Antioxidant Properties of Novel Dimers Derived from Natural β-Elemene through Inhibiting H2O2-Induced Apoptosis

Article abstract of DOI:10.1021/acsmedchemlett.7b00035

A series of novel β-elemene dimer derivatives were synthesized and evaluated for their antioxidant activities. The results indicated that most of the target compounds showed more potent cytoprotective effects than positive control vitamin E. In particular, dimer D5 exhibited the strongest antioxidant activity, which was significantly superior to the active compound D1 obtained in our previous study. Besides, D5 did not produce obvious cytotoxicity in normal human umbilical vein endothelial cells (HUVECs) and increased the viability of HUVECs injured by H₂O₂ in a concentration-dependent manner. Further studies suggested that the cytoprotective action of D5 might be mediated, at least in part, by increasing the intracellular superoxide dismutase activity and nitric oxide secretion as well as decreasing the intracellular malonyldialdehyde content and lactate dehydrogenase release. Furthermore, D5 observably inhibited ROS generation and prevented H₂O₂-induced apoptosis in HUVECs possibly via inhibiting the activation of the MAPK signaling pathway.

Full text of DOI:10.1021/acsmedchemlett.7b00035

Letter
pubs.acs.org/acsmedchemlett
Antioxidant Properties of Novel Dimers Derived from Natural
β‑Elemene through Inhibiting H2O2‑Induced Apoptosis
Jichao Chen,† Ruifan Wang,† Tianyu Wang,† Qilong Ding,‡ Aliahmad Khalil,‡ Shengtao Xu,† Aijun Lin,†
Hequan Yao,*,† Weijia Xie,† Zheying Zhu,*,§ and Jinyi Xu*,†
†State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia
Xiang, Nanjing 210009, P. R. China
‡Department of Pharmacology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
§Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus,
Nottingham NG7 2RD, U.K.
S
* Supporting Information
ABSTRACT: A series of novel β-elemene dimer derivatives
were synthesized and evaluated for their antioxidant activities.
The results indicated that most of the target compounds showed
more potent cytoprotective effects than positive control vitamin
E. In particular, dimer D5 exhibited the strongest antioxidant
activity, which was significantly superior to the active compound
D1 obtained in our previous study. Besides, D5 did not produce
obvious cytotoxicity in normal human umbilical vein endothelial
cells (HUVECs) and increased the viability of HUVECs injured
by H2O2 in a concentration-dependent manner. Further studies
suggested that the cytoprotective action of D5 might be
mediated, at least in part, by increasing the intracellular
superoxide dismutase activity and nitric oxide secretion as well
as decreasing the intracellular malonyldialdehyde content and lactate dehydrogenase release. Furthermore, D5 observably
inhibited ROS generation and prevented H2O2-induced apoptosis in HUVECs possibly via inhibiting the activation of the MAPK
signaling pathway.
KEYWORDS: β-Elemene, dimer, antioxidant activity, apoptosis, MAPK pathway
ardiovascular diseases are the leading cause of death in the
Cworld, accounting for nearly 30% of the annual global
mortality.1 Atherosclerosis is the underlying pathological process
of many diseases in the cardiovascular system.2 Although
hypercholesterolemia has traditionally been considered as a
major cause of atherogenesis, it has now been widely appreciated
Figure 1. Structures of β-elemene (1) and dimers D1 and D2.
human cancers.11,12 Because of its low toxicity, β-elemene is well
that endothelial dysfunction is a characteristic feature and key
initiating event in the development of atherosclerosis.3−5 There is
evidence that excessive production of reactive oxygen species
tolerated and accepted by patients with cancers.13,14 Recent
studies have discovered that β-elemene possessed moderate
antioxidant effect against oxidative damage. It may protect the
endothelial cells from injury induced by H2O2 in vitro and inhibit
neointimalhyperplasiainvivoaftervascularinjury.15 Inaddition, it
may block H2O2-induced monocyte-endothelial cells interactions
in vitro16 and retard the progression of atherosclerosis in vivo.17
Our previous studies indicated that β-elemene ester derivatives
had more potent antioxidant activities than parent compound β-
elemene in H2O2-injured human umbilical vein endothelial cells
(HUVECs). Especially, the two 13-monosubstituted dimers (D1
−
(ROS) such as OH•, O2 , and H2O2 is able to evoke vascular
endothelial cells (VECs) injury and induce VECs apoptosis,
which is frequently linked with endothelial dysfunction.6−8 VECs
apoptosis disrupts the integrity of the endothelial monolayer,
which causes degeneration of vascular structures and increase of
endothelial permeability, thus exposing the underlying cell layers
to a deleterious inflammatory process, contributing to the
formation of atherosclerotic lesions.9,10 Therefore, antioxidants
that preferentially inactivate ROS may be an effective strategy for
the prevention and treatment of atherosclerosis.
β-Elemene (1, Figure 1), a natural sesquiterpene isolated from
the essential oils of Curcuma wenyujin, has been approved by the
Chinese Food and Drug Administration for the treatment of
Received: January 23, 2017
Accepted: March 13, 2017
Published: March 13, 2017
© XXXX American Chemical Society
A
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andD2, Figure1)exhibited themostpotentantioxidant activities,
which were significantly superior to that of positive control
vitamin E.18
Encouraged by the above findings, in our ongoing studies, we
further designed and synthesized a series of novel 13-
monosubstituted β-elemene dimer derivatives to improve the
antioxidant activity of natural β-elemene. Herein, we report their
synthesis, antioxidant activity, and antioxidant mechanism in
H2O2-treated HUVECs.
reaction of β-elemene with NaClO afforded the chlorinated
mixture of 2a and 2b, which was directly reacted with NaOAc to
give the acylated compounds 3a and 3b. Then the resulting
products were subjected to alkaline hydrolysis to produce a
mixture of 4a and 4b, which was separated by HPLC to provide
the main product 13-β-elemol (4a). Finally, 4a reacted with
anhydrides/EDCI/DMAP or acyl chlorides/DMAP/Et3N to
yield the target compounds D3−D12. Dimer D13 was obtained
from alkylation of 4a with 1,4-dibromobutane in the presence of
NaH.
The β-elemene dimer derivatives D3−D12 were synthesized
according to our previous work.18 As depicted in Scheme 1,
ThepreparationofdimersD14−D22wasillustratedinScheme
2. Reaction of 4a with NBS/PPh3 gave the brominated
intermediate 5, which was treated with N,N′-dimethylethylenedi-
amine or piperazine to afford dimer D14 or D15. Treatment of 4a
with 3-bromopropionyl chloride in the presence of DMAP/TEA
led to intermediate 6, followed by treatment with N,N′-
dimethylethylenediamine or piperazine through the Michael
addition reaction to provide dimer D16 or D17. Reaction of 4a
with 4-bromobutyric acid in the presence of DCC and DMAP
produced intermediate 7, which was treated with N,N′-
dimethylethylenediamine or piperazine to give dimers D18 or
D19. Compound 4a reacted with Boc-L-Asp-OH or Boc-L-Glu-
OH in the presence of EDCI and DMAP, the resulting
intermediate followed the N-Boc deprotection using TFA to
give dimer D20 or D21. Treatment of 4a with succinic anhydride
in the presence of DMAP/TEA gave intermediate 8, followed by
its conversion to the acyl chloride intermediate using oxalyl
chloride, which then reacted with piperazine to provide dimer
D22.
a
Scheme 1. Synthetic Routes of Dimers D3−D13
The synthesis of dimer compounds D23−D32 was shown in
Scheme 3. Reaction of 4a with propiolic acid/DCC/DMAP or 3-
bromopropyne in the presence of NaH gave intermediate 9 or 10.
Treatment of 4a with BrR3COOH/DCC/DMAP provided
intermediate 11, which was further reacted with NaN3 to afford
intermediate 12. Similarly, intermediate 13 was prepared from
reaction of dibromoalkane with NaN3. Then, treatment of 9 or 10
with 12 or 13 through “click reaction” gave dimers D23−D28 or
D29−D32, respectively.
a
Reagents and conditions: (a) NaClO, HOAc/CH2Cl2, 0−5 °C, 6 h,
55%; (b) DMF, NaOAc, 120 °C, 8 h, 75%; (c) MeOH/CHCl3, KOH,
reflux, 2 h, 85%; (d) separated by HPLC, hexane/EtOH = 98/2 (V/
V), UV = 214 nm; (e) anhydrides/EDCI/DMAP or acyl chlorides/
DMAP/Et3N, CH2Cl2, rt, 2−8 h, 74−87%; (f) Br(CH2)4Br, NaH,
anhydrous DMF, rt, 3 h, 47%.
Based on the structures of dimers D1 and D2, dimers D3−D13
wereinitiallypreparedandevaluatedfortheirprotectiveeffectson
a
Scheme 2. Synthetic Routes of Dimers D14−D22
a
Reagents and conditions: (a) NBS/PPh3, CH2Cl2, rt, 10 min, 88%; (b) N,N′-dimethylethylenediamine or piperazine, TEA, DMF, 100 °C, 1 h, 73−
76%; (c) Br(CH2)2COCl, DMAP, TEA, rt, 2 h, 78%; (d) N,N′-dimethylethylenediamine or piperazine, THF/MeOH, 80 °C, 1.5 h, 58−62%; (e)
Br(CH3)3COOH, DCC, DMAP, rt, 6 h, 87%; (f) N,N′-dimethylethylenediamine or piperazine, TEA, dry DMF, 100 °C, 4 h, 62−67%; (g) Boc-L-
Asp-OH or Boc-L-Glu-OH, EDCI, DMAP, CH2Cl2, rt, 4 h; (h) TFA, CH2Cl2, rt, 2 h, 62−66%; (i) succinic anhydride/DMAP/TEA, CH2Cl2, rt, 2 h;
(j) oxalyl chloride, cat. DMF, CH2Cl2, rt, 1.5 h; (k) piperazine, DMAP, TEA, CH2Cl2, rt, 1 h, 55%.
B
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a
It is well-known that the poor solubility of β-elemene limits its
application in clinic.19 To address this issue, dimers D14−D32
were further prepared through introducing some water-soluble
moieties such as amine and triazole. As depicted in Figure 2, most
of them showedpotent antioxidant activities, whichweresuperior
toVEorcomparabletoD2. Introductionofaminegroupsintothe
alkyl linker (e.g., D16, D17) showed stronger activity than those
linked with β-elemene directly via the amine bond instead of the
ester bond (e.g., D14, D15). Moreover, increasing the linker
length of D16 or D17 by two carbons (D18 or D19) had no
significant effect on the activity. Whereas change of the amine
bond in D19 to the amido bond (D22) led to slightly decreased
activity. When succinic anhydride in D1 was substituted by L-Asp-
OH (D20), the activity remarkably reduced, suggesting that
introduction of a polar amino group (−NH2) into the linker has a
detrimental effect on the activity. Surprisingly, replacement of L-
Asp-OH (D20) with L-Glu-OH (D21) led to further decreased
activity. When the ester bond in D23−D25 or D29−D30 was
converted to the ether bond (D26−D28 or D31−D32), the
activity was less influenced. It was observed that the activity
gradually enhanced when the R3 length was increased from C3 to
C5 (e.g., D26 < D27 < D28). Similarly, extending the R4 length
from C4 to C6 resulted in slightly improved activity (e.g., D31 <
D32). Besides, comparison of the activities of D23−D28 with
D29−D32 suggested that compounds containing one triazole
were obviously preferred. However, the structural modifications
by introducing such water-soluble moieties did not result in
markedly increased activity. Dimer D5 showed the strongest
antioxidant activity in all the target compounds.
Subsequently, dimer D5 at lower concentrations was examined
for the antioxidant activity in H2O2-injured HUVECs. As seen in
Figure 3A, D5 at concentrations of 10, 1, 0.1, and 0.01 μM
increased the survival rate of HUVECs by 96.97%, 85.53%,
76.72%, and 65.47% from 60.21% in the model group,
respectively. The results indicated that D5 improved the cell
viability in a dose-dependent manner, and the EC50 value of D5
was 0.22 μM. It was proved that D5 could protect HUVECs from
H2O2-induced cell injuries.
To exclude the proliferative effect of dimer D5, we further
checked its cytotoxicity on normal HUVECs by MTT assay. As
shown in Figure 3B, the cell viability was above 90% after
incubation with D5 at concentrations of 0.1−50 μM for 24 h. The
results indicated treatment with D5 at these doses did not
significantly influence cell proliferation. In addition, the
concentrations of the target compound used in this experiment
did not lead to more than 50% cell killing, suggesting D5 had low
Scheme 3. Synthetic Routes of Dimers D23−D32
a
Reagents and conditions: (a) propiolic acid, DCC, DMAP, ice-water
bath, 6 h, 54%; (b) 3-bromopropyne, NaH, dry DMF, rt, 3 h, 72%; (c)
BrR3COOH, DCC, DMAP, CH2Cl2, 6−8 h, 78−85%; (d) NaN3,
DMF, 80 °C, 4 h, 81−87%; (e) AscNa, CuSO4·5H2O, CH2Cl2/H2O,
rt, 8−12 h, 62−73%.
H2O2-injured HUVECs by MTT assay. D1, D2, and vitamin E
(VE) were chosen as positive controls in the experiments. As
shown in Figure 2, all of the synthesized compounds showed
more potent cytoprotective effects than VE in H2O2-injured
HUVECs. Among them, compound D5 exhibited the strongest
antioxidant activity, which was significantly superior to the active
compound D1, indicating that introduction of a double bond into
in the linker may be beneficial for the activity. It was found that
improvement of the activity was acquired by increasing the linear
alkyl chain length such as D3 < D4 < D6. Replacement of
CH2CH2 in D1 with CH2OCH2 (D7) led to decreased activity.
When the alkyl chain was substituted by the phenyl ring (e.g., D8,
D9), the activity remarkably decreased. Reducing the phenyl ring
to saturated cyclohexane had no effect on the activity (e.g., D11,
D12). It is surprising that the activity was slightly enhanced when
the phenyl ring was replaced with the naphthalene ring (D10).
Changing the ester bond in D1 to the ether bond (D13) resulted
in markedly increased activity, suggesting the ester bond maybe
not essential for the activity.
Figure 2. Effects of β-elemene dimer derivatives on the viability of H2O2-injured HUVECs. Results are expressed as means SD, n = 3. ##P < 0.01 vs
control group, *P < 0.05, **P < 0.01 vs model group.
C
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Figure 3. Effects of dimer D5 on the viability of H2O2-injured (A) and normal (B) HUVECs. Results are expressed as means SD, n = 3. ##P < 0.01 vs
control group, *P < 0.05, **P < 0.01 vs model group.
Figure 4. ROS inhibitory activity of dimer D5 in H2O2-injured HUVECs. (A) Shown are representative images of DCF fluorescence in HUVECs with or
without treatment. (B) ROS fluorescent intensity index was expressed as the percentage of the control group fluorescence intensity. Results shown are
expressed as means SD, n = 3. ##P < 0.01 vs control group, *P < 0.05, **P < 0.01 vs model group.
Figure 5. Effect of dimer D5 on H2O2-induced cell apoptosis.
cytotoxicity. As a result, dimer D5 with concentrations of 10, 1,
and 0.1 μM was selected for subsequent mechanism study.
The maladaptive state ofimpaired HUVECs is characterized by
abnormal metabolism of some active substances. The malonyl-
dialdehyde (MDA) content often reflects the extent of lipid
peroxidation in an organism and the level of cell damage.20
Antioxidant enzymes, such as superoxide dismutase (SOD),
modulate basal levels of superoxide and protect against
endothelial dysfunction, ensuing vasomotor and trophic
response.2 Nitric oxide (NO) is one of the important molecules
synthesized by endothelial cells, and NO bioavailability is
regarded as the primary marker for endothelial dysfunction.21
Lactate dehydrogenase (LDH) release into the bloodstream was
usually used as an indicator for the integrity of cell membranes or
necrosis in response to the oxidant burden.22 Incubation of
HUVECs with 0.5 mM H2O2 for 2 h led to notable decrease in the
D
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intracellular SOD activity and NO secretion, and increase in the
intracellular MDA content and LDH release, compared to that of
the control group. However, it was observed that the pretreat-
ment with D5 at concentrations of 0.1, 1, and 10 μM for 24 h
significantly increased SOD activity and NO secretion, and
decreased MDA content and LDH release in a concentration-
dependent manner (see Supporting Information Figure S1). The
results suggest that the mechanism underlying the protective
action of D5 may be involved in reducing the changes of these
bioactive substances in H2O2-injured HUVECs.
Vascular endothelial dysfunction often represents the first step
inthe development of atherosclerosis.4 The accumulation ofROS
contributes to VEC apoptosis, the leading cause of endothelial
dysfunction.8 Thus, dimer D5 was examined for its ROS
inhibitory activity. As shown in Figure 4, the pretreatment with
D5 at concentrations of 0.1−10 μM decreased the level of ROS
from 2.40 to 1.16 as compared to 3.30 in the model group. The
results indicated that D5 could significantly inhibit ROS
generation in a dose-dependent manner.
In summary, a series of novel β-elemene dimer derivatives were
synthesized, and their antioxidant activities were evaluated in
H2O2-injured HUVECs. The bioassay results indicated that most
of the compounds markedly increased the survival rate of
HUVECs compared to the model group. Among them, dimer D5
exhibited the most potent antioxidant activity, which was
significantly superior to positive control vitamin E and the active
compound D1. Besides, D5 did not produce significant
cytotoxicity in normal HUVECs and increased the viability of
HUVECsinjuredbyH2O2 inaconcentration-dependent manner.
Further studies demonstrated that the cytoprotective action of
D5 was possibly mediated, at least in part, through affecting the
changes of various bioactive substances (e.g., SOD, MDA, NO,
LDH) in H2O2-treated HUVECs. Furthermore, D5 markedly
inhibited ROS generation and prevented H2O2-induced
apoptosis of HUVECs potentially by inhibiting the activation of
the MAPK signaling pathway. Collectively, the current study may
provide a new insight for the treatment of cardiovascular diseases
such as atherosclerosis related to oxidative stress.
To verify whether the cytoprotective effect of dimer D5 is
associatedwithinhibition ofcellapoptosis, anAnnexinV-APC/7-
AAD binding assay was performed by flow cytometry. As shown
in Figure 5, incubation of HUVECs with 0.5 mM H2O2 for 2 h
resulted in 45.74% apoptotic cells (Q2 + Q4) as compared with
8.83% in an untreated control group. While the cells were
pretreatedwith D5atconcentrations of0.1, 1, and 10μMfor 24h,
the percentage of apoptotic cells decreased to 41.14%, 31.51%,
and 25.53%, respectively. The results indicated that D5 potently
inhibited H2O2-induced cell apoptosis in a concentration-
dependent manner.
It was reported that mitogen activated protein kinases
(MAPKs) such as ERK1/2, JNK, and p38 can be regulated by
oxidative stress. ROS activates and phosphorylates MAPKs,
which modulates cell proliferation, apoptosis, and program.23,24
ROS-inducedapoptosis may beaggravated through the activation
of the MAPK pathway. As shown in Figure 6, D5 markedly
ASSOCIATED CONTENT
■
S
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acsmedchemlett.7b00035.
Synthetic methods and characterization of target com-
pounds; procedures for pharmacological activities (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*(H.Y.) Tel: +86-25-83271042. E-mail: hyao@cpu.edu.cn.
*(Z.Z.) E-mail: zheying.zhu@nottingham.ac.uk.
*(J.X.) Tel: +86-25-83271299. E-mail: jinyixu@china.com.
ORCID
Aijun Lin: 0000-0001-5786-4537
Jinyi Xu: 0000-0002-1961-0402
Funding
This study was supported from the National Natural Science
Foundation of China (Nos. 81373280, 81673306), the Project
Program of State Key Laboratory of Natural Medicines, China
Pharmaceutical University (No. SKLNMKF201710), and the
Innovation project of Jiangsu Province (No. KYLX15_0633).
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
EDCI, 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydro-
chloride; DCC, N,N′-dicyclohexylcarbodiimide; DMAP, 4-
dimethylamiopryidine; TEA, triethylamine; TFA, trifluoroacetic
acid; DMF, N,N-dimethylformamide; NBS, N-bromosuccini-
mide; PPh3, triphenylphosphine; THF, tetrahydrofuran; AscNa,
sodium ascorbate
Figure 6. Effect of dimer D5 on the MAPK phosphorylation in H2O2-
injured HUVECs.
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