Synthesis and neuroprotective effect of E-3,4-dihydroxy styryl aralkyl ketones derivatives against oxidative stress and inflammation

Article abstract of DOI:10.1016/j.bmcl.2013.05.016

E-3,4-Dihydroxy styryl aralkyl ketones as well as their 3,4-diacetylated derivatives as the analogues of neuroprotective agent CAPE were designed and synthesized for improving stability and lipid solubility. The neuroprotective activities of target compounds 10a-g and 11a-g were tested by three models in vitro, including 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity, neuronal protecting effect against damage induced by H₂O₂ in PC12 cells and nitric oxide suppression effect in BV2 microglial cells. The results demonstrated that compounds 10f and 11f exhibited the most potent neuroprotective effect against oxidative stress and inflammation, which is higher than that of the lead compound CAPE.

Full text of DOI:10.1016/j.bmcl.2013.05.016

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3700–3703
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and neuroprotective effect of E-3,4-dihydroxy styryl aralkyl
ketones derivatives against oxidative stress and inflammation
Xianling Ning a, Ying Guo a, Xiaoyan Ma a, Renzong Zhu a, Chao Tian a, Xiaowei Wang a, Zhizhong Ma c,
Zhili Zhang a, , Junyi Liu a,b,
⇑
⇑
a Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
c Department of the Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
E-3,4-Dihydroxy styryl aralkyl ketones as well as their 3,4-diacetylated derivatives as the analogues of
neuroprotective agent CAPE were designed and synthesized for improving stability and lipid solubility.
The neuroprotective activities of target compounds 10a–g and 11a–g were tested by three models
in vitro, including 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity, neuronal protecting effect
against damage induced by H2O2 in PC12 cells and nitric oxide suppression effect in BV2 microglial cells.
The results demonstrated that compounds 10f and 11f exhibited the most potent neuroprotective effect
against oxidative stress and inflammation, which is higher than that of the lead compound CAPE.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 10 April 2013
Revised 3 May 2013
Accepted 7 May 2013
Available online 16 May 2013
Keywords:
E-3,4-Dihydroxy styryl aralkyl ketones
Caffeic acid phenethyl ester
Neuroprotective agents
Antioxidants
Anti-inflammatory
Oxidative stress and inflammation have been implicated in
many neurodegenerative diseases including Alzheimer’s disease
(AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis
(ALS).1,2 Oxidative stress induced by overproduction of reactive
oxygen species causes damage of basic components in nerve cells,
such as lipids, DNA and proteins.3 Inflammation also plays a vital
role in pathogenesis of neurodegenerative diseases. Although this
process is vital for normal function in the central nervous system
(CNS), it is postulated that this process may spiral out of control
with over activation of microglia, over production of cytokines
and other proinflammatory mediators such as inducible nitric
oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and tumour
necrosis factor (TNF)-alpha which at last result in cell injury.1 Re-
cently, the antioxidative and anti-inflammatory strategies have
shown promise in the treatment of neurodegenerative diseases.
Compound 1 (Caffeic acid phenethyl ester, CAPE) (Fig. 1) which
is the active component of the propolis produced by the hives of
honeybees is found to possess antioxidant,4 anti-inflammatory,5
antiviral,6 antibacterial,7 antiatherosclerotic,8 immunostimulatory9
and antitumor10 properties. The antioxidant property of 1 is re-
flected by means of blocking production of reactive oxygen species
and the xanthine/xanthine oxidase system.11 And the anti-inflam-
matory property is revealed through reducing prostaglandin and
leukotriene synthesis by inhibiting cyclooxygenase enzyme activ-
ity or the down-regulation of cyclooxygenase gene expression.12,13
It is deduced that both antioxidative and antiinflammatory proper-
ties of 1 can contribute to their neuroprotective effects in kinds of
neurodegeneration. Many recent studies have confirmed that 1 has
a neuroprotective property. Compound 1 is able to block 6-
hydroxydopamine,14 glutamate,15 spinal ischemia,16 hypoxia-
ischemic brain injury17,18 and low potassium19-induced neuronal
death in vivo models. Thus, 1 can be recognized as a promising
neuroprotective agent with multiple targets effects.
Although many preclinical studies have demonstrated biologi-
cal activities of 1 in vitro and vivo models, pharmacokinetic studies
show that 1 as an aryl ester is dramatically degraded by esterases
in rats after the rapid oral absorption.20 Additionally, with two
phenolic hydroxyl functions 1 has a poor solubility in lipophilic
environment, so most probably only small amount of 1 can pass
through blood–brain barrier (BBB). The aim of this study, therefore,
is to design and synthesize its analogues with better neuroprotec-
tive activity, stability and BBB permeability, and to discuss struc-
ture–activity relationships.
From previous studies, 1 seems to exert some of its effects
through its catechol ring functionality which provides free radical
scavenging and antioxidant activity, and the unsaturated double
bond of the side chain which maximizes the stabilization of the
phenolic radical.21,22 Therefore, E-3,4-dihydroxy styryl aralkyl
⇑
Corresponding authors. Tel./fax: +86 10 82805203 (Z.Z.).
E-mail addresses: lilybmu@bjmu.edu.cn (Z. Zhang), jyliu@bjmu.edu.cn (J. Liu).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.05.016

X. Ning et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3700–3703
3701
ryl aralkyl ketones (10a–g) were acetylated by acetic anhydride
with pyridine as the catalyst to afford the corresponding E-3,4-dia-
O
O
R
R'O
R'O
R'O
R'O
cetyl styryl aralkyl ketones (11a–g) in high yields. The 1H NMR, 13
C
n
O
NMR and HRMS data of all compounds synthesized were in full
agreement with the proposed structures. The E geometry of the
target compounds was confirmed by the coupling constants
(J ꢀ 16 Hz).
R = H, OCH3, OH, Cl;
R' = H, Ac; n = 2, 3, 4
target compounds
1
2
R' = H CAPE
R' = Ac Ac-CAPE
The neuroprotective properties of E-3,4-dihydroxy styryl aral-
kyl ketones (10a–g) and their 3,4-diacetylated derivatives (11a–
g) were assessed by way of several experimental pharmacological
models in vitro, in which the antioxidant properties were evalu-
ated by two models of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radi-
cal scavenging capacity and neuronal protecting effect against
damage induced by hydrogen peroxide (H2O2) in PC12 cells, and
the anti-inflammatory property was tested by the model of nitric
oxide suppression effect in BV2 microglial cells.
The free radicals contribute to the pathogenesis of neurodegen-
erative disorders, therefore, antioxidant therapy is considered as
one of options in treatment of neurodegenerative disorders.30
DPPH free radicals can be used in preliminary screening of com-
pounds with capability of scavenging reactive free radicals.31 The
free radical scavenging capacities of target compounds 10a–g
and 11a–g were evaluated by the published test method32 over
Figure 1. The structures of 1, 2 and target compounds.
ketones (Fig. 1) are designed which reserve E-3,4-dihydroxy styryl
group and introduce the ketone group instead of the unstable ester
group. In order to improve BBB permeability, two phenolic hydro-
xyl functions of target compounds are acetylated rather than
methylated to get corresponding high liposoluble compounds, be-
cause the methylation of phenolic hydroxyl functions may result in
the moderate loss of biological activity.23 It is also reported that
acetylated phenolic compounds exhibit the same or higher neuro-
protective activities compared with the initial phenolic com-
pounds.24 To explore the structure–activity relationships, the
compounds with various lengths of alky chains and with various
substituted groups on the aromatic ring are also designed.
E-3,4-dihydroxy styrene aralkyl ketones were synthesized as
showed in Scheme 1. The intermediates, substituted 4-phenyl-
but-3-en-2-one (4a–e), 5-phenyl-pent-3-en-2-one (6) and 6-phe-
nyl-hexa-3,5-dien-2-one (8) were prepared by different pathways.
The 4a–e and 8 were prepared by the Claisen–Schimidt condensa-
tion reaction of substituted benzaldehydes (3a–e) or cinnamyl
the concentration range of 1–50 lM. The ethanol solution of test
compounds and DPPH were mixed. After 60 min of incubation,
the capacities of scavenging free radicals were monitored by mea-
suring the change in light absorption at 517 nm. The results of
10a–g are shown in Table 1. From the results, compounds 10a–g
show the similar or stronger free radical scavenging capacities than
aldehyde (7) with acetone using a well-known procedure.25,26
6
1. Especially compound 10f (IC50 = 9.2 0.4
nent activity, which is 1.3-fold higher than that of
(IC50 = 12.1 0.3 M). The compounds 10f–g (IC50 = 9.2 0.4 and
10.6 0.5 M) with 3C and 4C alkyl chains show more potent free
radicals quenching abilities compared with the compound 10a
(IC50 = 12.7 0.5 M) with 2C alkyl chain. It is also noteworthy that
lM) exhibits promi-
was obtained by Wittig reaction. The 1-chloro-propan-2-one was
converted to the corresponding phosphonium salt by heating with
triphenylphosphine in CHCl3. The salt reacted with phenylacetal-
dehyde (5), Na2CO3 as the catalyst, to produce 6.27 In the next step,
4a–e, 6 and 8 were hydrogenated using 10% Pd/C as the catalyst in
CH2Cl2 to afford saturated compounds 9a–g in high yields.28,29
Then, the 9a–g reacted with 3,4-dihydroxy benzaldehyde by con-
densation using the pyrrolidine and acetic acid as the catalysts to
obtain E-3,4-dihydroxy styryl aralkyl ketones (10a–g) in desired
yields. Further, to improve BBB permeability, E-3,4-dihydroxy sty-
1
l
l
l
the electron-withdrawing chloro substituted compound (10b)
exhibits more effective activities than electron-donating methoxyl
substituted compounds (10c–e). In addition, acetylated com-
pounds 2 and 11a–g do not show detectable scavenging capacities
under the concentration of 50
lM, which implies that two phenolic
R1
R1
O
O
R2
R3
R2
R3
a
H
R3
R2
R1
3a-e
4a-e
O
R2
R3
HO
HO
c
n
O
H
O
d
b
n
R1
O
O
5
9a-g
6
10a-g
O
a
e
H
R3
R2
O
7
8
AcO
AcO
n
a: n = 2, R1 = H, R2 = H, R3 = H;
b: n = 2, R1 = H, R2 = Cl, R3 = H;
R1
11a-g
c: n = 2, R1 = H, R2 = OCH3, R3 = OCH3;
d: n = 2, R1 = OCH3, R2 = H, R3 = OCH3;
e: n = 2, R1 = H, R2 = OCH3, R3 = OH (3a-e, 4a-e, 9a-g and 10a-g); R3 = Ac (11a-g);
f: n = 3, R1 = H, R2 = H, R3 = H;
g: n = 4, R1 = H, R2 = H, R3 = H.
Scheme 1. Synthesis of E-3,4-dihydroxy styryl aralkyl ketones and their 3,4-diacetylated derivatives. Reagents and conditions: (a) acetone, NaOH or K2CO3, H2O, rt, 80–95%;
(b) 1-chloro-propan-2-one, PPh3, CHCl3, reflux; 10% Na2CO3, rt; phenylacetaldehyde, THF, rt; 62%; (c) 10% Pb/C, H2, CH2Cl2, rt, 90–95%; (d) 3,4-dihydroxy-benzaldehyde,
pyrrolidine, acetic acid, THF, reflux, 60–85%; (e) pyridine, acetic anhydride, rt, 92–96%.

3702
X. Ning et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3700–3703
Table 1
uncontrolled activation of microglia cells may cause neuronal
damage through the overproduction of proinflammatory sub-
stances, such as nitric oxide.34 Therefore, suppression nitric oxide
is a useful strategy for treating neurodegenerative disorders. The
inhibition effect of target compounds 10a–g and 11a–g on nitric
oxide can be measured by the Griess assay.35 The culture media
supernatants were incubated in the dark with equal amounts of
Griess reagent. And the absorbance was subsequently read at
540 nm. The nitric oxide suppression activities of tested
compounds are summarized in Table 2. All target compounds
significantly exhibit nitric oxide suppression activities in LPS-
stimulated BV2 microglial cells. Among those compounds, 10e–g
and 11e–g display similar or higher activities compared with 1
Free radical scavenging capacities of 1 and target compounds 10a–g by the DPPH
method
a
a
Compound
IC50
(
lM)
Compound
IC50 (lM)
10a
10b
10c
10d
12.7 0.5
11.1 0.3
13.2 0.6
14.0 0.5
10e
10f
10g
1
12.1 0.4
9.2 0.4
10.6 0.5
12.1 0.3
a
IC50: the concentration that produces 50% inhibitory effect; data are expressed
as the mean SD, n = 3.
hydroxyl groups of target compounds really play an important role
in free radical scavenging capacity.
and 2. Especially, compound 11g (IC50 = 4.2 0.3
strongest nitric oxide suppression activity and has 1.5-fold
higher activity than that of (IC50 = 6.4 0.4 M) and
(IC50 = 6.2 0.2 M). Compounds with 3C–4C alkyl chain, 10f–g
and 11f–g, show more potent activities compared with compounds
10a (IC50 = 14.1 0.4 M) and 11a (IC50 = 12.3 0.6 M) with
lM) shows the
In order to determine further the antioxidant properties of tar-
get compounds in nerve cells, target compounds 10a–g and 11a–g
were also assayed by the H2O2 model on PC12 cells. H2O2 could in-
jure nerve cells for the generation of exogenous free radicals. PC12
cells, commonly as a screening model for studies of neurodegener-
ative diseases, were used in this study.33 The protection effect of
compounds against H2O2 can be conveniently evaluated by the cell
viability. PC12 cells were pretreated with test compounds for 3 h,
then were exposed to 500 lM H2O2 for 5 h. Levels of cell viability
were measured by the MTT assay. The cell viabilities attributable
to the protective efficiency of target compounds (10a–g and 11a–
g) against H2O2 at 10 lM are listed in Figure 2. From the result,
all target compounds exhibit protection effects against damage in-
duced by H2O2, although the activities of target compounds display
lower activities compared with 1 and its diacetylated derivative
(2). Acetylated compounds 11a–g display similar protection effects
against damage induced by H2O2 to corresponding un-acetylated
compounds 10a–g. Compounds with 3C–4C alkyl chains (10f–g
and 11f–g) show stronger protection effects compared with com-
pounds with 2C alkyl chains (10a and 11a), which is consistent
with the result of DPPH model. Additionally, two methoxyl substi-
tuted compounds 10c–d and 11c–d display weaker protection ef-
fects than un-substituted compounds 10a and 11a.
1
l
2
l
l
l
shorter 2C chain. All of acetylated target compounds (11a–g) re-
veal the higher nitric oxide suppression effects than corresponding
un-acetylated compounds (10a–g) which is presumably due to
their higher lipophilicity. The acetylated derivatives probably
could be hydrolyzed into hydroxyl compounds by the esterase in
cells to produce nitric oxide suppression effects. The nitric oxide
suppression mechanism, based on the literatures, is presumably
that target compounds could inhibit the activity of COX-2 and iNOS
which play important roles in the inflammatory mechanism.36
Moreover, it is observed that compounds 10e and 11e with three
phenolic hydroxyl groups on the aromatic ring have more effective
activities compared with compounds 10a–d and 11a–d with two
phenolic hydroxyl groups, therefore, introducing of phenolic hy-
droxyl groups on the aromatic ring is presumably conductive to
improvement of nitric oxide suppression activities. Additionally,
the concentrations of target compounds used in our experiment
do not lead to any significant cytotoxicity even at a high concentra-
tion (50 lM) up to 24 h of incubation, and in all cases cell viability
The anti-neuroinflammatory properties of target compounds
were evaluated by assaying the nitric oxide suppression effect in
BV2 microglial cells. The microglial cells are believed to play a
key role in the pathway that leads to inflammation-mediated neu-
ronal cell death in a number of neurodegenerative diseases. The
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.
In summary, we report the design, synthesis and biological
evaluation of E-3,4-dihydroxy styryl aralkyl ketones and their
Figure 2. Protective effects of 1, 2 and target compounds 10a–11g against H2O2 induced injury in PC12 cells at 10
lM, respectively. PC12 cells were pretreated with test
compounds for 3 h, then were exposed to 500 M H2O2 for 5 h. Levels of cell viability were measured by the MTT assay. The viability of control cells untreated with tested
l
compounds and H2O2 was defined as 100%. The viability of cells treated with drugs was calculated by the following formula: OD (drug-treated)/OD (control) Â100%. Data are
expressed as the mean SD, n = 3.

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References and notes
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