Design, synthesis and pharmacological evaluation of (E)-3,4-dihydroxy styryl sulfonamides derivatives as multifunctional neuroprotective agents against oxidative and inflammatory injury

Article abstract of DOI:10.1016/j.bmc.2013.05.043

A novel class of (E)-3,4-dihydroxy styryl sulfonamides and their 3,4-diacetylated derivatives as caffeic acid phenethyl ester (CAPE) analogs was designed and prepared for improving stability and solubility of the lead compound. Their neuroprotective properties were assessed by several models. The results showed that target compounds displayed positive free radical quenching abilities, superior to that of CAPE. Compounds 6j-k and 7j-k demonstrated remarkable protection effects against damage induced by hydrogen peroxide which were apparently stronger than that of CAPE. Most of target compounds could inhibit nitric oxide production. Additionally, target compounds showed high blood-brain barrier permeability.

Full text of DOI:10.1016/j.bmc.2013.05.043

Bioorganic & Medicinal Chemistry 21 (2013) 5589–5597
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis and pharmacological evaluation of
(E)-3,4-dihydroxy styryl sulfonamides derivatives as multifunctional
neuroprotective agents against oxidative and inflammatory injury
Xianling Ning a, Ying Guo a, Xiaoyan Ma a, Renzong Zhu a, Chao Tian a, Zhili Zhang a, Xiaowei Wang a,
Zhizhong Ma c, Junyi Liu a,b,
⇑
a Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China
c Department of the Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel class of (E)-3,4-dihydroxy styryl sulfonamides and their 3,4-diacetylated derivatives as caffeic
acid phenethyl ester (CAPE) analogs was designed and prepared for improving stability and solubility
of the lead compound. Their neuroprotective properties were assessed by several models. The results
showed that target compounds displayed positive free radical quenching abilities, superior to that of
CAPE. Compounds 6j–k and 7j–k demonstrated remarkable protection effects against damage induced
by hydrogen peroxide which were apparently stronger than that of CAPE. Most of target compounds
could inhibit nitric oxide production. Additionally, target compounds showed high blood–brain barrier
permeability.
Received 22 March 2013
Revised 27 April 2013
Accepted 18 May 2013
Available online 31 May 2013
Keywords:
(E)-3,4-Dihydroxy styryl sulfonamides
Caffeic acid phenethyl ester
Neuroprotective agents
Antioxidants
Ó 2013 Published by Elsevier Ltd.
Blood–brain barrier permeability
1. Introduction
and anti-inflammatory properties of 1 is recognized to be benefi-
cial for treatment of neurodegenerative disorders. Numerous re-
Neurodegenerative disorders are a heterogeneous group of dis-
eases of the nervous system, characterized by loss of nerve cells
from brain and spinal cord, which leads either functional loss
(ataxia) or sensory dysfunction (dementia).1 Oxidative stress and
inflammation have been linked to neuronal cell death and believed
to be fundamental mechanisms of progressive neurodegenerative
disorders such as Alzheimer’s, Parkinson’s and Huntington’s dis-
ease as well as amyotrophic lateral sclerosis.2,3
Compound 1 (Caffeic acid phenethyl ester, CAPE) (Fig. 1) de-
rived from the propolis of honeybee hives has long been known
to possess a wide spectrum of biological activities including
antioxidant,4 anti-inflammatory,5 antiviral,6 antibacterial,7 anti-
atherosclerotic,8 immunostimulatory9 and antitumor10 properties.
Compound 1 can significantly exhibit the antioxidant property by
means of blocking production of reactive oxygen species and the
xanthine/xanthine oxidase system,11 and the anti-inflammatory
property through reducing prostaglandin (PG) and leukotriene
synthesis by inhibiting cyclooxygenase (COX) enzyme activity or
the down-regulation of COX gene expression.12,13 The antioxidant
cent studies have demonstrated effects of 1 against a variety of
toxicities in different types of neuronal cells, including hydrogen
peroxide (H2O2),14 6-hydroxydopamine14 and glutamate.15 It is
also reported that 1 can block hypoxia–ischemic brain injury16,17
and MPTP-induced dopaminergic neurodegeneration18 in animal
models. From the previous studies, it is confirmed that 1 is a prom-
ising neuroprotective agent with multiple targets effects.
Although many preclinical studies have demonstrated primary
safety and biological activities of 1 in animal and in vitro models,
pharmacokinetic studies demonstrate that 1 is easily hydrolyzed
by plasmatic esterases in rats after the rapid oral absorption.19,20
In addition, with two phenolic hydroxyl functions 1 does not have
a good solubility in lipophilic environment and is difficult to pass
through blood-brain barrier (BBB). The aim of this study, therefore,
is to design and synthesize its analogs with better stability and
higher BBB permeability, and to discuss structure–activity rela-
tionships of target compounds.
From the previous reported data, the structural feature respon-
sible for the antioxidant activity of 1 was the ortho-dihydroxyl
function in the catechol ring, and the unsaturated double bond of
the side chain also maximized the stabilization of the phenolic rad-
ical.21,22 Therefore, E-3,4-dihydroxy styryl sulfonamides reserving
⇑
Corresponding author. Tel./fax: +86 10 82805203.
E-mail address: jyliu@bjmu.edu.cn (J. Liu).
0968-0896/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmc.2013.05.043

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X. Ning et al. / Bioorg. Med. Chem. 21 (2013) 5589–5597
nagel condensation of the aromatic sulfamoyl-acetic acids (7a–k)
with 3,4-dihydroxy benzaldehyde using the pyrrolidine and acetic
acid as the catalysts in the refluxed THF followed by chromato-
graphic purification obtained E-3,4-dihydroxy styryl sulfonamides
(8a–k) in desired yields. Furthermore, to improve BBB permeabil-
ity, E-3,4-dihydroxy styryl sulfonamides (8a–k) were acetylated
by acetic anhydride with pyridine as the catalyst to afford the cor-
responding E-3,4-diacetyl styryl sulfonamides (9a–k) in the yields
of 92–96%. The E geometry of the target compounds was confirmed
by the coupling constants (J = 16 Hz).
O
O
O
R2O
R2O
S
R1O
R1O
N
R3
O
n
R4
1
2
R1 = H CAPE
1 = Ac Ac-CAPE
R
2 = H, Ac; n = 1, 2, 3, 4
R3 = H, CH3; R4 = H, F, Cl, CF3, CH3, CH3O
target compounds
R
Figure 1. The Structures of 1, 2 and target compounds.
(E)-3,4-dihydroxy styryl group were designed (Fig. 1). The sulfon-
amide group introduced to target compounds was more stability
than the ester group of compound 1. Meanwhile, the unsaturated
sulfonamide function consists of skeleton structures of many
promising neuroprotective agents including branched-chain amino
acid aminotransferase inhibitors,23 caspase-3 inhibitors24 and
NMDA receptor antagonists.25 In order to improve BBB permeabil-
ity, two phenolic hydroxyl functions of target compounds were
acetylated rather than methylated to get corresponding high lipo-
soluble compounds, because the methylation of phenolic hydroxyl
functions may lead to the moderate loss of biological activity.26 It is
also reported that the acetylated phenolic compounds display the
same or higher neuroprotective activity compared with the initial
phenolic compounds.27 To explore the structure–activity relation-
ships, the compounds with various lengths of alky chains and with
various substituted groups on the aromatic ring were designed too.
2.2. Biological evaluation
The neuroprotective properties of E-3,4-dihydroxy styryl
sulfonamides (8a–k) and their 3,4-diacetylated derivatives
(9a–k) were assessed by way of several experimental pharmaco-
logical models in vitro, including 1,1-diphenyl-2-picrylhydrazyl
(DPPH) radical scavenging capacity, neuronal protecting effect
against damage induced by H2O2, nitric oxide production
inhibiting effect and a parallel artificial membrane permeation
assay for blood–brain barrier (PAMPA-BBB). The results showed
that target compounds exhibited significant neuroprotective
activities and higher BBB permeability compared with 1 and 2,
and the preliminary structure–activity relationship was also
discussed.
2.2.1. Free radical scavenging capacity
DPPH, a stable free radical existing in vitro, can be used in pre-
liminary screening of compounds capable of scavenging reactive
free radical. The free radical scavenging capacities of the
(E)-3,4-dihydroxy styryl sulfonamides (8a–k) were measured by
the published test method28,29 over the concentration range of
2. Results and discussion
2.1. Chemistry
E-3,4-Dihydroxy styryl sulfonamides (8a–k) and their 3,4-
diacetylated derivatives (9a–k) were synthesized as shown in
Scheme 1. Commercially available mercaptoacetic acid methyl es-
ter (3) served as starting material was oxidized at 0 °C with Cl2 in
the mixed solvent of CH2Cl2 and H2O followed by pumping N2 to
expel Cl2 to provide chlorosulfonyl-acetic acid methyl ester (4).
The reaction of aromatic amines (5a–k) with chlorosulfonyl-acetic
acid methyl ester (4) in THF in the presence of triethylamine pro-
duced the corresponding aromatic sulfamoyl-acetic acid methyl
ester (6a–k) after chromatography in good yields (86–98%). These
intermediates (6a–k) were hydrolyzed at room temperature with
Na2CO3 as the catalyst followed by recrystallization purification
to afford the aromatic sulfamoyl-acetic acids (7a–k). Then Knoeve-
1–50 lM. The results are shown in Table 1. The compounds 1
and 8a–k exhibit significant free radicals quenching abilities,
comparable to that of the positive control Vitamin C. The reason
of the result above is presumably that the conjugated system con-
sisting of catechol group, double bond and sulfonamide group in
compound 1 and 8a–k can offer a higher electron delocalization
than Vitamin C, and compounds 1 and 8a–k as better hydrogen
donors are easier to scavenge free radicals. It is observed that
all target compounds show the similar or stronger free radical
scavenging capacities than 1. It is also noteworthy that the elec-
tron-withdrawing chloro, trifluoromethyl and fluoro substituted
compounds (8e–g) exhibit more effective activities than elec-
tron-donating methyl and methoxyl substituted compounds
R3
nN
R4
R4
R3
N
H
R3
N
O
O
O
O
R4
a
MeO
c
HO
5a-k
S
HS
S
S
OMe
Cl
OMe
O
O
O
O
O
b
O
6a-k
7a-k
3
4
a: n = 1, R3 = H, R4 = H
b: n = 2, R3 = H, R4 = H
c: n = 3, R3 = H, R4 = H
d: n = 4, R3 = H, R4 = H
e: n = 1, R3 = H, R4 = Cl
f: n = 1, R3 = H, R4 = CF3
g: n = 1, R3 = H, R4 = F
h: n = 1, R3 = H, R4 = CH3
i: n = 1, R3 = H, R4 = OCH3
j: n = 2, R3 = H, R4 = Cl
k: n = 2, R3 = CH3, R4 = H
O
O
O
O
HO
HO
S
AcO
AcO
S
e
d
n
n
N
R3
N
R3
R4
R4
9a-k
8a-k
Scheme 1. Synthesis of E-3,4-dihydroxy styryl sulfonamides and their 3,4-diacetylated derivatives. Reagents and conditions: (a) Cl2, H2O, CH2Cl2, 0 °C, 92%; (b) (CH3CH2)3N,
THF, rt, 86–98%; (c) Na2CO3, MeOH, rt, 82–90%; (d) 3,4-dihydroxy-benzaldehyde, pyrrolidine, acetic acid, THF, reflux, 50–75%; (e) pyridine, acetic anhydride, rt, 92–96%.

X. Ning et al. / Bioorg. Med. Chem. 21 (2013) 5589–5597
5591
Table 1
ducing two acetyl groups of target compounds 9a–k leads to neg-
ligible improvement in protective effects against H2O2 induced
injury compared with the corresponding un-acetylated com-
pounds 8a–k.
Free radical scavenging capacities of 1, target compounds 8a–k by the DPPH methoda
b
b
Compound
IC50
(
lM)
Compound
IC50 (lM)
8a
8b
8c
8d
8e
8f
10.1 0.4
9.1 0.3
7.0 0.6
8.3 0.2
7.8 0.4
7.2 0.4
8.3 0.3
8h
8i
8j
8k
10.7 0.5
11.2 0.2
8.3 0.4
6.8 0.5
12.1 0.3
25.7 0.5
2.2.3. Nitric oxide production inhibiting effect in LPS-
stimulated BV2 microglial cells
1
The microglial cells are believed to play an important role in the
pathway that leads to inflammation-mediated neuronal cell death
in a number of neurodegenerative diseases.31 The uncontrolled
activation of microglia cells may cause neuronal damage through
the overproduction of proinflammatory substances, such as nitric
oxide.31,32 Therefore, inhibiting nitric oxide production is a useful
strategy for treating neurodegenerative disorders. The inhibition
effect on nitric oxide production of target compounds (8a–k and
9a–k) can be measured by the Griess assay.33 The results are sum-
marized in Table 2. From the results, most of the target compounds
inhibit nitric oxide production in LPS-stimulated BV2 microglial
cells, although the activities of target compounds do not display
highlighted activities compared with 1. Almost all of acetylated
compounds (9a–k) reveal the higher nitric oxide production inhi-
bition effects compared with corresponding un-acetylated com-
pounds (8a–k). The results above are presumably because that
acetylated compounds possess higher lipophilicity, compared with
un-acetylated compounds. Furthermore, it seems that electron-
withdrawing groups substituted compounds (8e–g and 9e–g) exhi-
bit more effective activities compared with electron-donating
groups substituted compounds (8h–i and 9h–i), which is similar
to the results of DPPH assay and H2O2 model. In addition, the se-
lected concentrations of target compounds used in our experiment
do not lead to any significant cytotoxicity even at a high concentra-
Vitamin C
8g
a
Data are expressed as the mean SD, n = 3.
IC50: the concentration that produces 50% inhibitory effect.
b
(8h–i). Compound 8k (IC50 = 6.8 0.5 lM) exhibits prominent
radical scavenging activity among the compounds, and its activity
is superior to 1 and 8b without N-substituent. The possible reason
is that N-substituent compounds may possess higher free radical
scavenging capacities, due to their tertiary amine groups liable to
oxidation. Moreover, the compounds 2 and 9a–k do not show
detectable scavenging capacities under the concentration of
50 lM, which implies that two phenolic hydroxyl groups of target
compounds play a significant role in free radical scavenging
capacity.
2.2.2. Neuronal protecting effect against damage induced by
H2O2
The neuroprotective capacities of target compounds against
oxidative stress were assayed by the H2O2 model. H2O2 could in-
jure nerve cells for the generation of exogenous free radicals. Rat
pheochromocytoma (PC12) cells, commonly as a screening model
for studies of neurodegenerative diseases,30 were used in this
experiment. The protection effect against H2O2 can be conveniently
evaluated by the cell viability via MTT assay. The cell viabilities
attributable to the protective efficiency of target compounds
tion (80 lM) up to 24 h of incubation, and in all cases cell viability
is above 90% by MTT assay, confirming that inhibition of nitric
oxide production in LPS-stimulated BV2 microglial cells is not
due to a cytotoxic action of target compounds.
(8a–k and 9a–k) against H2O2 at 5 lM are listed in Figure 2. All tar-
get compounds significantly exhibit protection effects against
damage induced by H2O2 and compounds 8e–g, 8j–k, 9e–g and
9j–k display higher activities than 1. It seems that chloro, trifluoro-
methyl and fluoro substituted compounds (8e–g and 9e–g) exhibit
more effective activities compared with unsubstituted (8a and 9a)
and methyl and methoxyl substituted compounds (8h–i and 9h–i).
And 8k and 9k with N-substituent display more potent than 8b
and 9b without N-substituent. The results are similar to those of
DPPH assay. In addition, compounds possessing longer alkyl chain
(8d and 9d) show weaker activities compared with shorter alkyl
chain compounds (8a–c and 9a–c). It is also observed that intro-
2.2.4. In vitro evaluation of BBB permeability
Effectiveness of target compounds against neurodegenerative
diseases greatly depends upon their BBB penetration capacities.
To explore whether target compounds would be able to penetrate
into BBB, a high throughput technique, Parallel Artificial Mem-
brane Permeability Assay (PAMPA) was used. This simple and rapid
model was described by Di et al.34 and successfully applied by us to
different compounds. The in vitro permeability (Pe) of target com-
pounds (8a–k and 9a–k) and control drugs (Verapamil, Hydrocor-
tisone and Clonidine) through the porcine polar brain lipid (PBL)
were determined using PBS as the solvent according to the method
Figure 2. Protective effects of 1, 2 and target compounds 8a–9k against H2O2 induced injury in PC12 cells at 5
the cells were treated with 500 M H2O2 for 5 h. Levels of cell viability were measured by the MTT assay. The viability of untreated control cells was defined as 100%. Data are
expressed as the mean SD, n = 3.
lM, respectively. PC12 cells were pretreated for 3 h. After 3 h,
l

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X. Ning et al. / Bioorg. Med. Chem. 21 (2013) 5589–5597
Table 2
tion, they display obvious inhibiting nitric oxide production effects,
although their activities are lower than 1 and 2. The effects of elec-
tron-donating versus electron-withdrawing group substituents on
the aromatic ring as well as short versus long alkyl chain on the
tested pharmacological activities are also discussed. The electron-
withdrawing group substituted compounds exhibit more effective
activities compared with unsubstituted and electron-donating
group substituted compounds in all test models. The activities of
compounds possessing various lengths of alky chains (n = 1–4)
have no obvious regularity in the DPPH assay and NO model, how-
ever, compounds possessing longer alkyl chain, 8d and 9d, show
weaker protection effects compared with shorter alkyl chain com-
pounds in H2O2 model. Additionally, acetylated compounds reveal
higher inhibiting effects on nitric oxide production and similar pro-
tection effects against damage induced by H2O2 compared to corre-
sponding un-acetylated compounds. According to the PAMPA-BBB,
both the acetoxyl group instead of the phenolic hydroxyl group
and the sulfonamide group instead of carboxylic ester group im-
prove BBB permeability which is consistent with our prior design.
Besides, the superior activities of compounds 8k and 9k when
compared to compounds 8b and 9b suggest that N-substituent
compounds may possess higher antioxidant properties, because
their tertiary amine groups are liable to oxidation. The N-substitu-
ent compounds of E-3,4-dihydroxy styryl sulfonamides should be
emphasized in future studies. Above all, the findings reported in
this study provide insights in future drug design and development
for the treatment of neurodegenerative disorders.
Nitric oxide suppression activities of 1, 2 and target compounds 8a–9k in LPS-
stimulated BV2 microglial cellsa
b
b
Compound
IC50
(
l
M)
Compound
IC50 (lM)
8a
8b
8c
8d
8e
8f
8g
8h
8i
21.5 0.3
39.2 0.5
17.5 0.4
23.8 0.3
13.7 0.2
12.6 0.5
18.9 0.6
43.9 0.5
26.5 0.3
9.8 0.5
9a
9b
9c
9d
9e
9f
9g
9h
9i
19.5 0.4
30.8 0.6
15.6 0.2
20.8 0.4
11.0 0.2
9.3 0.2
15.5 0.3
32.0 0.5
26.3 0.4
8.6 0.3
8j
8k
1
9j
9k
2
17.0 0.2
6.4 0.4
10.2 0.2
6.2 0.2
a
Data are expressed as the mean SD, n = 3.
IC50: the concentration that produces 50% inhibitory effect.
b
Table 3
Permeability results of 1, 2, target compounds and control drugs from the PAMPAa
Compound
Pe
Prediction Compound Pe
(10ꢀ6 cm sꢀ1
)
Prediction
(10ꢀ6 cm sꢀ1
)
8a
8b
8c
8d
8e
8f
8g
8h
8i
12.2 0.6
8.2 0.3
5.7 0.4
3.8 0.3
2.5 0.2
2.8 0.5
6.0 0.4
6.7 0.4
4.7 0.6
3.4 0.3
4.8 0.5
CNS+
CNS+
CNS+
CNS+/ꢀ
CNS+/ꢀ
CNS+/ꢀ
CNS+
CNS+
CNS+
9a
9b
9c
9d
9e
9f
9g
9h
9i
15.1 0.5
10.1 0.3
Ndb
CNS+
CNS+
Ndb
5.1 0.2
CNS+
Ndb
7.5 0.3
8.6 0.5
11.6 0.3
Ndb
CNS+
CNS+
CNS+
4. Experimental
4.1. Chemistry
8j
8k
CNS+/ꢀ
9j
CNS+
9k
1
Ndb
Hydrocortisone 1.8 0.2
Verapamil
Clonidine
CNSꢀ
CNS+
CNS+
1.8 0.3
CNSꢀ
16.9 0.4
5.2 0.5
2
Ndb
The structural characterization was done by NMR and high res-
onance mass spectrometer (HRMS). NMR spectra were recorded on
a Bruker AVANCE III-400 spectrometer with tetramethylsilane
(TMS) as an internal standard, and chemical shifts are reported in
d (ppm). High resolution mass spectrum (HRMS) was recorded on
a Bruker Apex IV FTMS spectrometer. Melting points were mea-
sured on an X4-type apparatus and left uncorrected. Thin-layer
chromatography (TLC) was performed on precoated silica gel F254
plates. Detection was by iodine vapor staining and UV light irradi-
ation (UV lamp, model UV-IIB). Column chromatography was car-
ried out with Silica gel H (200–300 mesh or 500 mesh). Unless
otherwise stated, all reagents were purchased from commercial
sources. When necessary, they were purified and dried by standard
methods. Organic solutions were dried over anhydrous sodium
sulfate.
a
Data are expressed as the mean SD, n = 3. PBS was used as solvent.
Not determined due to poor solubility in PBS.
b
described by Di et al.34 The results are summarized in Table 3.
From the results, the Pe values of control drugs are consistent with
the literature of Di et al. In this literature, compounds are classified
according to following ranges for BBB permeation prediction: (a)
‘CNS+’ (high BBB permeation predicted), Pe (10ꢀ6 cm sꢀ1) > 4.0;
(b) ‘CNSꢀ’ (low BBB permeation predicted), Pe (10ꢀ6 cm sꢀ1) < 2.0;
(c) ‘CNS+/ꢀ’ (BBB permeation uncertain), Pe (10ꢀ6 cm sꢀ1) from 4.0
to 2.0. Based on results and ranges above, we can consider that
majority of target compounds are able to cross the BBB and only
8d, 8e, 8f and 8j exhibit weaker permeability. Compared to 1
(1.8 0.3 ꢁ 10ꢀ6 cm sꢀ1), all target compounds possess higher per-
meability. Especially, compound 8b displays greater permeability
than 1, which demonstrates that the sulfonamide group instead
of carboxylic ester group improves BBB permeability. Some acety-
lated compounds are not determined due to poor solubility in PBS.
However, it can be still concluded that acetylated compounds pos-
sess greater permeability than corresponding un-acetylated com-
pounds which are consistent with our prior design.
4.1.1. Synthesis of chlorosulfonyl-acetic acid methyl ester (4)
A solution of mercaptoacetic acid methyl ester (35 mmol) in
CH2Cl2 (15 mL) was added dropwise to the ice water (10 mL) and
Cl2 was pumped in the solution. The solution was stirred at 0 °C
until maintaining greenish, followed by pumping N2 to expel Cl2.
After standing, the solution was separated. The organic fraction
was concentrated under reduced pressure to obtain the title com-
pound. Yellow liquid (92%). 1H NMR (400 MHz, CDCl3) d = 3.75 (s,
2H, SO2CH2), 3.68 (s, 3H, COOCH3).
3. Conclusions
4.1.2. General procedure for the synthesis of aromatic
sulfamoyl-acetic acid methyl ester (6a–k)
In summary, this study discloses that E-3,4-dihydroxy styryl
sulfonamides and their 3,4-diacetylated derivatives demonstrate
multifunctional neuroprotective activities against oxidative and
inflammatory injury such as remarkable potency of scavenging
reactive free radical as well as excellent protection effects against
damage induced by H2O2, which are more potent than 1. In addi-
The triethylamine (1.2 mmol) was added to the solution of aro-
matic amines 5a–k (1 mmol) and chlorosulfonyl-acetic acid
methyl ester 4 (1 mmol) in THF (15 mL) and stirred at RT until ab-
sence of the aromatic amines (checked by TLC). The reaction mix-
ture was concentrated in vacuo and diluted with H2O2, followed by

X. Ning et al. / Bioorg. Med. Chem. 21 (2013) 5589–5597
5593
neutralization with 5% HCl to pH 7 and extracting with ethyl ace-
tate. The combined organic fractions were washed with brine,
dried (Na2SO4), and concentrated under reduced pressure. Purifica-
tion of the crude residue by column chromatography (petroleum
ether/ethyl acetate) afforded the title compound.
d = 164.54, 138.07, 132.99, 129.56, 128.13, 55.49, 53.08, 47.54,
21.14. MS (ESI) m/z: 256.2158 [MꢀH]ꢀ.
4.1.2.9. (4-Methoxy-benzylsulfamoyl)-acetic acid methyl ester
(6i).
White solid (93%), mp 82–83 °C. 1H NMR (400 MHz,
CDCl3) d = 6.89–7.31 (m, 4H, ArH), 5.19 (s, 1H, NH), 4.31 (s, 1H, SO2-
CH2COOCH3), 4.29 (s, 1H, SO2CH2COOCH3), 3.89 (s, 2H, ArCH2), 3.83
(s, 3H, COOCH3), 3.79 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3)
d = 164.56, 159.57, 129.58, 128.01, 114.26, 55.48, 55.33, 53.08,
47.30. MS (ESI) m/z: 272.2048 [MꢀH]ꢀ.
4.1.2.1.
(6a).
Benzylsulfamoyl-acetic
acid
methyl
ester
White solid (93%), mp 50–51 °C. 1H NMR (400 MHz,
CDCl3) d = 7.33–7.40 (m, 5H, ArH), 5.17 (s, 1H, NH), 4.38 (s, 1H, SO2-
CH2COOCH3), 4.37 (s, 1H, SO2CH2COOCH3), 3.91 (s, 2H, ArCH2), 3.80
(s, 3H, COOCH3).
4.1.2.10.
methyl ester (6j).
[2-(4-Chloro-phenyl)-ethylsulfamoyl]-acetic
acid
4.1.2.2.
(6b).
Phenethylsulfamoyl-acetic
acid
methyl
ester
White solid (98%), mp 76–77 °C. 1H NMR
White solid (90%), mp 63–64 °C. 1H NMR (400 MHz,
(400 MHz, CDCl3) d = 7.17–7.33 (m, 4H, ArH), 4.82 (s, 1H, NH),
3.96 (s, 2H, SO2CH2COOCH3), 3.79 (s, 3H, SO2CH2COOCH3), 3.43
(q, 2H, ArCH2CH2SO2), 2.90 (t, 2H, ArCH2CH2SO2). MS (ESI) m/z:
290.1635 [MꢀH]ꢀ.
CDCl3) d = 7.23–7.35 (m, 5H, ArH), 4.75 (s, 1H, NH), 3.92 (s, 2H, SO2-
CH2COOCH3), 3.77 (s, 3H, SO2CH2COOCH3), 3.47 (q, 2H, ArCH2CH2-
SO2), 2.93 (t, 2H, ArCH2CH2SO2). MS (ESI) m/z: 256.2142 [MꢀH]ꢀ.
4.1.2.3. (3-Phenyl-propylsulfamoyl)-acetic acid methyl ester
(6c).
4.1.2.11. (Methyl-phenethyl-sulfamoyl)-acetic acid methyl ester
(6k).
Yellow liquid (88%). 1H NMR (400 MHz, CDCl3)
Colorless liquid (96%), mp 134–135°C. 1H NMR
d = 7.20–7.33 (m, 5H, ArH), 5.01 (s, 1H, NH), 4.01 (s, 2H, SO2CH2-
COOCH3), 3.81 (s, 3H, SO2CH2COOCH3), 3.19 (q, 2H, ArCH2CH2CH2-
SO2), 2.72 (t, 2H, ArCH2CH2CH2SO2), 1.94 (m, 2H,
ArCH2CH2CH2SO2). 13C NMR (100 MHz, CDCl3) d = 169.50, 145.79,
133.54, 133.39, 131.18, 59.97, 58.12, 48.16, 37.67, 36.53. MS (ESI)
m/z: 270.2258 [MꢀH]ꢀ.
(400 MHz, CDCl3) d = 7.24–7.33 (m, 5H, ArH), 3.83 (s, 2H, SO2CH2-
COOCH3), 3.79 (s, 3H, COOCH3), 3.49 (t, 2H, ArCH2CH2SO2), 2.95
(s, 3H, NCH3), 2.92 (t, 2H, ArCH2CH2SO2).
4.1.3. General procedure for the synthesis of aromatic
sulfamoyl-acetic acids (7a–k)
A solution of Na2CO3 (1 mmol) in MeOH (5 mL) was added
dropwise to the solution of aromatic sulfamoyl-acetic acid methyl
ester 6a–k (1 mmol) in MeOH (10 mL) and the solution was stirred
at RT until absence of the aromatic sulfamoyl-acetic acid methyl
ester (checked by TLC). The reaction mixture was concentrated in
vacuo and diluted with H2O, followed by neutralization with 5%
HCl to pH 7 and extracting with ethyl acetate. The combined or-
ganic fractions were washed with brine, dried (Na2SO4), and con-
centrated under reduced pressure. The crude residue is purified
by recrystallizing from petroleum ether and ethyl acetate to obtain
the title compound.
4.1.2.4. (4-Phenyl-butylsulfamoyl)-acetic acid methyl ester
(6d).
Colorless liquid (86%). 1H NMR (400 MHz, CDCl3)
d = 7.18–7.32 (m, 5H, ArH), 4.93 (s, 1H, NH), 4.00 (s, 2H, SO2CH2-
COOCH3), 3.80 (s, 3H, SO2CH2COOCH3), 3.18 (q, 2H, ArCH2CH2CH2-
CH2SO2), 2.66 (m, 2H, ArCH2CH2CH2CH2SO2), 1.72 (m, 2H,
ArCH2CH2CH2CH2SO2), 1.64 (m, 2H, ArCH2CH2CH2CH2SO2). 13C
NMR (100 MHz, CDCl3) d = 169.51, 146.77, 133.39, 130.92, 59.95,
58.09, 48.57, 40.27, 34.43, 33.18. MS (ESI) m/z: 284.2364 [MꢀH]ꢀ.
4.1.2.5. (4-Chloro-benzylsulfamoyl)-acetic acid methyl ester
(6e).
White solid (95%), mp 85–86 °C. 1H NMR (400 MHz,
CDCl3) d = 7.32–7.37 (m, 4H, ArH), 5.26 (s, 1H, NH), 4.34 (s, 1H, SO2-
CH2COOCH3), 4.33 (s, 1H, SO2CH2COOCH3), 3.95 (s, 2H, ArCH2), 3.80
(s, 3H, COOCH3). 13C NMR (100 MHz, CDCl3) d = 164.53, 134.66,
134.16, 129.44, 129.07, 55.54, 53.21, 47.01. MS (ESI) m/z:
276.1536 [MꢀH]ꢀ.
4.1.3.1. Benzylsulfamoyl-acetic acid (7a).
White solid (85%),
mp 155–156 °C. 1H NMR (400 MHz, DMSO-d6) d = 13.16 (s, 1H,
COOH), 7.89 (s, 1H, NH), 7.26–7.35 (m, 5H, ArH), 4.19 (s, 2H, SO2-
CH2 COOH), 4.04 (s, 2H, ArCH2).
4.1.3.2. Phenethylsulfamoyl-acetic acid (7b).
White solid
4.1.2.6. (4-Trifluoromethyl-benzylsulfamoyl)-acetic acid methyl
(82%), mp 135–136 °C. 1H NMR (400 MHz, DMSO-d6) d = 13.09 (s,
1H, COOH), 7.42 (s, 1H, NH), 7.21–7.32 (m, 5H, ArH), 4.03 (s, 2H,
SO2CH2COOH), 3.21 (q, 2H, ArCH2CH2SO2), 2.78 (t, 2H, ArCH2CH2-
SO2). 13C NMR (100 MHz, DMSO-d6) d = 165.43, 139.29, 129.18,
128.80, 126.71, 55.91, 44.66, 36.27.
ester (6f).
White solid (95%), mp 108–109 °C. 1H NMR
(400 MHz, CDCl3) d = 7.50–7.65 (m, 4H, ArH), 5.52 (s, 1H, NH),
4.43 (s, 1H, SO2CH2COOCH3), 4.41 (s, 1H, SO2CH2COOCH3), 3.99
(s, 2H, ArCH2), 3.78 (s, 3H, COOCH3). 13C NMR (100 MHz, CDCl3)
d = 164.45, 140.47, 128.20, 125.84, 125.81, 125.77, 55.74, 53.18,
46.99. MS (ESI) m/z: 310.1673 [MꢀH]ꢀ.
4.1.3.3. (3-Phenyl-propylsulfamoyl)-acetic acid (7c).
White
solid (82%), mp 125–126 °C. 1H NMR (400 MHz, DMSO-d6)
d = 13.07 (s, 1H, COOH), 7.40 (s, 1H, NH), 7.16–7.30 (m, 5H, ArH),
4.04 (s, 2H, SO2CH2COOH), 2.99 (m, 2H, ArCH2CH2CH2SO2), 2.61
(q, 2H, ArCH2CH2CH2SO2), 1.75 (m, 2H, ArCH2CH2CH2SO2).
4.1.2.7. (4-Fluoro-benzylsulfamoyl)-acetic acid methyl ester
(6g).
White solid (98%), mp 74–75 °C. 1H NMR (400 MHz,
CDCl3) d = 7.00–7.35 (m, 4H, ArH), 5.65 (s, 1H, NH), 4.30 (s, 1H, SO2-
CH2COOCH3), 4.29 (s, 1H, SO2CH2COOCH3), 3.92 (s, 2H, ArCH2),
3.74(s, 3H, COOCH3). 13C NMR (100 MHz, CDCl3) d = 169.45,
137.28, 137.26, 134.91, 134.83, 120.79, 120.57, 60.78, 58.11,
51.81. MS (ESI) m/z: 260.1888 [MꢀH]ꢀ.
4.1.3.4. (4-Phenyl-butylsulfamoyl)-acetic acid (7d).
White
solid (87%), mp 117–118 °C. 1H NMR (400 MHz, DMSO-d6)
d = 13.13 (s, 1H, COOH), 7.17–7.29 (m, 6H, ArH, NH), 4.02 (s, 2H,
SO2CH2 COOH), 2.99 (q, 2H, ArCH2CH2CH2CH2SO2), 2.60 (m, 2H,
ArCH2CH2CH2CH2SO2), 1.59 (m, 2H, ArCH2CH2CH2CH2SO2), 1.47
(m, 2H, ArCH2CH2CH2CH2SO2). 13C NMR (100 MHz, DMSO-d6)
d = 170.45, 147.54, 133.75, 133.70, 131.12, 61.78, 47.89, 40.11,
36.16, 34.54, 33.50. MS (ESI) m/z: 272.1094 [M+H]+.
4.1.2.8. (4-Methyl-benzylsulfamoyl)-acetic acid methyl ester
(6h).
White solid (96%), mp 95–96 °C. 1H NMR (400 MHz,
CDCl3) d = 7.18–7.28 (m, 4H, ArH), 5.22 (s, 1H, NH), 4.33 (s, 1H, SO2-
CH2COOCH3), 4.31 (s, 1H, SO2CH2COOCH3), 3.90 (s, 2H, ArCH2), 3.79
(s, 3H, COOCH3), 2.37 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3)

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X. Ning et al. / Bioorg. Med. Chem. 21 (2013) 5589–5597
4.1.3.5. (4-Chloro-benzylsulfamoyl)-acetic acid (7e).
White
123.44, 121.64, 116.17, 115.40, 46.39. HRMS ESI+ m/z 306.07946
solid (83%), mp 153–154 °C. 1H NMR (400 MHz, DMSO-d6)
d = 13.19 (s, 1H, COOH), 7.97 (s, 1H, NH), 7.35–7.43 (m, 4H, ArH),
4.20 (s, 1H, SO2CH2COOH), 4.18 (s, 1H, SO2CH2COOH), 4.08 (s, 2H,
ArCH2).
[M+H]+. Found: 306.07922 [M+H]+.
4.1.4.2. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid phen-
ethyl-amide (8b).
White solid (60%), mp 158–159 °C. 1H
NMR (400 MHz, DMSO-d6) d = 9.61 (s, 1H, p-ArOH), 9.13 (s, 1H,
m-ArOH), 6.71–7.30 (m, 11H, ArH, ArCH@CHSO2, NH), 3.07 (q, 2H,
ArCH2CH2SO2), 2.76 (t, 2H, ArCH2CH2SO2). 13C NMR (100 MHz,
DMSO-d6) d = 148.64, 146.04, 140.26, 139.39, 129.17, 128.79,
126.69, 124.60, 123.10, 121.71, 116.14, 115.43, 44.37, 36.07. HRMS
ESI+ m/z 320.09511 [M+H]+. Found: 320.09518 [M+H]+.
4.1.3.6.
(7f).
(4-Trifluoromethyl-benzylsulfamoyl)-acetic
acid
White solid (85%). 1H NMR (400 MHz, DMSO-d6)
d = 13.22 (s, 1H, COOH), 8.07 (s, 1H, NH), 7.58–7.74 (m, 4H, ArH),
4.32 (s, 2H, SO2CH2COOH), 4.15 (s, 2H, ArCH2). 13C NMR
(100 MHz, DMSO-d6) d = 165.39, 143.83, 128.62, 128.43, 128.11,
126.12, 125.67, 125.63, 57.26, 46.06.
4.1.4.3. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid (3-phe-
4.1.3.7. (4-Fluoro-benzylsulfamoyl)-acetic acid (7g).
White
nyl-propyl)-amide (8c).
White solid (59%), mp 126–127 °C.
solid (83%), mp 171–172 °C. 1H NMR (400 MHz, DMSO-d6)
d = 13.17 (s, 1H, COOH), 7.92 (s, 1H, NH), 7.15–7.40 (m, 4H, ArH),
4.19 (s, 1H, SO2CH2COOH), 4.18 (s, 1H, SO2CH2COOH), 4.06 (s, 2H,
ArCH2).
1H NMR (400 MHz, DMSO-d6) d = 9.57 (s, 1H, p-ArOH), 9.18 (s,
1H, m-ArOH), 6.94–7.26 (m, 10H, ArH, ArCH@CHSO2), 4.55 (s, 1H,
NH), 3.35 (m, 2H, ArCH2CH2CH2SO2), 2.86 (m, 2H, ArCH2CH2CH2-
SO2), 2.60 (m, 2H, ArCH2CH2CH2SO2). 13C NMR (100 MHz, DMSO-
d6) d = 148.65, 146.07, 141.97, 140.25, 128.77, 128.73, 126.21,
124.62, 123.22, 121.67, 116.19, 115.41, 68.98, 56.29, 42.30, 32.66,
32.56, 31.60, 30.07. HRMS ESI+ m/z 334.11076 [M+H]+. Found:
334.11075 [M+H]+.
4.1.3.8. (4-Methyl-benzylsulfamoyl)-acetic acid (7h).
White
solid (86%), mp 157–158 °C. 1H NMR (400 MHz, DMSO-d6)
d = 13.14 (s, 1H, COOH), 7.84 (s, 1H, NH), 7.14–7.24 (m, 4H, ArH),
4.15 (s, 1H, SO2CH2COOH), 4.14 (s, 1H, SO2CH2COOH), 4.02 (s, 2H,
ArCH2), 2.29(s, 3H, CH3).
4.1.4.4. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid (4-phe-
nyl-butyl)-amide (8d).
White solid (68%), mp 129–130 °C. 1H
4.1.3.9. (4-Methoxy-benzylsulfamoyl)-acetic acid (7i).
White
NMR (400 MHz, DMSO-d6) d = 9.59 (s, 1H, p-ArOH), 9.13 (s, 1H, m-
ArOH), 6.73–7.27 (m, 10H, ArH, ArCH@CHSO2), 2.86 (q, 2H, ArCH2-
CH2CH2CH2SO2), 2.54 (m, 2H, ArCH2CH2CH2CH2SO2), 1.58 (m, 2H,
ArCH2CH2CH2CH2SO2), 1.46 (m, 2H, ArCH2CH2CH2CH2SO2). 13C
NMR (100 MHz, DMSO-d6) d = 148.61, 146.06, 142.47, 140.06,
128.73, 128.67, 126.11, 124.64, 123.32, 121.62, 116.18, 115.40,
42.58, 35.13, 29.44, 28.54. HRMS ESI+ m/z 348.12641 [M+H]+.
Found: 348.12619 [M+H]+.
solid (86%). 1H NMR (400 MHz, DMSO-d6) d = 13.14 (s, 1H, COOH),
7.84 (s, 1H, NH), 7.14–7.24 (m, 4H, ArH), 4.15 (s, 1H, SO2CH2COOH),
4.14 (s, 1H, SO2CH2COOH), 4.02 (s, 2H, ArCH2), 2.29 (s, 3H, CH3).
4.1.3.10.
(7j).
[2-(4-Chloro-phenyl)-ethylsulfamoyl]-acetic
acid
White solid (88%), mp 153–154 °C. 1H NMR (400 MHz,
DMSO-d6) d = 13.14 (s, 1H, COOH), 7.45 (s, 1H, NH), 7.26–7.37 (m,
4H, ArH), 4.05 (s, 2H, SO2CH2COOH), 3.20 (q, 2H, ArCH2CH2SO2),
2.77 (t, 2H, ArCH2CH2SO2). 13C NMR (100 MHz, DMSO-d6)
d = 165.49, 138.35, 131.35, 131.16, 128.70, 56.78, 44.36, 35.39.
4.1.4.5. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid 4-chloro-
benzylamide (8e).
White solid (61%), mp 154–155 °C. 1H
NMR (400 MHz, DMSO-d6) d = 9.61 (s, 1H, p-ArOH), 9.13 (s, 1H,
m-ArOH), 7.75 (t, 1H, NH), 6.73–7.40 (m, 9H, ArH, ArCH@CHSO2),
4.08 (s, 1H, ArCH2SO2), 4.06 (s, 1H, ArCH2SO2). 13C NMR
(100 MHz, DMSO-d6) d = 148.68, 146.04, 140.38, 137.91, 132.13,
129.93, 128.67, 124.57, 123.30, 121.65, 116.16, 115.45, 45.61.
HRMS ESI+ m/z 340.04048 [M+H]+. Found: 340.04013 [M+H]+.
4.1.3.11.
(7k).
(Methyl-phenethyl-sulfamoyl)-acetic
acid
White solid (90%), mp 46–47 °C. 1H NMR (400 MHz,
DMSO-d6) d = 13.23 (s, 1H, COOH), 7.21–7.33 (m, 5H, ArH), 4.09
(s, 2H, SO2CH2COOH), 3.35 (t, 2H, ArCH2CH2SO2), 2.84 (t, 2H, ArCH2-
CH2SO2), 2.09 (s, 3H, NCH3). 13C NMR (100 MHz, DMSO-d6)
d = 165.34, 139.02, 129.26, 128.86, 126.80, 54.40, 51.84, 35.24,
34.62, 31.17.
4.1.4.6. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid 4-trifluo-
romethyl -benzylamide (8f).
White solid (75%), mp 173–
4.1.4. General procedure for the synthesis of E-3,4-dihydroxy
styryl sulfonamides (8a–k)
174 °C. 1H NMR (400 MHz, DMSO-d6) d = 9.61 (s, 1H, p-ArOH),
9.12 (s, 1H, m-ArOH), 7.85 (t, 1H, NH), 6.75–7.70 (m, 9H, ArH,
ArCH@CHSO2), 4.19 (s, 1H, ArCH2SO2), 4.17 (s, 1H, ArCH2SO2). 13C
NMR (100 MHz, DMSO-d6) d = 148.71, 146.04, 143.83, 140.51,
128.73, 125.61, 125.54, 124.53, 123.43, 123.21, 121.63, 116.14,
115.49, 45.80. HRMS ESI+ m/z 374.06684 [M+H]+. Found:
374.06689 [M+H]+, 391.09335 [M+NH4]+.
The 3,4-dihydroxy benzaldehyde (2.2 mmol), the pyrrolidine
(catalytic amount) and acetic acid (catalytic amount) were added
to a solution of the aromatic sulfamoyl-acetic acid 7a–k (2 mmol)
solution in THF (15 mL) and heated to reflux until no longer reduc-
ing of the 3,4-dihydroxy benzaldehyde (checked by TLC). The reac-
tion mixture was concentrated in vacuo, diluted with H2O and
extracted with ethyl acetate. The combined organic fractions were
washed with brine, dried (Na2SO4), and concentrated under re-
duced pressure. Purification of the crude residue by column chro-
matography (petroleum ether/ethyl acetate) afforded the title
compound.
4.1.4.7. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid 4-Fluoro-
benzylamide (8g).
White solid (65%), mp 155–156 °C. 1H
NMR (400 MHz, DMSO-d6) d = 9.62 (s, 1H, p-ArOH), 9.14 (s, 1H,
m-ArOH), 7.72 (t, 1H, NH), 6.72–7.39 (m, 9H, ArH, ArCH@CHSO2),
4.07 (s, 1H, ArCH2SO2), 4.06 (s, 1H, ArCH2SO2). 13C NMR
(100 MHz, DMSO-d6) d = 148.66, 146.04, 140.30, 134.96, 130.13,
130.05, 124.58, 123.35, 121.65, 116.15, 115.56, 115.40, 115.35,
45.61. HRMS ESI+ m/z 324.07003 [M+H]+. Found: 324.06985
[M+H]+, 341.09666 [M+NH4]+, 346.05214 [M+Na]+.
4.1.4.1. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid benzyla-
mide (8a).
White solid (50%), mp 136–137 °C. 1H NMR
(400 MHz, DMSO-d6) d = 9.59 (s, 1H, p-ArOH), 9.13 (s, 1H, m-ArOH),
7.70 (t, 1H, NH), 6.71–7.69 (m, 10H, ArH, ArCH@CHSO2), 4.09 (s, 1H,
ArCH2SO2), 4.07 (s, 1H, ArCH2SO2). 13C NMR (100 MHz, DMSO-d6)
d = 148.65, 146.04, 140.19, 138.73, 128.11, 127.56, 124.62,
4.1.4.8. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid 4-
Methyl-benzylamide (8h).
White solid (61%), mp 116–
117 °C. 1H NMR (400 MHz, DMSO-d6) d = 9.60 (s, 1H, p-ArOH),

X. Ning et al. / Bioorg. Med. Chem. 21 (2013) 5589–5597
5595
9.13 (s, 1H, m-ArOH), 7.64 (t, 1H, NH), 6.66–7.22 (m, 9H, ArH,
ArCH@CHSO2), 4.04 (s, 1H, ArCH2SO2), 4.02 (s, 1H, ArCH2SO2),
2.26 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) d = 148.61,
146.03, 140.65, 136.70, 135.61, 129.28, 128.14, 124.62, 123.49,
121.63, 116.14, 115.36, 46.21, 21.12. HRMS ESI+ m/z 342.07705
[M+Na]+. Found: 342.07713 [M+Na]+.
137.64, 131.36, 128.87, 126.96, 126.62, 126.22, 124.15, 122.98,
44.12, 36.15, 30.95, 20.67, 20.63. HRMS ESI+ m/z 404.11623
[M+H]+. Found: 404.11678 [M+H]+.
4.1.5.3. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid (3-phe-
nyl-propyl)-amide (9c).
White solid (96%), mp 104–105 °C.
1H NMR (400 MHz, CDCl3) d = 7.42 (d, J = 15.2 Hz, 1H,
ArCH@CHSO2), 7.17–7.38 (m, 8H, ArH), 6.68 (d, J = 15.2 Hz, 1H,
ArCH@CHSO2), 4.33 (t, 1H, NH), 3.09 (q, 2H, ArCH2CH2CH2SO2),
2.70 (m, 2H, ArCH2CH2CH2SO2), 2.34 (s, 6H, 2ArOCOCH3), 1.93
(m, 2H, ArCH2CH2CH2SO2). 13C NMR (100 MHz, CDCl3) d = 168.03,
167.90, 143.94, 142.60, 140.72, 139.79, 131.38, 128.57, 128.37,
126.57, 126.22, 124.19, 122.96, 42.52, 32.77, 31.49, 20.62. HRMS
ESI+ m/z 418.13188 [M+H]+. Found: 418.13259 [M+H]+,
440.11451 [M+Na]+.
4.1.4.9. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid 4-Meth-
oxy-benzylamide (8i).
White solid (63%), mp 161–162 °C. 1H
NMR (400 MHz, DMSO-d6) d = 9.59 (s, 1H, p-ArOH), 9.13 (s, 1H, m-
ArOH), 7.60 (t, 1H, NH), 6.66–7.25 (m, 9H, ArH, ArCH@CHSO2), 4.01
(s, 1H, ArCH2SO2), 4.00 (s, 1H, ArCH2SO2), 3.71 (s, 3H, OCH3). 13C
NMR (100 MHz, DMSO-d6) d = 158.90, 148.61, 146.03, 140.05,
130.52, 129.49, 124.63, 123.53, 121.60, 116.14, 115.38, 114.14,
55.51, 45.94. HRMS ESI+ m/z 358.07196 [M+Na]+. Found:
358.07176 [M+Na]+.
4.1.5.4. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid (4-phe-
4.1.4.10. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid [2-(4-
nyl-butyl)-amide (9d).
White solid (93%), mp 70–71 °C. 1H
chloro-phenyl)-ethyl]-amide (8j).
White solid (65%), mp
NMR (400 MHz, CDCl3) d = 7.42 (d, J = 15.6 Hz, 1H, ArCH@CHSO2),
7.16–7.38 (m, 8H, ArH), 6.68 (d, J = 15.6 Hz, 1H, ArCH@CHSO2),
4.35 (t, 1H, NH), 3.07 (q, 2H, ArCH2CH2CH2CH2SO2), 2.65 (m, 2H,
ArCH2CH2CH2CH2SO2), 2.34 (s, 6H, 2ArOCOCH3), 1.68 (m, 2H,
ArCH2CH2CH2CH2SO2), 1.62 (m, 2H, ArCH2CH2CH2CH2SO2). 13C
NMR (100 MHz, CDCl3) d = 168.05, 167.92, 143.91, 142.59,
141.73, 139.66, 131.41, 128.40, 126.55, 126.31, 125.93, 124.19,
122.97, 42.97, 35.28, 29.50, 28.29, 20.66. HRMS ESI+ m/z
423.14753 [M+H]+. Found: 432.14842 [M+H]+.
153–154 °C. 1H NMR (400 MHz, DMSO-d6) d = 9.61 (s, 1H, p-ArOH),
9.13 (s, 1H, m-ArOH), 6.71–7.34 (m, 10H, ArH, ArCH@CHSO2, NH),
3.07 (q, 2H, Ar CH2CH2SO2), 2.76 (t, 2H, ArCH2 CH2SO2). 13C NMR
(100 MHz, DMSO-d6) d = 148.65, 146.05, 140.30, 138.43, 131.34,
131.13, 128.67, 124.59, 123.04, 121.65, 116.17, 115.48, 44.06,
35.23. HRMS ESI+ m/z 354.05613 [M+H]+. Found: 354.05614
[M+H]+.
4.1.4.11. 2-(3,4-Dihydroxy-phenyl)-ethenesulfonic acid methyl-
phenethyl-amide (8k).
White solid (68%), mp 103–104 °C. 1H
4.1.5.5. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid 4-chloro-
benzylamide (9e).
NMR (400 MHz, DMSO-d6) d = 9.66 (s, 1H, p-ArOH), 9.09 (s, 1H, m-
ArOH), 6.75–7.32 (m, 10H, ArH, ArCH@CHSO2), 3.26 (t, 2H, ArCH2-
CH2SO2), 2.85 (t, 2H, ArCH2CH2SO2), 2.73 (s, 3H, NCH3). 13C NMR
(100 MHz, DMSO-d6) d = 148.86, 146.02, 142.45, 139.20, 129.25,
128.83, 126.75, 124.64, 121.99, 119.37, 116.07, 115.77, 51.49,
35.01, 34.34. HRMS ESI+ m/z 334.11076 [M+H]+. Found:
334.11082 [M+H]+.
White solid (92%), mp 109–110 °C. 1H
NMR (400 MHz, CDCl3) d = 7.40 (d, J = 15.2 Hz, 1H, ArCH@CHSO2),
7.25–7.34 (m, 7H, ArH), 6.62 (d, J = 15.2 Hz, 1H, ArCH@CHSO2),
4.84 (t, 1H, NH), 4.23 (s, 1H, ArCH2SO2), 4.21(s, 1H, ArCH2SO2),
2.34 (s, 3H, p-ArOCOCH3), 2.33 (s, 3H, m-ArOCOCH3). 13C NMR
(100 MHz, CDCl3) d = 168.09, 167.95, 143.99, 142.58, 139.92,
135.06, 133.97, 131.22, 129.39, 129.01, 126.63, 126.38, 124.23,
122.95, 46.45, 20.67. HRMS ESI+ m/z 424.06161 [M+H]+. Found:
424.06160 [M+H]+, 441.08837 [M+NH4]+.
4.1.5. General procedure for the synthesis of E-3,4-diacetyl
styryl sulfonamides (9a–k)
The E-3,4-dihydroxy styryl sulfonamide 8a–k (1 mmol) was
added to a solution of the pyridine (2.2 mmol) solution in acetic
anhydride (3 mL) and stirred at RT until absence of the E-3,4-dihy-
droxy styryl sulfonamide (checked by TLC). The reaction mixture
was diluted with H2O and extracted with ethyl acetate. The com-
bined organic fractions were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. Purification of the crude
residue by column chromatography (petroleum ether/ethyl ace-
tate) afforded the title compound.
4.1.5.6. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid 4-trifluo-
romethyl-benzylamide (9f).
White solid (96%), mp 115–
116 °C. 1H NMR (400 MHz, CDCl3) d = 7.25–7.63 (m, 8H, ArH,
ArCH@CHSO2), 6.63 (d, J = 15.6 Hz, 1H, ArCH@CHSO2), 4.92 (t, 1H,
NH), 4.33 (s, 1H, ArCH2SO2), 4.31 (s, 1H, ArCH2SO2), 2.34 (s, 6H,
2ArOCOCH3). 13C NMR (100 MHz, CDCl3) d = 168.09, 167.93,
144.06, 142.61, 140.65, 140.12, 131.11, 128.21, 126.63, 126.24,
125.82, 125.78, 124.24, 122.94, 46.55, 20.66, 20.62. HRMS ESI+ m/
z
458.08797 [M+H]+. Found: 458.08860 [M+H]+, 475.11516
[M+NH4]+.
4.1.5.1. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid benzyla-
mide (9a).
White solid (94%), mp 109–110 °C. 1H NMR
4.1.5.7. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid 4-fluoro-
benzylamide (9g).
(400 MHz, CDCl3) d = 7.22–7.44 (m, 9H, ArH, ArCH@CHSO2), 6.63
(d, J = 15.2 Hz, 1H, ArCH@CHSO2), 4.73 (t, 1H, NH), 4.28 (s, 1H,
ArCH2SO2), 4.26 (s, 1H, ArCH2SO2), 2.34 (s, 6H, 2ArOCOCH3). 13C
NMR (100 MHz, CDCl3) d = 168.02, 167.91, 143.93, 142.55,
139.72, 136.43, 131.36, 128.90, 128.18, 128.12, 128.01, 126.58,
126.55, 124.15, 122.99, 47.18, 20.65. HRMS ESI+ m/z 390.10058
[M+H]+. Found: 390.10151 [M+H]+, 412.08310 [M+Na]+.
White solid (94%), mp 99–100 °C. 1H NMR
(400 MHz, CDCl3) d = 7.43 (d, J = 15.2 Hz, 1H, ArCH@CHSO2), 7.03–
7.34 (m, 7H, ArH), 6.63 (d, J = 15.2Hz, 1H, ArCH@CHSO2), 4.71 (t,
1H, NH), 4.24 (s, 1H, ArCH2SO2), 4.23 (s, 1H, ArCH2SO2), 2.35 (s,
3H, p-ArOCOCH3), 2.34 (s, 3H, m-ArOCOCH3). 13C NMR (100 MHz,
CDCl3) d = 168.07, 167.93, 143.99, 142.59, 139.89, 132.30, 132.27,
131.25, 129.83, 129.75, 126.63, 126.42, 124.22, 122.94, 115.91,
115.70, 46.46, 20.67. HRMS ESI+ m/z 408.09116 [M+H]+. Found:
408.09177 [M+H]+, 425.11823 [M+NH4]+.
4.1.5.2. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid phen-
ethyl-amide (9b).
White solid (92%), mp 56–57°C. 1H NMR
(400 MHz, CDCl3) d = 7.39 (d, J = 15.6 Hz, 1H, ArCH@CHSO2),
7.19–7.35 (m, 8H, ArH), 6.54 (d, J = 15.6 Hz, 1H, ArCH@CHSO2),
4.37 (t, 1H, NH), 3.35 (q, 2H, ArCH2CH2SO2), 2.89 (t, 2H, ArCH2CH2-
SO2), 2.34 (s, 3H, p-ArOCOCH3), 2.33 (s, 3H, m-ArOCOCH3). 13C NMR
(100 MHz, CDCl3) d = 168.05, 167.93, 143.91, 142.55, 139.63,
4.1.5.8. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid 4- Methyl
-benzylamide (9h).
(400 MHz, CDCl3) d = 7.38 (d, J = 15.6 Hz, 1H, ArCH@CHSO2), 7.14–
7.32 (m, 7H, ArH), 6.59 (d, J = 15.6 Hz, 1H, ArCH@CHSO2), 4.65 (t,
1H, NH), 4.23 (s, 1H, ArCH2SO2), 4.22 (s, 1H, ArCH2SO2), 2.34 (s,
White solid (95%), mp 98–99 °C. 1H NMR

5596
X. Ning et al. / Bioorg. Med. Chem. 21 (2013) 5589–5597
3H, p-ArOCOCH3), 2.33 (s, 3H, m-ArOCOCH3), 2.32 (s, 3H, CH3). 13C
NMR (100 MHz, CDCl3) d = 168.04, 167.95, 143.87, 142.53, 139.55,
137.95, 133.36, 131.41, 129.54, 128.06, 126.63, 126.56, 124.13,
122.93, 46.99, 21.06, 20.67, 20.64. HRMS ESI+ m/z 404.09818
[M+H]+. Found: 404.11683 [M+H]+, 426.09894 [M+Na]+.
5% horse serum, 100U mLꢀ1 penicillin and 100U mLꢀ1 streptomy-
cin in a humidified atmosphere of 5% CO2 at 37 °C. PC12 cells were
seeded into 96-well microplates at a density of 4 ꢁ 105 cells mLꢀ1
(100 lL per well). After 24 h of incubation to allow for cell attach-
ment, the PC12 cells were preincubated with samples for 3 h,
which were dissolved in DMSO and diluted with medium to the fi-
4.1.5.9. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid 4-meth-
oxy-benzylamide (9i).
nal concentrations. Then, 20 L of H2O2 (diluted with medium to a
final concentration of 500 lM) solution was added. After 5 h, the
l
White solid (94%), mp 96–97 °C. 1H
NMR (400 MHz, CDCl3) d = 7.37 (d, J = 15.6 Hz, 1H, ArCH@CHSO2),
6.85–7.31 (m, 7H, ArH), 6.58 (d, J = 15.6 Hz, 1H, ArCH@CHSO2),
4.79 (t, 1H, NH), 4.20(s, 1H, ArCH2SO2), 4.18 (s, 1H, ArCH2SO2),
3.77 (s, 3H, OCH3), 2.34 (s, 3H, p-ArOCOCH3), 2.33 (s, 3H, m-ArO-
COCH3). 13C NMR (100 MHz, CDCl3) d = 168.07, 167.96, 159.41,
143.86, 142.53, 139.48, 131.42, 129.49, 128.45, 126.70, 126.57,
124.13, 122.93, 114.22, 55.31, 46.72, 20.67, 20.63. HRMS ESI+ m/z
442.09309 [M+Na]+. Found: 442.09358 [M+Na]+.
cell viability was measured with MTT assay. The absorbance was
determined at 570 nm using a microplate reader. Compared with
the normal cells, the viability of cells treated with drugs is calcu-
lated by the following formula: OD (drug-treated)/OD (normal
cells) ꢁ 100%.
4.2.3. Inhibiting effect on nitric oxide production in LPS-
stimulated BV2 microglial cells
BV2 microglial cells were purchased from Institute of Basic
Medicine, Chinese Academy of Medical Sciences. LPS was bought
from Sigma. BV2 microglial cells were maintained in high-glucose
DMEM supplemented with 5% fetal bovine serum, 100 UmLꢀ1 pen-
icillin and 100U mLꢀ1 streptomycin in a humidified atmosphere of
5% CO2 at 37 °C. BV2 microglial cells were seeded into 96-well
4.1.5.10. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid [2-(4-
chloro-phenyl)-ethyl]-amide (9j).
White solid (94%), mp
92–93 °C. 1H NMR (400 MHz, CDCl3) d = 7.39 (d, J = 15.2 Hz, 1H,
ArCH@CHSO2), 7.13–7.35 (m, 7H, ArH), 6.53 (d, J = 15.2 Hz, 1H,
ArCH@CHSO2), 4.33 (t, 1H, NH), 3.32(q, 2H, ArCH2CH2SO2), 2.87
(q, 2H, ArCH2CH2SO2), 2.34 (s, 3H, p-ArOCOCH3), 2.33 (s, 3H, m-
ArOCOCH3). 13C NMR (100 MHz, CDCl3) d = 168.09, 167.92,
143.97, 142.59, 139.81, 136.17, 132.79, 131.23, 130.26, 128.97,
126.62, 126.06, 124.23, 122.98, 43.99, 35.63, 20.66. HRMS ESI+ m/
microplates at a density of 4 ꢁ 105 cells mLꢀ1 (100
lL per well).
After 24 h of incubation to allow for cell attachment, the BV2
microglial cells were preincubated with samples for 3 h, which
were dissolved in DMSO and diluted with medium to the final con-
z
438.07726 [M+H]+. Found: 438.07768 [M+H]+, 460.06001
centrations. Then, 20 lL of LPS solution (diluted with medium to a
[M+Na]+.
final concentration of 100 nM) was added. After 24 h, the nitric
oxide assay kit was used to perform nitrite assays. The nitric oxide
assay kit was gained from Applygen. The culture media was mixed
with an equal volume of reagent of the nitric oxide assay kit in 96-
well plates. The absorbance was determined at 540 nm using a
microplate reader. The release amount of nitric oxide was calcu-
lated by the offered linear equation of the nitric oxide assay kit.
The percentage inhibition of nitric oxide was calculated from the
following formula: ½ðRL ꢀ R0 ꢀ RcÞ=ðRL ꢀ R0Þꢂ ꢁ 100%, where RL is
the release amount of only LPS treated group, R0 is the release
amount of normal control and Rc is the release amount of the test
compound and LPS treated group. The IC50 values of test
compounds were calculated by linear regression of plots where
the x-axis represented the various concentrations of test com-
pounds while the y-axis represented the percentage inhibition of
nitric oxide.
4.1.5.11. 2-(3,4-Diacetoxy-phenyl)-ethenesulfonic acid methyl-
phenethyl-amide (9k).
White solid (95%), mp 104–105 °C. 1H
NMR (400 MHz, CDCl3) d = 7.35 (d, J = 15.2 Hz, 1H, ArCH@CHSO2),
7.24–7.33 (m, 8H, ArH), 6.33 (d, J = 15.2 Hz, 1H, ArCH@CHSO2),
3.45 (t, 2H, ArCH2CH2SO2), 2.93 (t, 2H, ArCH2CH2SO2), 2.84 (s, 3H,
NCH3), 2.34 (s, 3H, p-ArOCOCH3), 2.33 (s, 3H, m-ArOCOCH3). 13C
NMR (100 MHz, CDCl3) d = 168.08, 167.94, 143.83, 142.52,
139.97, 138.26, 131.53, 128.96, 128.68, 126.70, 126.65, 124.10,
123.91, 122.88, 51.52, 34.97, 34.60, 20.66, 20.62. HRMS ESI+ m/z
418.13188 [M+H]+. Found: 418.13228 [M+H]+.
4.2. Biological assays
4.2.1. DPPH free radical scavenging activity
Free radical scavenging activity was studied using DPPH. The
DPPH were bought from Sigma. The reaction was carried out in
96-well microplates. Test compounds and DPPH were dissolved
4.2.4. In vitro BBB permeability assay
Prediction of crossing BBB was evaluated using PAMPA. PBL
(catalog no. 141101-p) was bought from Avanti Polar Lipids. Dode-
cane was obtained from Alfa Aesar. The 96-well filter plate (catalog
no. MAIPN4550) and the donor plate (catalog no. MATRNPS50)
were both from Millipore. Filter PDVF membrane units were from
Symta. Verapamil, Hydrocortisone and Clonidine were bought
from Sigma. Test compounds were dissolved in DMSO at
5 mg mLꢀ1. Ten microlitre of this compound stock solution was di-
luted in PBS to make secondary stock solution (final concentration
in ethanol. Various concentrations of test solutions (100
DPPH (100 L) were mixed in per well. The mixture of neat ethanol
(100 L) and DPPH (100 L) was used as experimental control. The
lL) and
l
l
l
final concentration of DPPH was 0.1 mM. After 30 min of incuba-
tion at room temperature, the reduction in the number of free
radical was measured by reading the absorbance at 517 nm. Vita-
min C was used as reference free radical scavenger. For statistical
viability, every sample was analyzed in three wells and in three
independent runs. The percentage inhibition was calculated from
the following formula: [(A0ꢀAc)/A0] ꢁ 100%, where A0 is absor-
bance of control and Ac is absorbance of the test sample.
25 l
g mLꢀ1) and these solutions were filtered. 300 mL of the sec-
ondary stock solution was added to the donor well. The filter mem-
brane was coated with PBL in dodecane (selected empirically as
4 l
L volume of 20 mg mLꢀ1 PBL in dodecane) and the acceptor well
4.2.2. Protection effect against H2O2-induced cell Injury
was filled with 150 mL of PBS. The acceptor filter plate was care-
fully put on the donor plate to form a ‘sandwich’ (consisting of
the donor with test compounds on the bottom, artificial lipid mem-
brane in the middle, and the acceptor on the top). The ‘sandwich’
was incubated undisturbed at room temperature for 18 h while
the permeation occurred. After incubation, the donor plate was re-
moved. UV plate reader determined the concentration of tested
compounds in the acceptor and reference solutions. Reference
The PC12 cells were bought from the Shanghai Institute of Cell
Biology, Chinese Academy of Sciences. Fetal bovine serum, trypsin–
EDTA, penicillin streptomycin were obtained from Invitrogen.
High-glucose DMEM and donor equine serum were obtained from
Thermo Scientific. H2O2 was purchased from Sigma. MTT and
DMSO were acquired from AMRESCO. PC12 cells were maintained
in high-glucose DMEM supplemented with 10% fetal bovine serum,

X. Ning et al. / Bioorg. Med. Chem. 21 (2013) 5589–5597
5597
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solutions were prepared by diluting the sample secondary stock
solution to the same concentration as that with no membrane bar-
rier. Every sample was analyzed at three wavelengths, in three
wells and in three independent runs. The permeability coefficient
through the artificial membrane (Pe) was calculated using the fol-
lowing equation.35,36
!
Vdn ꢁ Vac
½drugꢂac
½drugꢂref
Pe ¼ ꢀ
ln 1 ꢀ
stðVdn þ VacÞ
Vdn (mL) = volume of the donor compartment
Vac (mL) = volume of the acceptor compartment
[drug]ac = optical density of the solution of the acceptor
compartment
[drug]ref = optical density of the reference solution
s (cm2) = membrane area
t (s) = incubation time
Acknowledgements
This study was supported by the National Natural Science Foun-
dation of China (Grant nos. 20972011, 21042009 and 21172014)
and Ministry of Science and Technology of China (2009ZX09301-
010).
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Supplementary data
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