a more
detailed structure–activity relationship included ethyl (11b),
trifluoromethyl (11e), p-toluyl (11g), p-chlorophenyl (11h), and
20,60-dichlorophenyl (11s) sulfonylamide curcumin mimic deriva-
tives. The double bond in the feruloyl structure was confirmed to
the trans configuration because of a large coupling constant
(approximately J = 15 Hz) between its two protons.11 The structure
of synthetic intermediate (10) and all sulfonylamide linked cur-
cumin compounds (11a–11u) were identified by 1H and 13C NMR
spectroscopy, and GC/MS analysis and were evaluated for vasodila-
tion effect on rabbit basilar artery contracted with depolarization
(50 mM K+) and ET-1.
cell-proliferation functions, whereas ETB1R mainly mediates
vasodilatation, inhibition of growth, and inflammation via NO
and prostaglandin I2.31 ETB1R is also involved in the clearance of
ET-1 peptides from the circulation,32 since its blockade increases
the concentration of ET-1 peptide in plasma, whereas activation
of this receptor on EC also exerts a negative feedback and inhibits
ET-1 peptide synthesis.33 Thus, the vasoactive effect of ET-1
depends mainly on the overall ET receptor profile, defined as the
relative density of ETAR and ETB2R on VSMCs compared to ETB1
R
on ECs.34
2.2. Vasodilatation effect of curcumin and synthetic curcumin
mimics on depolarization-induced constriction of the rabbit
basilar artery
The pathological significance of ET-1 is well characterized in
atherosclerosis, vascular complications associated with diabetes
mellitus, chronic renal disease, and pulmonary hypertension.23,35
In accordance with its multiple activities, ET-1 production has been
shown to be modulated by several factors including hypoxia,
glucose, insulin, cytokines, angiotensin II, growth factor,
and vasoactive substances.36–38 In particular, increasing ET-1
We first evaluated the vasodilatation potency of curcumin and
synthetic sulfonylamide-linked mimics on depolarization-induced
constriction of rabbit basilar artery, a common cerebral artery,

C.-B. Park et al. / Bioorg. Med. Chem. 23 (2015) 6673–6682
6675
O
O
O
O
H
N
NH2
H3CO
HO
R
O2
RSO2Cl
H3CO
HO
H3CO
HO
NH2
40% KOH
EtOH
H3C
S
H
+
dioxane/water
=1:1
9
11a - 11u
8
10
CH3
CH3
CH3
CH2CH3
CF3
(e)
CH2CH2CH3
(a)
(g)
(b)
(c)
(f)
(d)
CF3
F
NO2
OCH3
OCF3
Cl
CF3
R:
(i)
(j)
(k)
(h)
(l)
(m)
(n)
Cl
Cl
Cl
Cl
Cl
Cl
O
S
Cl
Cl
Cl
Cl
(s)
(t)
(p)
(r)
(u)
(o)
(q)
Scheme 1. Synthesis of novel curcumin mimics with the sulfonyl units including the various alkyl and aryl groups. Yields for 10, 45%; 11a, 20%; 11b, 20%; 11c, 19%; 11d, 15%;
11e, 16%; 11f, 66%; 11g, 76%; 11h, 74%; 11i, 76%; 11j, 75%; 11k, 55%; 11l, 67%; 11m, 67%; 11n, 68%; 11o, 19%; 11p, 66%; 11q, 38%; 11r, 80%; 11s, 60%; 11t, 50%; 11u, 40%.
using an organ bath system. When treated with high K+ (50 mM) as
Table 1
Vasodilatation percentage of curcumin mimics in 10
ization-induced constriction of rabbit basilar artery
lM concentration on depolar-
a hypothetical depolarizing condition, the basilar artery was
isometrically contracted and reached steady-state within
10 min. As summarized in Table 1, a single application of curcumin
a
Effective percentage (%) at
Effective percentage (%) at
10
10
lM
lM
and sulfonyl curcuminoids at 10 lM induced vasodilatation of the
basilar artery contracted with 50 mM K+. Among the 22 com-
11a 4.2 ( 2.8)a
11b 55.3 ( 3.8)
11c 42.3 ( 4.3)
11d 20.5 ( 2.7)
11e 10.7 ( 2.5)
11l
76.7 ( 5.5)
65.8 ( 5.3)
52.3 ( 4.5)
67.9 ( 4.7)
4.2 ( 2.2)
53.4 ( 4.9)
30.2 ( 4.8)
99.4 ( 0.4)
37.3 ( 6.4)
32.4 ( 3.6)
11m
11n
11o
11p
11q
11r
11s
11t
pounds tested, including curcumin (1), eight compounds showed
a stronger vasodilatation effect (P60%) in 10 lM concentration
than curcumin (58.4% vasodilation activity at the same concentra-
tion). Interestingly, those compounds showing strong effect are
curcumin mimics that have a functional group at the para position
of benzene except for 11s, which has 20,60-dichloro groups, and
electron-withdrawing groups, except for 11g, which has a methyl
group. Conversely, five alkyl sulfonamide curcumin derivatives
(11a–11e) exhibited a weak vascular dilation effect. However,
the strongest three molecules (11g, 11h, and 11s) showing a
greater than 90% vasodilation effect did not show any benzyl
substituent tendency of the electronic property. Based on this
SAR analysis, we can conclude that the change in vasodilation
effect is caused by the addition of para benzene electron-
withdrawing groups. Considering the previous SAR analysis, we
confirm that a para electron-withdrawing group-substituted phe-
nyl sulfonamide on the half curcumin structure plays an important
role in increasing the vasodilation effect on depolarization-induced
constriction of rabbit basilar artery.
11f
50.4 ( 4.7)
11g 98.7 ( 1.1)
11h 93.4 ( 3.8)
11i
11j
71.8 ( 6.4)
70.7 ( 5.6)
11u
11k 26.4 ( 4.4)
Curcumin 58.4 ( 6.4)
a
Data for observed effects represent means of five independent experiments;
standard deviation is shown within parentheses.
2.3. Vasodilatation effect of curcumin and synthetic curcumin
mimics on endothelin-1-induced vasoconstriction of rabbit
basilar artery
Endothelin-1 (ET-1) is a potent vasoconstrictor, proinflamma-
tory, and proliferative endothelial cell-derived peptide. ET-1 is
pathophysiologically important in developing several cardiovascu-
lar diseases including atherosclerosis, diabetic retinopathy,
nephropathy, and insulin resistance.45 Therefore, antagonists of
ET-1 actions or ETA/B2R might have potent therapeutic applica-
tions.47 In this study, we investigated the vasodilatation potency
of curcumin and synthetic curcumin mimics on a basilar artery
contracted with ET-1 (3 nM). It is well known that ET-1 evokes vas-
cular constriction via [Ca2+]i increase through inositol-3-phosphate
(IP3)-mediated Ca2+ release from the sarcoplasmic reticulum (SR),
extracellular Ca2+ entry by receptor-operated Ca2+ entry (ROCC),
and L-type Ca2+ channels.23 Consistent with this, when treated
with ET-1 (3 nM), the basilar artery contracted and reached a
stationary phase within 15 min.
The serial application of curcumin (1) and the strongest three
molecules (11g, 11h, and 11s) at 3, 10, and 30 lM concentration
yielded vasodilatation of the basilar arteries constricted by
depolarization in a concentration-dependent manner. As shown
in Figure 2, the curve fittings of the concentration–response rela-
tionship based on the Hill equation confirmed that the concentra-
tion required for half maximal dilatation (EC50) of curcumin (1) and
the three other compounds (11g, 11h, and 11s) were 7.48 0.28,
3.67 0.45, 5.58 0.64, and 2.78 0.33 lM (n = 4), respectively.
These results indicated that curcumin mimics, especially com-
pounds 11g, 11h, and 11s, exerted a more potent vasodilatation
effect on the basilar artery than curcumin at an equimolar concen-
tration. When considering that vascular tone is mainly dependent
on the increment of intracellular Ca2+ ([Ca2+]i) concentration by
L-type Ca2+ channels on the vascular smooth muscle cell (VSMC)
membrane, selected three compounds (11g, 11h, and 11s) can be
acted as strong L-type Ca2+ channel blockers.
The vasodilatation potencies of curcumin and synthetic cur-
cumin mimics at 10
screening using ET-1 as a vascular constriction inducer, curcumin
showed a weak vasodilation effect; 8.5 2.4% and 48.5 4.2
of EC50, which are weaker than the vasodilation effect determined
lM concentration are shown in Table 2. In this
l
M

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C.-B. Park et al. / Bioorg. Med. Chem. 23 (2015) 6673–6682
N
O
N
N
O
O
O
R1
R2
H
R
H3CO
HO
OCH3
OH
H3CO
HO
N
R
O
3 R1: -OCH3; R2: -OH
4 R1: -OH; R2: -OCH3
1
2
O
N
O
N
N
O
H3CO
HO
H
N
R
N
H3CO
HO
R
O2
S
N
H3C
N
7
5
6
R
Figure 1. Structures of curcumin and synthetic curcumin mimic derivatives.
Figure 2. Concentration-dependent vasodilatation effect and their EC50 of curcumin and selected curcumin mimics on depolarization-induced vasoconstriction of the rabbit
basilar artery. Representative normalized traces were acquired by a single application of curcumin 1 (A), 11g (B), 11h (C), and 11s (D) in log scale concentration (10ꢀ5.5, 10ꢀ5
,
10ꢀ4.5 M) for 40 min after pre-contraction with high K+ (50 mM), and the effect reached a stationary phase (10 min). The vasodilatation efficacy was plotted as a function of
the log scale concentration of curcumin (1) and the other compounds (12 and 20), and the curves were fitted using the Hill equation, E = (1 + EC50/[compound]n)ꢀ1 (E). The
estimated EC50 values of curcumin 1 (A), 11g (B), 11h (C), and 11s (D) are 7.48 0.28, 3.67 0.45, 5.58 0.64, and 2.78 0.33
mean SD (n = 4).
lM, respectively (F). Data are represented as
in the depolarization-induced system. Among the tested curcumin
mimics, seven compounds (11g, 11h, 11i, 11j, 11l, 11p, and 11s)
exhibited a strong vasodilatation effect greater than 70%. Simply
comparing the vasodilatation efficacy between depolarization-
and ET-1-induced basilar artery contraction, we found that six
compounds (11g, 11h, 11i, 11j, 11l, and 11s) showed similarly
strong activity on both systems. Interestingly, 11p having a
2,4-dichlorobenzene sulfonyl group showed weak vasodilation
potent vasodilatation of the basilar artery contracted with ET-1
in a concentration-dependent manner. Among them, the EC50 of
compounds, 11s and 11g, were 1.8 0.2 and 2.7 0.2 lM, respec-
tively, which represent the strongest vasodilatation agents for
ET-1-induced basilar artery contraction. This result suggests that
11s and 11g can act as novel and potent ETA/B2R antagonist.
2.4. Structure-vasodilation effect relationship of curcumin and
synthetic curcumin mimics on high K+ induced and endothelin-
1-induced vasoconstriction of rabbit basilar artery
effect (only 4.2 2.2% in 10
contraction induced by high K+ but strong potency (83.4 6.2% in
10 M concentration) on ET-1 induced contraction. When consid-
lM concentration) on the basilar artery
l
ering the vasodilation effect on both systems with two inducers,
depolarization and ET-1, the tendencies of vasodilatation effect
according to structure variation are consistent. Based on these
results, we have potentially discovered a novel vasodilation agent
created through structural modification.
When considering vasodilation effect on both inducer systems,
depolarization and ET-1, the tendencies according to structure
variation are very similar. The curcumin mimics showing strong
vasodilation effect include six compounds (11g, 11h, 11i, 11j,
11l, and 11s) for depolarization-induced and seven compounds
(11g, 11h, 11i, 11j, 11l, 11p, and 11s) for ET-1-induced vasocon-
striction. Except for 11p, the other compounds simultaneously
and strongly dilate the contracted rabbit basilar artery. Considering
that structural modification only occurred in benzene groups via
sufonyl linkage, the variation of vasodilation effect is quite large.
However, we observe structural consistency when considering
strongly active curcumin mimics; namely, most of them, except
To confirm dose-dependency and the effective concentration of
half-maximal vasodilatation (EC50
)
of the selected seven
compounds (11g, 11h, 11i, 11j, 11l, 11p, and 11s) and curcumin,
we monitored the basilar artery vasodilatation, and the resultant
EC50 values are summarized in Table 2. Also, the curve fitting of
concentration responses for 11g, 11h, 11j, 11s, and curcumin using
the Hill equation are shown in Figure 3. The compounds induced

C.-B. Park et al. / Bioorg. Med. Chem. 23 (2015) 6673–6682
6677
Table 2
Vasodilatation potency of curcumin mimics on endothelin 1-induced constriction of rabbit basilar artery
Effective percentage (%) at 10
lM
EC50
(l
M)a
Effective percentage (%) at 10
lM
EC50 (lM)
c
11a
11b
11c
11d
11e
11f
11g
11h
11i
22.3 ( 4.3)b
19.7 ( 5.1)
30.8 ( 2.9)
31.2 ( 3.3)
34.6 ( 4.2)
40.2 ( 3.9)
99.6 ( 0.2)
78.3 ( 4.5)
75.1 ( 5.3)
98.9 ( 0.4)
56.8 ( 5.5)
—
11l
81.4 ( 4.8)
46.1 ( 6.8)
36.5 ( 4.4)
68.7 ( 3.7)
83.4 ( 6.2)
30.4 ( 6.7)
41.8 ( 5.6)
99.8 ( 0.1)
55.9 ( 7.1)
39.1 ( 6.6)
8.5 ( 2.4)
6.1 ( 0.6)
—
—
—
8.8 ( 0.3)
—
—
1.8 ( 0.2)
—
—
—
—
—
—
—
11m
11n
11o
11p
11q
11r
11s
11t
11u
2.7 ( 0.2)
5.9 ( 0.4)
6.4 ( 0.3)
3.9 ( 0.3)
—
11j
11k
Curcumin
48.5 ( 4.2)
a
b
c
Effective concentration of half maximal vasodilatation.
Data for observed effects represent means of five independent experiments; standard deviation is shown within parentheses.
Not determined because of low potency.
Figure 3. Vasodilatative effects of curcumin and synthetic curcumin mimics with aromatic ring on endothelin-1-induced vasoconstriction of rabbit basilar artery.
Representative normalized traces were acquired by single application of curcumin (A), 11g (B), 11h (C), 11j (D), and 11s (E) in log scale concentration (10ꢀ6–10ꢀ4 M range) for
20 min after pre-contracted with endothelin-1 (3 nM) reached a maximal contraction (15 min) on the basilar artery of white rabbits. The vasodilatation efficacy were plotted
as a function of log scale concentration for compounds and the curves were fitted using Hill equation, E = (1 + EC50/[compound]n)ꢀ1 (F). Data are represented as mean SD
(n = 4).
11s, have a functional group in the para position of the benzene
sulfonyl group, although their electronic properties do not
perfectly coincide. Compound 11j has a strong activating group,
–NO2, but the others (11g, 11h, 11i, 11l, and 11p) have moderate
activating groups such as methyl, halogen (–F and –Cl), and
–OCF3, respectively. Only 11s has a 2,6-dichloro group. Based on
the structure–vasodilation effect relationship of the curcumin
nature-mimetic library, half of the curcumin compounds with a
benzenesulfonyl group having para-position functionality on
benzene can be novel vasodilation candidates for contracted
vasculature induced by both depolarization and ET-1.
ET-1-induced basilar artery contraction. Although curcumin (1), a
natural compound in this mimetic library, disclosed a weak
vasodilation effect on the contracted basilar arteries induced by
both depolarization and ET-1, our synthetic curcumin mimics were
more potent than curcumin (1). We found that six curcumin
mimics (11g, 11h, 11i, 11j, 11l, and 11s) in depolarization- and
seven compounds (11g, 11h, 11i, 11j, 11l, 11p, and 11s) in
ET-1-induced vasoconstriction system are promising as novel
vasodilators. When considering their vasodilation effect on basilar
arteries constricted by depolarization and ET-1, we can conclude
that selected curcumin mimic vasodilators are novel dual antago-
nists of L-type Ca2+ channel and ETA/B2R. In particular, compounds
11g and 11s are the strongest vasodilatation molecules among the
tested curcumin mimics and are now being tested in an in vivo
study for potential use in the treatment of vascular-related
diseases.
3. Conclusion
In order to discover novel vasodilation agents for the treatment
of cardiovascular diseases such as atherosclerosis, essential
hypertension, PAH, coronary artery disease, stroke, and diabetic
complications of vasculature, we synthesized a library of curcumin
mimics with alkylsulfonyl group and variously substituted
benzenesulfonyl linkages through a simple addition reaction of
an important intermediate, 1-(3-Amino-phenyl)-3-(4-hydroxy-3-
methoxy-phenyl)-propenone (10), with various sulfonyl chlorides,
and tested their vasodilatation effect on depolarization- and
4. Experimental
4.1. General
Melting points were determined on Electrothermal IA9200
apparatus and were not corrected. 1H and 13C NMR spectra

6678
C.-B. Park et al. / Bioorg. Med. Chem. 23 (2015) 6673–6682
recorded on Bruker 400 MHz FT-NMR spectrometer at 400 MHz,
respectively, in the indicated solvent using TMS as internal
standard. Elemental analysis was carried out on CE instruments
EA1110 elemental analyzer. Thin-layer chromatography (TLC) has
been performed on precoated Merck silica gel 60 F254 plates.
Column chromatography was performed over silica gel (230–400
mesh). All other reagents were commercially available.
Male New Zealand white rabbits weighing 2–2.5 kg were
purchased from Orient BIO Inc. (Sungnam, Gyeonggi, Korea), and
acclimated for 1 week at a temperature of 25 1 °C and humidity
of 50 5%. All experiments were performed according to the Care
and Use of Laboratory Animals published by the US National
Institutes of Health and has been approved by the Committee for
the Care and Use of Laboratory Animals in Catholic Kwandong
University. NaCl, KCl, CaCl2, MgCl2, and NaHCO3 were purchased
from Sigma Chemical Co. (St. Louis, MO, USA).
4.2.3. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-
ethanesulfonamide (11b)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with ethanesul-
fonyl chloride (0.048 g, 0.372 mmol) as sulfonylation agent. The
resulting solid was purified by silica gel column chromatography
(ethyl acetate/n-hexane = 8:2). Yield 20%; mp 118–120 °C; TLC
(ethyl acetate/n-hexane = 8:2) Rf = 0.52; 1H NMR (CDCl3): d 2.80
(3H, t, J = 7.37 Hz, CH2CH3), 3.17 (2H, q, J = 7.40 Hz, CH2CH3), 3.98
(3H, s, OCH3), 5.94 (1H, s, OH), 6.91 (1H, s, NH), 6.97 (1H, d,
J = 8.27 Hz, CH3OC6H3), 7.17 (1H, d, J = 1.26 Hz, CH3OC6H3), 7.26
(1H, dd, J = 5.36 and 1.71 Hz, CH3OC6H3), 7.35 (1H, d, J = 15.58 Hz,
CH@CHAr), 7.50 (1H, t, J = 7.85 Hz, NHC6H4), 7.58 (1H, d,
J = 8.02 Hz, NHC6H4), 7.80 (1H, d, J = 7.63 Hz, NHC6H4), 7.84 (1H,
d, J = 15.62 Hz, CH@CHAr), 7.89 (1H, s, NHC6H4) ppm. 13C NMR
(CDCl3 + DMSO-d6): d 8.2, 46.0, 56.0, 110.4, 115.3, 119.4, 119.9,
123.6, 123.9, 124.1, 127.1, 129.7, 138.6, 139.8, 145.8, 147.3, 149.0,
190.1. MS (FAB+) (m/z) 361 (M+); Anal. Calcd for C18H19NO5S:
C, 59.82; H, 5.30; N, 3.88; S, 8.87. Found: C, 59.95; H, 5.26; N,
3.83; S, 8.77.
4.2. Synthesis
4.2.1. 1-(3-Amino-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-
propenone (10)
A
mixture of 4-hydroxy-3-methoxybenzaldehyde (8, 1.5 g,
10.0 mmol) and 30-aminoacetophenon (9, 1.4 g, 10.0 mmol) is dis-
solved in 15 mL of ethanol and allowed to stir for several min at
5 °C (ice bath). 10 mL of a 40% KOH solution in water is added
dropwise to the flask over several min. The mixture is then allowed
to stir at room temperature for approximately 10 h. After the reac-
tion was complete, the reaction mixture was neutralized with a
dilute HCl. The solution was extracted with anhydrous ether
(3 ꢁ 10 mL). The organic layer was concentrated and purified by
silica gel column chromatography (CH2Cl2/methanol = 94:6). Yield
45%; mp 154–155 °C; TLC (methylene chloride/methanol = 94:6)
Rf = 0.39; 1H NMR (CDCl3): d 3.82 (2H, s, NH2), 3.97 (3H, s, OCH3),
5.89 (1H, s, OH), 6.88–6.90 (1H, m, NH2C6H4), 6.96 (1H, d,
J = 8.21 Hz, CH3OC6H3), 7.13 (1H, d, J = 1.76 Hz, CH3OC6H3), 7.21
(1H, dd, J = 8.21 and 1.80 Hz, CH3OC6H3), 7.28–7.39 (3H, m,
NH2C6H4), 7.33 (1H, d, J = 15.63 Hz, CH@CHAr), 7.73 (1H, d,
J = 15.63 Hz, CH@CHAr) ppm. 13C NMR (CDCl3): d 56.0, 110.2,
114.4, 115.1, 118.7, 119.2, 119.9, 123.4, 127.3, 129.4, 139.6,
145.0, 146.9, 147.1, 148.6, 190.9. MS (EI+) (m/z) 269 (M+); Anal.
Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.72;
H, 5.66; N, 5.10.
4.2.4. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-
propanesulfonamide (11c)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 1-propane-
sulfonyl chloride (0.053 g, 0.372 mmol) as sulfonylation agent.
The resulting solid was purified by silica gel column chromatogra-
phy (ethyl acetate/n-hexane = 1:1). Yield 19%; mp 117–119 °C; TLC
(ethyl acetate/n-hexane = 1:1) Rf = 0.23; 1H NMR (CDCl3): d 1.03
(3H, t, J = 7.42 Hz, CH2CH2CH3), 1.86–1.91 (2H, m, CH2CH2CH3),
3.09–3.13 (2H, m, CH2CH2CH3), 3.98 (3H, s, OCH3), 5.96 (1H, s,
OH), 6.87 (1H, s, NH), 6.97 (1H, d, J = 8.20 Hz, CH3OC6H3), 7.16
(1H, d, J = 1.59 Hz, CH3OC6H3), 7.26 (1H, dd, J = 7.57 and 1.65 Hz,
CH3OC6H3), 7.35 (1H, d, J = 15.58 Hz, CH@CHAr), 7.50 (1H, t,
J = 7.80 Hz, NHC6H4), 7.56 (1H, d, J = 8.33 Hz, NHC6H4), 7.80 (1H,
d, J = 7.55 Hz, NHC6H4), 7.83 (1H, d, J = 15.73 Hz, CH@CHAr), 7.85
(1H, s, NHC6H4) ppm. 13C NMR (CDCl3): d 12.9, 17.3, 53.7, 56.1,
110.5, 114.9, 118.7, 120.2, 123.7, 123.9, 124.7, 127.3, 129.9,
138.1, 139.7, 146.7, 146.8, 148.7, 189.9. MS (FAB+) (m/z) 375
(M+); Anal. Calcd for C19H21NO5S: C, 60.78; H, 5.64; N, 3.73; S,
8.54. Found: C, 61.21; H, 5.72; N, 3.79; S, 8.63.
4.2.2. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-
methanesulfonamide (11a)
4.2.5. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-
isopropanesulfonamide (11d)
To a solution of 1-(3-Amino-phenyl)-3-(4-hydroxy-3-methoxy-
phenyl)-propenone (1) (0.1 g, 0.373 mmol) in 2.5 mL of dioxane/
H2O (50:50) was added methanesulfonyl chloride (0.043 g,
0.372 mmol) over a 20 min period at 0 °C followed by 5 h of vigor-
ous stirring at room temperature. The solvent was removed in
vacuo, and the resulting solid was purified by silica gel column
chromatography (CHCl3/methanol = 95:5). Yield 20%; mp 140–
142 °C; TLC (chloroform/methanol = 95:5) Rf = 0.19; 1H NMR
(CDCl3): d 3.06 (3H, s, CH3), 3.98 (3H, s, OCH3), 5.99 (1H, s, OH),
6.97 (1H, d, J = 8.22 Hz, CH3OC6H3), 7.02 (1H, s, NH), 7.16 (1H, d,
J = 1.55 Hz, CH3OC6H3), 7.25 (1H, dd, J = 7.48 and 1.62 Hz,
CH3OC6H3), 7.35 (1H, d, J = 15.58 Hz, CH@CHAr), 7.52 (1H, t,
J = 7.76 Hz, NHC6H4), 7.57 (1H, d, J = 7.77 Hz, NHC6H4), 7.82 (1H,
s, NHC6H4), 7.76 (1H, d, J = 15.59 Hz, CH@CHAr), 7.87 (1H, d,
J = 7.18 Hz, NHC6H4) ppm. 13C NMR (CDCl3 + DMSO-d6): d 50.6,
56.0, 110.4, 115.3, 119.4, 120.3, 123.6, 124.3, 124.4, 127.1, 129.7,
138.5, 139.8, 145.8, 147.3, 149.0, 190.0. MS (FAB+) (m/z) 347
(M+); Anal. Calcd for C17H17NO5S: C, 59.78; H, 4.93; N, 4.03; S,
9.23. Found: C, 60.03; H, 5.06; N, 4.08; S, 9.28.
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with isopropylsul-
fonyl chloride (0.053 g, 0.372 mmol) as sulfonylation agent. The
resulting solid was purified by silica gel column chromatography
(ethyl acetate/n-hexane = 1:1). Yield 15%; mp 124–126 °C; TLC
(ethyl acetate/n-hexane = 1:1) Rf = 0.21; 1H NMR (CDCl3): d 1.42
(6H, d, J = 6.85 Hz, CH(CH3)2), 3.31–3.33 (1H, m, CH(CH3)2), 3.98
(3H, s, OCH3), 5.98 (1H, s, OH), 6.80 (1H, s, NH), 6.97 (1H, d,
J = 8.25 Hz, CH3OC6H3), 7.16 (1H, d, J = 1.28 Hz, CH3OC6H3), 7.25
(1H, dd, J = 11.41 and 1.58 Hz, CH3OC6H3), 7.34 (1H, d,
J = 15.62 Hz, CH@CHAr), 7.48 (1H, t, J = 7.83 Hz, NHC6H4), 7.57
(1H, d, J = 8.06 Hz, NHC6H4), 7.78 (1H, d, J = 7.90 Hz, NHC6H4), 7.79
(1H, d, J = 16.99 Hz, CH@CHAr), 7.84 (1H, s, NHC6H4) ppm. 13C
NMR (CDCl3): d 16.6, 53.0, 56.1, 110.4, 114.9, 118.9, 120.0, 123.6,
123.8, 124.5, 127.3, 129.9, 138.3, 139.7, 146.6, 146.8, 148.6, 189.9.
MS (FAB+) (m/z) 375 (M+); Anal. Calcd for C19H21NO5S: C, 60.78;
H, 5.64; N, 3.73; S, 8.54. Found: C, 60.98; H, 5.71; N, 3.80; S, 8.61.

C.-B. Park et al. / Bioorg. Med. Chem. 23 (2015) 6673–6682
6679
4.2.6. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-
trifluoromethanesulfonamide (11e)
4.2.9. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-
4-chlorobenzenesulfonamide (11h)
The same procedure described above was employed for
the preparation of 11a by addition reaction of 1-(3-Amino-
phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-propenone (10) with
trifluromethanesulfonyl chloride (0.063 g, 0.372 mmol) as
sulfonylation agent. The resulting solid was purified by silica gel
column chromatography (CHCl3/methanol = 95:5). Yield 16%; mp
120–122 °C; TLC (chloroform/methanol = 95:5) Rf = 0.19; 1H NMR
(CDCl3): d 3.98 (3H, s, OCH3), 5.98 (1H, s, OH), 6.91 (1H, s, NH),
6.98 (1H, d, J = 8.20 Hz, CH3OC6H3), 7.29 (1H, d, J = 1.62 Hz,
CH3OC6H3), 7.27 (1H, dd, J = 4.60 and 1.71 Hz, CH3OC6H3), 7.34
(1H, d, J = 15.58 Hz, CH@CHAr), 7.55 (1H, t, J = 7.87 Hz, NHC6H4),
7.63 (1H, d, J = 8.02 Hz, NHC6H4), 7.85 (1H, d, J = 15.35 Hz,
CH@CHAr), 7.93 (1H, d, J = 7.69 Hz, NHC6H4), 8.01 (1H, s, NHC6H4)
ppm. 13C NMR (CDCl3 + DMSO-d6): d 55.9, 110.7, 115.6, 119.0,
121.4, 122.1, 123.6, 125.8, 125.9, 126.6, 129.5, 136.0, 139.6,
146.1, 147.8, 149.7, 189.8. MS (FAB+) (m/z) 401 (M+); Anal. Calcd
for C17H14F3NO5S: C, 50.87; H, 3.52; N, 3.49; S, 7.99. Found:
C, 49.75; H, 3.36; N, 3.36; S, 7.84.
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 4-chloroben-
zenesulfonyl chloride (0.079 g, 0.372 mmol) as sulfonylation
agent. The resulting solid was purified by silica gel column
chromatography (ethyl acetate/n-hexane = 1:1). Yield 74%; mp
162–164 °C; TLC (ethyl acetate/n-hexane = 1:1) Rf = 0.31; 1H NMR
(CDCl3): d 3.97 (3H, s, OCH3), 5.92 (1H, s, OH), 6.97 (1H, d,
J = 8.21 Hz, CH3OC6H3), 7.00 (1H, s, NH), 7.15 (1H, d, J = 1.64 Hz,
CH3OC6H3), 7.24 (2H, dd, J = 10.12 and 1.72 Hz, CH3OC6H3), 7.30
(1H, d, J = 15.61 Hz, CH@CHAr), 7.41 (2H, d, J = 8.65 Hz,
4-chlorobenzenesulfonyl-H), 7.41–7.44 (2H, m, NHC6H4), 7.72
(2H, d, J = 8.55 Hz, 4-chlorobenzenesulfonyl-H), 7.73 (1H, s,
NHC6H4), 7.77–7.80 (1H, m, NHC6H4), 7.82 (1H, d, J = 15.72 Hz,
CH@CHAr) ppm. 13C NMR (CDCl3 + DMSO-d6):
d 56.0, 110.5,
115.4, 119.3, 120.8, 124.5, 124.7, 128.5, 128.6, 129.1, 129.2,
129.4, 137.9, 138.2, 139.1, 139.5, 145.7, 147.4, 149.2, 190.0. MS
(FAB+) (m/z) 443 (M+); Anal. Calcd for C22H18ClNO5S: C, 59.53; H,
4.09; N, 3.16; S, 7.22. Found: C, 59.29; H, 3.98; N, 3.09; S, 7.09.
4.2.7. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-
benzenesulfonamide (11f)
4.2.10. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-
4-fluorobenzenesulfonamide (11i)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with benzenesul-
fonyl chloride (0.066 g, 0.372 mmol) as sulfonylation agent. The
resulting solid was purified by silica gel column chromatography
(ethyl acetate/n-hexane = 1:1). Yield 66%; mp 165–167 °C; TLC
(ethyl acetate/n-hexane = 1:1) Rf = 0.28; 1H NMR (CDCl3 + DMSO-
d6): d 3.95 (3H, s, OCH3), 6.94 (1H, d, J = 7.92 Hz, CH3OC6H3),
7.14–7.16 (2H, m, CH3OC6H3), 7.25 (1H, d, J = 15.54 Hz, CH@CHAr),
7.31–7.36 (1H, m, benzenesulfonyl-H), 7.39–7.41 (2H, m, benzene-
sulfonyl-H), 7.41–7.51 (2H, m, NHC6H4), 7.50 (1H, d, J = 7.40 Hz,
NHC6H4), 7.62 (1H, s, OH), 7.68 (1H, d, J = 15.45 Hz, CH@CHAr),
7.77 (1H, s, NHC6H4), 7.83 (2H, m, benzenesulfonyl-H), 9.77 (1H,
s, NH) ppm. 13C NMR (CDCl3): d 56.0, 110.7, 115.5, 119.2, 120.5,
123.5, 124.1, 124.5, 127.0, 128.8, 128.9, 129.3, 132.7, 138.2,
139.4, 139.7, 145.7, 147.7, 149.4, 190.0. MS (FAB+) (m/z) 409
(M+); Anal. Calcd for C22H19NO5S: C, 64.53; H, 4.68; N, 3.42; S,
7.83. Found: C, 65.01; H, 4.74; N, 3.52; S, 7.91.
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 4-fluoroben-
zenesulfonyl chloride (0.072 g, 0.372 mmol) as sulfonylation agent.
The resulting solid was purified by silica gel column chromatogra-
phy (ethyl acetate/n-hexane = 1:1). Yield 76%; mp 163–165 °C; TLC
(ethyl acetate/n-hexane = 1:1) Rf = 0.29; 1H NMR (CDCl3): d 3.97
(3H, s, OCH3), 5.92 (1H, s, OH), 6.93 (1H, s, NH), 6.97 (1H, d,
J = 8.24 Hz, CH3OC6H3), 7.10 (2H, d, J = 8.49 Hz, 4-fluorobenzene-
sulfonyl-H), 7.14 (1H, d, J = 2.94 Hz, CH3OC6H3), 7.24 (1H, dd,
J = 9.93 and 1.28 Hz, CH3OC6H3), 7.29 (1H, d, J = 15.77 Hz,
CH@CHAr), 7.42–7.43 (2H, m, NHC6H4), 7.71 (1H, s, NHC6H4),
7.80 (2H, d, J = 8.92 Hz, 4-fluorobenzenesulfonyl-H), 7.81 (1H, d,
J = 10.73 Hz, NHC6H4), 7.82 (1H, d, J = 15.71 Hz, CH@CHAr) ppm.
13C NMR (CDCl3 + DMSO-d6): d 56.0, 110.5, 115.4, 116.1, 116.3,
119.3, 120.8, 123.5, 124.4, 124.7, 127.0, 129.4, 129.8, 129.9,
138.0, 139.5, 145.7, 147.4, 149.2, 190.0. MS (FAB+) (m/z) 427
(M+); Anal. Calcd for C22H18FNO5S: C, 61.82; H, 4.24; N, 3.28; S,
7.50. Found: C, 59.98; H, 4.12; N, 3.22; S, 7.24.
4.2.8. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-
4-methylbenzenesulfonamide (11g)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 4-methyl-
benzenesulfonyl chloride (0.071 g, 0.372 mmol) as sulfonylation
agent. The resulting solid was purified by silica gel column
chromatography (ethyl acetate/n-hexane = 1:1). Yield 76%; mp
170–172 °C; TLC (ethyl acetate/n-hexane = 1:1) Rf = 0.26; 1H NMR
(CDCl3): d 2.36 (3H, s, CH3), 3.97 (3H, s, OCH3), 5.92 (1H, s, OH),
6.94 (1H, s, NH), 6.96 (1H, d, J = 8.27 Hz, CH3OC6H3), 7.15 (1H, d,
J = 1.75 Hz, CH3OC6H3), 7.22 (2H, d, J = 10.63 Hz, 4-methylbenzene-
sulfonyl-H), 7.23 (1H, d, J = 8.19 Hz, CH3OC6H3), 7.29 (1H, d,
J = 15.65 Hz, CH@CHAr), 7.38–7.42 (2H, m, NHC6H4), 7.68 (2H, d,
J = 8.28 Hz, 4-methylbenzenesulfonyl-H), 7.70 (1H, s, NHC6H4),
7.74–7.76 (1H, m, NHC6H4), 7.80 (1H, d, J = 15.59 Hz, CH@CHAr)
ppm. 13C NMR (CDCl3 + DMSO-d6): d 21.5, 56.0, 110.6, 115.4,
119.3, 120.5, 123.5, 124.0, 124.4, 126.7, 127.1, 129.3, 129.6,
136.7, 138.3, 139.4, 143.4, 145.6, 147.6, 149.3, 190.1. MS (FAB+)
(m/z) 423 (M+); Anal. Calcd for C23H21NO5S: C, 65.23; H, 5.00; N,
3.31; S, 7.57. Found: C, 66.17; H, 5.15; N, 3.40; S, 7.76.
4.2.11. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-
4-nitrobenzenesulfonamide (11j)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 4-nitroben-
zenesulfonyl chloride (0.082 g, 0.372 mmol) sulfonylation agent.
The resulting solid was purified by silica gel column chromatogra-
phy (ethyl acetate/n-hexane = 1:1). Yield 75%; mp 140–142 °C; TLC
(ethyl acetate/n-hexane = 1:1) Rf = 0.26; 1H NMR (CDCl3): d 3.97
(3H, s, OCH3), 5.94 (1H, s, OH), 6.97 (1H, d, J = 8.28 Hz, CH3OC6H3),
7.17 (1H, d, J = 1.68 Hz, CH3OC6H3), 7.27 (1H, dd, J = 8.78 and
1.76 Hz, CH3OC6H3), 7.34 (1H, d, J = 15.55 Hz, CH@CHAr), 7.47
(1H, t, J = 8.07 Hz, NHC6H4), 7.55 (1H, d, J = 8.49 Hz, NHC6H4),
7.63 (1H, s, NH), 7.82 (1H, s, NHC6H4), 7.83 (1H, d, J = 2.09 Hz,
NHC6H4), 7.92 (1H, d, J = 15.55 Hz, CH@CHAr), 7.97 (2H, d,
J = 8.87 Hz, 4-nitrobenzenesulfonyl-H), 8.27 (2H, d, J = 8.83 Hz,
4-notrobenzenesulfonyl-H) ppm. 13C NMR (CDCl3 + DMSO-d6): d
56.0, 110.7, 115.6, 119.0, 120.9, 123.5, 124.1, 124.8, 124.9, 126.7,
128.4, 129.5, 137.5, 139.6, 145.6, 145.9, 147.7, 149.6, 149.9,

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C.-B. Park et al. / Bioorg. Med. Chem. 23 (2015) 6673–6682
189.8. MS (FAB+) (m/z) 454 (M+); Anal. Calcd for C22H18N2O7S: C,
58.14; H, 3.99; N, 6.16; S, 7.06. Found: C, 60.22; H, 4.15; N, 6.53;
S, 7.31.
J = 12.12 Hz, CH@CHAr), 7.82 (1H, d, J = 4.22 Hz, NHC6H4), 7.88
(1H, s, NHC6H4), 7.93 (2H, d, J = 7.78 Hz, 4-(trifluoromethyl)ben-
zenesulfonyl-H) ppm. 13C NMR (CDCl3 + DMSO-d6): d 56.0, 110.5,
115.4, 119.2, 120.9, 123.5, 124.6, 124.7, 126.0, 126.1, 126.2,
127.0, 127.7, 129.5, 137.7, 139.6, 143.4, 145.8, 147.4, 149.2,
189.9. MS (FAB+) (m/z) 477 (M+); Anal. Calcd for C23H18F3NO5S:
C, 57.86; H, 3.80; N, 2.93; S, 6.72. Found: C, 56.82; H, 3.79; N,
2.88; S, 6.60.
4.2.12. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phen-
yl}-4-methoxybenzenesulfonamide (11k)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 4-methoxy-
benzenesulfonyl chloride (0.077 g, 0.372 mmol) as sulfonylation
agent. The resulting solid was purified by silica gel column chro-
matography (CHCl3/methanol = 8:2). Yield 55%; mp 189–191 °C;
TLC (chloroform/methanol = 8:2) Rf = 0.71; 1H NMR (CDCl3): d
3.81 (3H, s, 4-methoxylbenzenesulfonyl-OCH3), 3.97 (3H, s,
OCH3), 5.99 (1H, s, OH), 6.89 (2H, d, J = 8.88 Hz, 4-methoxylben-
zenesulfonyl-H), 6.95 (1H, s, NH), 6.96 (1H, d, J = 8.15 Hz,
CH3OC6H3), 7.14 (1H, d, J = 1.34 Hz, CH3OC6H3), 7.22 (1H, dd,
J = 8.28 and 1.42 Hz, CH3OC6H3), 7.28 (1H, d, J = 15.55 Hz,
CH@CHAr), 7.39–7.41 (2H, m, NHC6H4), 7.67 (1H, s, NHC6H4),
7.72 (2H, d, J = 8.89 Hz, 4-methoxylbenzenesulfonyl-H), 7.75 (1H,
d, J = 2.09 Hz, NHC6H4), 7.77 (1H, d, J = 15.50 Hz, CH@CHAr) ppm.
13C NMR (CDCl3 + DMSO-d6): d 50.5, 56.0, 110.5, 114.1, 115.3,
119.4, 120.6, 123.5, 124.2, 124.6, 127.1, 129.3, 129.4, 131.2,
138.2, 139.4, 145.6, 147.4, 149.0, 162.9, 190.1. MS (FAB+) (m/z)
439 (M+); Anal. Calcd for C23H21NO6S: C, 62.86; H, 4.82; N, 3.19;
S, 7.30. Found: C, 65.09; H, 5.01; N, 3.30; S, 7.55.
4.2.15. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phen-
yl}-3-trifluoromethylbenzenesulfonamide (11n)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 3-(trifluo-
romethyl)benzenesulfonyl chloride (0.091 g, 0.372 mmol) as sul-
fonylation agent. The resulting solid was purified by silica gel
column chromatography (ethyl acetate/n-hexane = 1:1). Yield
68%; mp 158–160 °C; TLC (ethyl acetate/n-hexane = 1:1)
Rf = 0.32; 1H NMR (CDCl3): d 3.97 (3H, s, OCH3), 5.93 (1H, s, OH),
6.97 (1H, d, J = 8.24 Hz, CH3OC6H3), 7.16 (1H, d, J = 1.57 Hz,
CH3OC6H3), 7.25 (1H, dd, J = 7.10 and 1.53 Hz, CH3OC6H3), 7.31
(1H, d, J = 15.55 Hz, CH@CHAr), 7.32 (1H, s, NH), 7.45 (1H, t,
J = 7.77 Hz, NHC6H4), 7.51 (1H, d, J = 7.77 Hz, NHC6H4), 7.58 (1H,
t, J = 7.85 Hz, 3-(trifluoromethyl)benzenesulfonyl-H), 7.75 (1H, s,
NHC6H4), 7.79 (1H, d, J = 9.70 Hz, 3-(trifluoromethyl)benzenesul-
fonyl-H), 7.81 (1H, d, J = 7.62 Hz, NHC6H4), 7.87 (1H, d,
J = 15.57 Hz, CH@CHAr), 7.95 (1H, d, J = 7.96 Hz, 3-(trifluo-
romethyl)benzenesulfonyl-H), 8.05 (1H, s, 3-(trifluoromethyl)
benzenesulfonyl-H) ppm. 13C NMR (CDCl3 + DMSO-d6): d 56.0,
110.7, 115.6, 119.0, 121.0, 121.9, 123.5, 124.1, 124.2 124.6, 124.9,
126.6, 129.2, 129.4, 129.7, 130.3, 137.7, 139.5, 140.9, 145.8,
147.8, 149.6, 189.8. MS (FAB+) (m/z) 477 (M+); Anal. Calcd for
4.2.13. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phen-
yl}-4-trifluoromethoxybenzenesulfonamide (11l)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 4-(trifluo-
romethoxy)benzenesulfonyl chloride (0.097 g, 0.372 mmol) as sul-
fonylation agent. The resulting solid was purified by silica gel
column chromatography (ethyl acetate/n-hexane = 1:1). Yield
67%; mp 154–156 °C; TLC (ethyl acetate/n-hexane = 1:1)
Rf = 0.36; 1H NMR (CDCl3): d 3.97 (3H, s, OCH3), 5.93 (1H, s, OH),
6.97 (1H, d, J = 8.20 Hz, CH3OC6H3), 7.17 (1H, d, J = 1.57 Hz,
CH3OC6H3), 7.25 (1H, d, J = 8.28 Hz, CH3OC6H3), 7.27 (2H, d,
J = 8.88 Hz, 4-(trifluoromethoxy)benzenesulfonyl-H), 7.33 (1H, d,
J = 15.57 Hz, CH@CHAr), 7.41 (1H, s, NH), 7.44 (1H, t, J = 7.80 Hz,
NHC6H4), 7.51 (1H, d, J = 8.57 Hz, NHC6H4), 7.80 (1H, d,
J = 7.77 Hz, NHC6H4), 7.81 (1H, s, NHC6H4), 7.85 (2H, d,
J = 8.89 Hz, 4-(trifluoromethoxy)benzenesulfonyl-H), 7.90 (1H, d,
J = 15.59 Hz, CH@CHAr) ppm. 13C NMR (CDCl3 + DMSO-d6): d 56.0,
110.5, 115.3, 119.3, 120.7, 120.8, 123.5, 124.5, 124.6, 127.0,
129.2, 129.3, 129.4, 137.8, 138.1, 139.6, 145.8, 147.4, 149.1,
152.0, 190.0. MS (FAB+) (m/z) 493 (M+); Anal. Calcd for
C23H18F3NO5S: C, 57.86; H, 3.80; N, 2.93; S, 6.72. Found: C, 57.08;
H, 3.78; N, 2.88; S, 6.69.
4.2.16. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phen-
yl}-4-acetylbenzenesulfonamide (11o)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 4-acethyl-
benzenesulfonyl chloride (0.081 g, 0.372 mmol) as sulfonylation
agent. The resulting solid was purified by silica gel column chro-
matography (CHCl3/methanol = 95:5). Yield 19%; mp 155–157 °C;
TLC (chloroform/methanol = 95:5) Rf = 0.07; 1H NMR (CDCl3): d
2.60 (3H, s, acetyl-H), 3.97 (3H, s, OCH3), 5.94 (1H, s, OH), 6.93
(1H, s, NH), 6.96 (1H, d, J = 8.25 Hz, CH3OC6H3), 7.13 (1H, d,
J = 1.59 Hz, CH3OC6H3), 7.22 (1H, dd, J = 8.27 and 1.85 Hz,
CH3OC6H3), 7.28 (1H, d, J = 15.54 Hz, CH@CHAr), 7.41–7.43 (2H,
m, NHC6H4), 7.68 (1H, s, NHC6H4), 7.77–7.79 (1H, m, NHC6H4),
7.78 (1H, d, J = 15.63 Hz, CH@CHAr), 7.88 (2H, d, J = 8.47 Hz,
4-acetylbenzenesulfonyl-H), 8.00 (2H, d, J = 8.43 Hz, 4-acetylben-
zenesulfonyl-H) ppm. 13C NMR (CDCl3 + DMSO-d6): d 26.8, 56.0,
110.4, 115.3, 119.3, 120.9, 123.5, 124.6, 124.8, 127.0, 127.5, 128.8,
129.5, 137.7, 139.5, 139.9, 143.6, 145.7, 147.3, 149.0, 189.9, 196.8.
MS (FAB+) (m/z) 451 (M+); Anal. Calcd for C24H21NO6S: C, 63.85;
H, 4.69; N, 3.10; S, 7.10. Found: C, 63.67; H, 4.72; N, 3.12; S, 7.06.
C23H18F3NO6S: C, 55.98; H, 3.68; N, 2.84; S, 6.50. Found: C, 59.70;
H, 3.96; N, 3.03; S, 6.94.
4.2.14. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phen-
yl}-4-trifluoromethylbenzenesulfonamide (11m)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 4-(trifluo-
romethyl)benzenesulfonyl chloride (0.091 g, 0.372 mmol) as sul-
fonylation agent. The resulting solid was purified by silica gel
column chromatography (ethyl acetate/n-hexane = 1:1). Yield
67%; mp 157–159 °C; TLC (ethyl acetate/n-hexane = 1:1)
Rf = 0.29; 1H NMR (CDCl3): d 3.97 (3H, s, OCH3), 5.93 (1H, s, OH),
6.97 (1H, d, J = 8.21 Hz, CH3OC6H3), 7.17 (1H, d, J = 1.13 Hz,
CH3OC6H3), 7.27 (1H, d, J = 6.33 Hz, CH3OC6H3), 7.33 (1H, d,
J = 15.56 Hz, CH@CHAr), 7.45 (1H, t, J = 7.82 Hz, NHC6H4), 7.49
(1H, s, NH), 7.52 (1H, d, J = 7.71 Hz, NHC6H4), 7.70 (2H, d,
J = 8.29 Hz, 4-(trifluoromethyl)benzenesulfonyl-H), 7.81 (1H, d,
4.2.17. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phen-
yl}-2,4-dichlorobenzenesulfonamide (11p)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-
3-(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 2,4-
dichlorobenzenesulfonyl chloride (0.091 g, 0.372 mmol) as
sulfonylation agent. The resulting solid was purified by silica gel
column chromatography (CHCl3/methanol = 95:5). Yield 66%; mp
169–171 °C; TLC (chloroform/methanol = 95:5) Rf = 0.38; 1H NMR

C.-B. Park et al. / Bioorg. Med. Chem. 23 (2015) 6673–6682
6681
(CDCl3): d 3.97 (3H, s, OCH3), 5.96 (1H, s, OH), 6.97 (1H, d,
J = 8.20 Hz, CH3OC6H3), 7.14 (1H, s, CH3OC6H3), 7.23 (1H, d,
J = 8.14 Hz, CH3OC6H3), 7.28 (1H, d, J = 15.17 Hz, CH@CHAr), 7.32
(1H, d, J = 8.94 Hz, 2,4-dichlorobenzenesulfonyl-H), 7.38 (1H, t,
J = 7.47 Hz, NHC6H4), 7.40 (1H, s, NH), 7.50 (1H, d, J = 4.08 Hz,
NHC6H4), 7.59 (1H, s, 2,4-dichlorobenzenesulfonyl-H), 7.74 (1H,
d, J = 6.06 Hz, NHC6H4), 7.79 (1H, d, J = 15.57 Hz, CH@CHAr), 7.80
(1H, s, NHC6H4), 7.99 (1H, d, J = 8.53 Hz, 2,4-dichlorobenzenesul-
fonyl-H) ppm. 13C NMR (CDCl3): d 56.1, 110.3, 114.9, 118.9,
121.1, 123.6, 124.7, 125.6, 127.2, 127.7, 129.8, 131.6, 132.4,
132.9, 134.7, 136.3, 139.7, 140.3, 146.4, 146.8, 148.6, 189.6. MS
(FAB+) (m/z) 477 (M+); Anal. Calcd for C22H17Cl2NO5S: C, 55.24;
H, 3.58; N, 2.93; S, 6.70. Found: C, 56.26; H, 3.68; N, 2.98; S, 6.82.
sulfonylation agent. The resulting solid was purified by silica gel
column chromatography (CHCl3/methanol = 95:5). Yield 60%; mp
177–179 °C; TLC (chloroform/methanol = 95:5) Rf = 0.50; 1H NMR
(CDCl3 + DMSO-d6): d 3.95 (3H, s, OCH3), 6.94 (1H, d, J = 8.58 Hz,
CH3OC6H3), 7.15 (1H, s, CH3OC6H3), 7.15–7.16 (1H, m, CH3OC6H3),
7.30 (1H, d, J = 15.58 Hz, CH@CHAr), 7.31 (1H, d, J = 6.83 Hz, 2,6-
dichlorobenzenesulfonyl-H), 7.37 (1H, t, J = 7.86 Hz, NHC6H4),
7.41–7.42 (1H, m, NHC6H4), 7.41–7.42 (2H, m, 2,6-dichloroben-
zenesulfonyl-H), 7.67 (1H, d, J = 7.54 Hz, NHC6H4), 7.70 (1H, d,
J = 15.59 Hz, CH@CHAr), 7.87 (1H, s, NHC6H4), 8.21 (1H, s, OH),
10.14 (1H, s, NH) ppm. 13C NMR (CDCl3 + DMSO-d6): d 56.3,
111.0, 115.9, 119.2, 119.3, 123.4, 123.9, 124.3, 127.1, 129.9,
131.9, 133.2, 134.7, 135.9, 137.7, 139.8, 146.1, 148.0, 149.8,
190.2. MS (FAB+) (m/z) 477 (M+); Anal. Calcd for C22H17Cl2NO5S:
C, 55.24; H, 3.58; N, 2.93; S, 6.70. Found: C, 57.52; H, 3.73; N,
3.06; S, 6.96.
4.2.18. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phen-
yl}-2,5-dichlorobenzenesulfonamide (11q)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-
3-(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 2,5-
dichlorobenzenesulfonyl chloride (0.091 g, 0.372 mmol) as
sulfonylation agent. The resulting solid was purified by silica gel
column chromatography (CHCl3/methanol = 95:5). Yield 38%; mp
153–155 °C; TLC (chloroform/methanol = 95:5) Rf = 0.45; 1H NMR
(CDCl3 + DMSO-d6): d 3.96 (3H, s, OCH3), 6.94 (1H, d, J = 7.94 Hz,
CH3OC6H3), 7.15 (1H, s, CH3OC6H3), 7.15––7.17 (1H, m, CH3OC6H3),
7.25 (1H, d, J = 15.72 Hz, CH@CHAr), 7.34–7.41 (2H, m, NHC6H4),
7.37–7.41 (2H, m, 2,5-dichlorobenzenesulfonyl-H), 7.67 (1H, d,
J = 7.40 Hz, NHC6H4), 7.69 (1H, d, J = 15.52 Hz, CH@CHAr), 7.79
(1H, s, NHC6H4), 8.09 (1H, s, 2,5-dichlorobenzenesulfonyl-H), 8.09
(1H, s, OH), 10.07 (1H, s, NH) ppm. 13C NMR (CDCl3 + DMSO-d6):
d 56.0, 110.7, 115.6, 119.1, 120.2, 123.5, 124.0, 124.4, 126.7.
129.5, 130.1, 131.5, 132.9, 133.1, 133.8, 137.1, 138.3, 139.5,
145.8, 147.7, 149.5, 189.9. MS (FAB+) (m/z) 477 (M+); Anal. Calcd
for C22H17Cl2NO5S: C, 55.24; H, 3.58; N, 2.93; S, 6.70. Found: C,
57.82; H, 3.78; N, 3.08; S, 6.99.
4.2.21. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-
phenyl}-3,5-dichlorobenzenesulfonamide (11t)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone
(10)
with
3,5-
dichlorobenzenesulfonyl chloride (0.091 g, 0.372 mmol) as
sulfonylation agent. The resulting solid was purified by silica gel
column chromatography (CHCl3/methanol = 95:5). Yield 50%; mp
187–189 °C; TLC (chloroform/methanol = 95:5) Rf = 0.24; 1H NMR
(CDCl3 + DMSO-d6): d 3.94 (3H, s, OCH3), 6.93 (1H, d, J = 8.68 Hz,
CH3OC6H3), 7.14–7.16 (2H, m, CH3OC6H3), 7.28 (1H, d,
J = 15.52 Hz, CH@CHAr), 7.39–7.41 (1H, m, NHC6H4), 7.45–7.46
(1H, m, NHC6H4), 7.47–7.48 (1H, m, 3,5-dichlorobenzenesulfonyl-
H), 7.65–7.69 (1H, m, NHC6H4), 7.70 (1H, d, J = 15.59 Hz,
CH@CHAr), 7.72–7.73 (2H, m, 3,5-dichlorobenzenesulfonyl-H),
7.78 (1H, s, NHC6H4), 8.64 (1H, s, OH), 10.26 (1H, s, NH) ppm. 13C
NMR (CDCl3 + DMSO-d6): d 56.0, 110.8, 115.7, 118.9, 120.9, 123.5,
124.7, 124.8, 125.4, 125.5, 129.5, 132.5, 135.6, 137.5, 139.5,
142.6, 145.8, 147.8, 149.7, 189.7. MS (FAB+) (m/z) 477 (M+); Anal.
Calcd for C22H17Cl2NO5S: C, 55.24; H, 3.58; N, 2.93; S, 6.70. Found:
C, 55.14; H, 3.50; N, 2.87; S, 6.58.
4.2.19. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phen-
yl}-3,4-dichlorobenzenesulfonamide (11r)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-
3-(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 3,4-
dichlorobenzenesulfonyl chloride (0.091 g, 0.372 mmol) as
sulfonylation agent. The resulting solid was purified by silica gel
column chromatography (CHCl3/methanol = 95:5). Yield 80%; mp
159–161 °C; TLC (chloroform/methanol = 95:5) Rf = 0.37; 1H NMR
(CDCl3 + DMSO-d6): d 3.94 (3H, s, OCH3), 6.94 (1H, d, J = 8.39 Hz,
CH3OC6H3), 7.14 (1H, s, CH3OC6H3), 7.14–7.19 (1H, m, CH3OC6H3),
7.28 (1H, d, J = 15.57 Hz, CH@CHAr), 7.37 (1H, t, J = 7.65 Hz,
NHC6H4), 7.40 (1H, d, J = 7.50 Hz, NHC6H4), 7.50 (1H, d, J =
8.44 Hz, 3,4-dichlorobenzenesulfonyl-H), 7.64 (1H, d, J = 8.42 Hz,
3,4-dichlorobenzenesulfonyl-H), 7.70 (1H, d, J = 15.30 Hz,
CH@CHAr), 7.71 (1H, d, J = 7.40 Hz, NHC6H4), 7.79 (1H, s, 3,4-
dichlorobenzenesulfonyl-H), 7.95 (1H, s, NHC6H4), 8.36 (1H, s,
OH), 10.15 (1H, s, NH) ppm. 13C NMR (CDCl3 + DMSO-d6): d 56.0,
110.7, 115.6, 119.0, 120.8, 123.5, 124.6, 124.7, 126.3, 126.6,
129.0, 129.5, 130.9, 133.3, 137.2, 137.6, 139.5, 139.6, 145.9,
147.7, 149.5, 189.8. MS (FAB+) (m/z) 477 (M+); Anal. Calcd for
4.2.22. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-
phenyl}-thiophene-2-sulfonamide (11u)
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
(4-hydroxy-3-methoxy-phenyl)-propenone (10) with 2-thio-
phenesulfonyl chloride (0.068 g, 0.372 mmol) as sulfonylation
agent. The resulting solid was purified by silica gel column chro-
matography (CHCl3/methanol = 95:5). Yield 40%; mp 164–166 °C;
TLC (chloroform/methanol = 95:5) Rf = 0.28; 1H NMR (CDCl3 +
DMSO-d6): d 3.96 (3H, s, OCH3), 6.95 (1H, d, J = 8.10 Hz, CH3OC6H3),
6.99 (1H, m, thiophene-H), 7.15 (1H, s, CH3OC6H3), 7.17 (1H, dd,
J = 9.12 and 1.86 Hz, CH3OC6H3), 7.28 (1H, d, J = 15.59 Hz,
CH@CHAr), 7.36 (1H, t, J = 7.73 Hz, NHC6H4), 7.44–7.47 (1H, m,
NHC6H4), 7.49–7.53 (2H, m, thiophene-H), 7.59–7.62 (1H, m,
NHC6H4), 7.71 (1H, d, J = 15.48 Hz, CH@CHAr), 7.73 (1H, s, NHC6H4),
7.84 (1H, s, OH), 9.68 (1H, s, NH) ppm. 13C NMR (CDCl3 + DMSO-d6):
d 56.0, 110.8, 115.7, 118.9, 120.5, 123.5, 124.3, 124.6, 126.5, 126.9,
127.2, 128.7, 129.3, 131.9, 132.1, 138.0, 139.3, 145.6, 147.9, 149.8,
189.7. MS (FAB+) (m/z) 415 (M+); Anal. Calcd for C20H17NO5S2: C,
57.82; H, 4.12; N, 3.37; S, 15.44. Found: C, 61.18; H, 4.41; N,
3.57; S, 16.39.
C22H17Cl2NO5S: C, 55.24; H, 3.58; N, 2.93; S, 6.70. Found: C,
56.32; H, 3.74; N, 3.01; S, 6.86.
4.2.20. N-{3-[3-(4-Hydroxy-3-methoxy-phenyl)-acryloyl]-phen-
yl}-2,6-dichlorobenzenesulfonamide (11s)
4.3. Measurements of vascular tension
The same procedure described above was employed for the
preparation of 11a by addition reaction of 1-(3-Amino-phenyl)-3-
Male New Zealand white rabbits weighing 2–2.5 kg were
anesthetized by inhaling enflurane. The basilar artery was rapidly
isolated under sterile conditions and placed in
(4-hydroxy-3-methoxy-phenyl)-propenone
(10)
with
2,6-
dichlorobenzenesulfonyl chloride (0.091 g, 0.372 mmol) as
a
Ca2+-free

6682
C.-B. Park et al. / Bioorg. Med. Chem. 23 (2015) 6673–6682
13. Kwon, D.; Oh, S.; Park, J.-H.; Lee, S.; Lee, S. Bull. Korean Chem. Soc. 2014, 35,
3339.
14. Woo, H. B.; Um, Y.; Park, K.-S.; Ham, J.; Ahn, C. M.; Lee, S. Bioorg. Med. Chem.
Lett. 2012, 22, 933.
15. Um, Y.; Oh, S.; Woo, H. B.; Ham, J.; Ahn, C. M.; Lee, S. Bull. Korean Chem. Soc.
2013, 34, 1272.
16. Ahn, C. M.; Park, B.-G.; Woo, H. B.; Ham, J.; Lee, S. Bioorg. Med. Chem. Lett. 2009,
19, 1481.
physiological salt solution (PSS) that contained the following
components (in mM): 135 NaCl, 5 KCl, 1.8 CaCl2, 1 MgCl2, 5.5 glu-
cose, and 23.8 NaHCO3 (pH 7.4, adjusted with a 95% O2 and 5%
CO2). Residual blood was rinsed from the lumen and adherent con-
nective tissue, fat, and adventitia were carefully removed. The basi-
lar artery was cut into rings (3 mm) in a dissecting chamber filled
with a Ca2+-free PSS saturated with a 95% O2 and 5% CO2 mixture.
The basilar ring was mounted using a pair of stainless steel hooks
under a resting tension of 0.8 g in organ baths containing 15 mL of
PSS, which was maintained 37 °C and bubbled with a 95% O2 and
5% CO2 mixture. One of the hooks was connected to a force dis-
placement transducer (MLT050; ADInstruments, Colorado Springs,
CO, USA) and the tension was recorded with chart 5 on a Power-
lab/400 (ADInstruments). After an equilibration was performed
for 30 min, each ring specimen was repeatedly exposed to the high
K+ solution (50 mM K+), which was prepared by replacing NaCl
with an equimolar concentration of KCl, until the responses
became stable. Functional endothelial cells were confirmed by
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