A novel salvianolic acid A analog with resveratrol structure and its antioxidant activities in vitro and in vivo

Article abstract of DOI:10.1002/ddr.21734

E-DRS is a novel salvianolic acid A (SAA) analog, which was synthesized from resveratrol (RES) and methyldopate. Its structure is similar to that of SAA, but the 3′,4′-dihydroxy-trans-stilbene group and the ester structure in SAA were replaced by the RES

Full text of DOI:10.1002/ddr.21734

Received: 11 March 2020
DOI: 10.1002/ddr.21734
Revised: 16 July 2020
Accepted: 22 July 2020
R E S E A R C H A R T I C L E
A novel salvianolic acid A analog with resveratrol structure and
its antioxidant activities in vitro and in vivo
Jin-Mei Qiu1 | Chang-Feng Qin1 | Shen-Gen Wu1 | Tong-Ying Ji1
Guo-Tao Tang1 | Xiao-Yong Lei1 | Xuan Cao1 | Zhi-Zhong Xie1,2
|
1Hunan Provincial Key Laboratory of Tumour
Abstract
Microenvironment Responsive Drug Research,
University of South China, Hengyang, China
E-DRS is a novel salvianolic acid A (SAA) analog, which was synthesized from resvera-
trol (RES) and methyldopate. Its structure is similar to that of SAA, but the 30,40-
dihydroxy-trans-stilbene group and the ester structure in SAA were replaced by the
RES structure and an amine group, respectively. E-DRS scavenged free oxygen radi-
cals effectively, including superoxide anion (ascorbic acid > E-DRS > SAA ≥ rutin >
RES) and DPPH radical (rutin > E-DRS ≥ ascorbic acid > SAA > RES), and exhibited
powerful total antioxidant capacity (ascorbic acid > E-DRS > SAA ≥ rutin > RES) in
vitro. Furthermore, oral administration of E-DRS dose-dependently and significantly
decreased CCl4-induced oxidative stress in mice as indicated by the decreased con-
tent of hepatic malondialdehyde (MDA). In addition, oral administration of E-DRS
also increased the content of nonenzymatic antioxidant glutathione (GSH) and the
activity of antioxidant enzymes such as catalase (CAT) and superoxide dismutase
(SOD) in the liver of mice. All these results demonstrated that E-DRS had good anti-
oxidant activities both in vitro and in vivo, and could be a potential antioxidant agent
after further optimization and evaluation.
2Hunan Provincial Cooperative Innovation
Centre for Molecular Target New Drug Study,
University of South China, Hengyang, China
Correspondence
Prof. Zhi-Zhong Xie, PhD and Dr. Xuan Cao,
PhD, Hunan Provincial Key Laboratory of
Tumour Microenvironment Responsive Drug
Research, University of South China, 28#
Chang-Sheng Road, Hengyang City, Hunan
Province, 421001, China.
Email: zhizhongx@126.com (Z.-Z. X.) and
290284047@qq.com (X. C.)
Funding information
Education Department General Project of
Hunan Province, Grant/Award Number:
09C830; Undergraduate Training Program for
Innovation and Entrepreneurship of Hunan
Province, Grant/Award Number: 2324;
Natural Science Foundation of Hunan
Province, Grant/Award Number:
2019JJ40251; Hunan Provincial Innovation
Foundation for Postgraduate, Grant/Award
Number: CX20190748
K E Y W O R D S
antioxidant, free radical scavenging ability, resveratrol, salvianolic acid A
1
|
INTRODUCTION
Both enzymes, like superoxide dismutase (SOD), catalase (CAT), and
glutathione peroxidase-1 (GPx-1), and nonenzymatic antioxidants,
Free radicals, like reactive oxygen species (ROS), which contain one
or more unpaired electrons in their outer orbital, are short-lived and
highly chemically reactive and have long been considered harmful
molecules although recent studies demonstrated they also play
important roles in some physiological reactions (Szewczyk-Golec,
Czuczejko, Tylzanowski, & Lecka, 2018). An excessive amount of free
radicals can damage sensitive tissues directly and has been implicated
in a variety of pathological events, such as neurodegenerative dis-
eases (Wojtunik-Kulesza, Oniszczuk, Oniszczuk, & Waksmundzka-
Hajnos, 2016), myocardial infarction (Rezvan, 2017; Zhou et al., 2019),
cancer (Katerji, Filippova, & Duerksen-Hughes, 2019), etc. The term
oxidative stress has been proposed indicating a serious imbalance
between the production of ROS and cellular antioxidant capacity.
like reduced glutathione (GSH), comprise a co-operative network to
minimize oxidative injury (Marengo et al., 2016; Xie, Liu,
&
Bian, 2016). High intake of natural antioxidant-rich food, like plant
polyphenols, has been proved to reduce the risk of oxidative stress-
related diseases (Sarubbo, Moranta, & Pani, 2018; Teixeira et al., 2019;
Zhang, 2015).
Resveratrol (RES) is a natural trans-stilbene compound derived
from the peel of several plants, including grapes, berries, and pome-
granates. It attracted little interest until the 1990s when it was found
rich in red wine and was to postulate as a possible explanation for the
paradoxical epidemiological finding that French people have a rela-
tively low incidence of cardiovascular disease despite a high saturated
fat diet (Bertelli et al., 1995; Chung, Teng, Cheng, Ko, & Lin, 1992).
Drug Dev Res. 2020;1–8.
wileyonlinelibrary.com/journal/ddr
© 2020 Wiley Periodicals LLC
1

2
QIU ET AL.
During the last two decades, growth studies dealing with the biologi-
cal activity of RES have been carried out and RES was shown numer-
ous health-promoting effects in both animals and humans (Lopez,
Dempsey, & Vemuganti, 2015). In several studies, RES, like other poly-
phenolic compounds, displayed a potent ability to scavenge free radi-
cals, and the antioxidant capacity of RES was thought to be essential
for its biological effects (Bonnefont-Rousselot, 2016; Santos, de
2.2
|
General procedure for the synthesis of E-DRS
(compound IV)
One gram RES (compound I, 4.4 mmol) was dissolved in 5 ml of N,N-
dimethylformamide (DMF) and 7.5 ml of Vilsmeier regent (POCl3
mixed with DMF 1:2) was added slowly to it with an ice/water bath.
The reaction mixture was stirred for 1 hr at room temperature, and
another 30 ml of ice-water was added slowly to make sure the tem-
perature was below 60 ꢀC, otherwise, the solution will turn black. An
additional 50 ml of water was added until suspended yellow solids
appear and stir the yellow solution overnight. Resveratrol aldehyde
((E)-2,4-dihydroxy-6-(4-hydroxystyryl)-benzaldehyde, compound II)
was obtained by filtration and vacuum drying at 80 ꢀC (95% yield)
(Huang et al., 2007; Kataria & Khatkar, 2019).
Carvaho, Oliveira, Raposo,
& da Silva, 2013; Truong, Jun, &
Jeong, 2018). However, the low bioavailability and stability of RES
make it worthwhile to develop newer derivatives or analogs to
improve its pharmacological activities.
Salvianolic acid A (SAA) is one of the main water-soluble polyphe-
nol compound extracted from the dried roots and rhizomes of Salvia
miltiorrhiza. It has been shown to reduce oxidative stress and exerts a
broad range of protective effects on hepatic fibrosis (Wang
et al., 2019), ischemia–reperfusion injury (Hou et al., 2016),
For the preparation of ethyl methyldopate, the dry hydrogen
chloride gas was bubbled into 3.3 g methyldopa (15.6 mmol) solution
suspended in 30 ml of ethanol, then stirred, heated, and refluxed for
4–8 hr, and the excess solvent was removed by vacuum distillation
(90% yield).
Alzheimer's disease (Zhang, Qian, Zhang,
& Wang, 2016), etc.
Although SAA has recently attracted many interests, the low abun-
dance of SAA in the raw material (<0.05% content in the roots of Sal-
via miltiorrhiza [Xu et al., 2018]) prevents it from being used widely in
clinic trials, and few follow-up studies of SAA have been carried out
because of two serious reasons. First, the complex structure of SAA
means that more expensive and complex synthesis methods are
needed, and a new method for the total asymmetric synthesis of SAA
was reported till 2016 (8 steps, overall yield <10%) (Zheng, Song, &
Xuan, 2016). Second, SAA could be hydrolyzed in vivo due to the
ester bond, which reduces its pharmacological activity. Recently, Tang
et al. (2016) replaced the C-9 ester bond of salvianolic acid C with
amide linkage to develop a series of analogs. They found that the
ortho-phenol hydroxyl group of these derivatives is essential to main-
tain their antioxidant properties, which were further enhanced by the
replacement of amide linkage. It is also worth noting that the scaffolds
of salvianolic acid are retained in these derivatives.
To get compound III, 0.3 g (1 mmol) resveratrol aldehyde (com-
pound II) and 0.5 ml (1.6 mmol) ethyl methyldopate were dissolved in
20 ml of methanol, and then the solution was heated to reflux for
3 hr. After cooling, the reaction mixture was poured into 50 ml of
water. The aqueous layer was extracted with ethyl acetate
(3 × 20 ml), and the organic layer was dried with sodium sulfate and
vacuum drying. Compound III was obtained when the crude product
was further purified by column chromatography (eluent
= dic-
hloromethane: methanol = 30:1) (50 ꢁ 90% yield).
Finally, 0.2 g (0.4 mmol) compound III was dissolved in 20 ml of
methanol at room temperature, and then 0.04 g solid NaBH4 was
added carefully. After stirring for 1 hr, the solution was poured into
50 ml of water, and the aqueous layer was extracted with ethyl ace-
tate (3 × 20 ml). Compound IV (the title compound) was finally
obtained by drying the organic layer with sodium sulfate and vacuum
drying (90% yield).
As SAA could be regarded as the ester of phenylpropionate and
trans-stilbene, if the trans-stilbene group in SAA is substituted by simi-
lar trans-stilbene structure and the amine structure is used as the link-
age instead of the ester structure, the SAA analog might show more
stability and more effective antioxidant potency. Herein, we design
and synthesis a kind of SAA analog, E-DRS. Its structure is similar to
that of SAA, but RES structure was substituted for the 30,40-
dihydroxy-trans-stilbene group and an amine group was used as the
linkage instead of the ester structure of SAA. In addition, its antioxi-
dant activity was further investigated in vitro and in vivo.
Compound IV is a yellowish powder, 1H NMR (400 MHz, MeOD)
δ 7.78 (d, J = 8 Hz, 2H), 7.62 (d, J = 8 Hz, 1H), δ 7.46 (m, 3H), δ 7.24 (d,
J = 4 Hz, 1H), δ 7.19 (d, J = 8 Hz, 1H), δ 7.16 (d, –CH=CH–, 1H), δ 6.57
(d,–CH=CH–, 1H), δ 6.36 (s, 1H), δ 6.25 (s, 1H), δ 4.15–4.11 (t, 2H), δ
4.00–3.95 (t, 2H), δ 2.56(s, 2H), δ 2.16 (s, 3H), δ 1.76–1.82 (t, 3H). 13C
NMR (101 MHz, MeOD) δ 158.22, 156.92, 139.95, 129.03, 128.04,
127.45, 125.61, 115.12, 104.44, 101.27, 48.31, 48.10, 47.89, 47.67,
47.46, 47.25, 47.04. MS (ESI): m/z Calcd. For C27H29NO7 [M + H]+:
479.195; found: 479.333. IR (KBr, 1 mg) νmax: 3459, 3340, 1586,
1608, 1516, 1276, 1173, 977, 811 cm−1
.
2
|
MATERIALS AND METHODS
Chemistry
2.1
|
2.3
|
Antioxidant activity assessment in vitro
| Total antioxidant capacity
RES (98%), methyldopa, SAA (99.5%), rutin, and ascorbic acid are
products of Sigma-Aldrich and were purchased from Maike Biological
Reagent Company (Changsha, China). Other chemicals were of analyt-
ical grade from commercial sources.
2.3.1
The total antioxidant capacity of E-DRS was measured by Ferric ion
reducing antioxidant power (FRAP) assay using a FRAP assay kit (Cat

QIU ET AL.
3
No. S0116, Beyotime Biotechnology, Shanghai, China) according to
the manufacturer's instructions. Simply, samples were mixed with
fresh Fe3+-TPTZ (Ferric-tripyridyltriazine) working solution and incu-
bated at 37 ꢀC for 40 min in dark. Then the absorbance of each sam-
ple was measured at 593 nm with a spectrophotometric plate reader
(BioTek, Winooski, VT). Deionized water instead of the sample was
used as a blank. Each sample was assayed at least three times.
2.3.2
|
Superoxide anion scavenging activity
The pyrogallol autoxidation method was carried out to determine
superoxide free radical scavenging ability of E-DRS as described previ-
ously with slight modifications (Li, 2012). Briefly, 200 μl sample was
mixed with 2,750 μl of Tris–HCl buffer (0.05 M, containing 1 mM
Na2EDTA, pH 8.2) and 50 μl of pyrogallol solution (60 mM in 1 mM
SCHEME 1 Synthetic routes for
E-DRS (title compound)
FIGURE 1 Chemical structure of
salvianolic acid A (a) and E-DRS (b)

4
QIU ET AL.
HCl, 37 ꢀC), vibrated with a vortex for several seconds, and then send
to the spectrophotometric plate reader quickly to monitor its absor-
bance at 325 nm every 30 s for 5 min. The superoxide free radical
scavenging ability was calculated using the following equation:
control group, and 10 mice for injured model group induced by CCl4)
by intragastric gavage for 14 days. Two hours after the last dosing,
mice except that of blank control group were injected with 5% CCl4
(dissolved in olive oil, 6 ml/kg body weight) intraperitoneally to induce
higher levels of oxidative stress, while the mice in the blank control
ÈÀ
Á
É
Scavenging abilityð%Þ = ΔA325,control −ΔA325,sample =ΔA325,control
× 100:
Here, ΔA325,control is the increase of absorbance at 325 nm in
5 min of the mixture without the sample and ΔA325,sample is that of
the mixture with the sample. The concentration of each sample
decreasing 50% of scavenging ability (IC50) was used to measure the
superoxide anion scavenging activity level. The assay was repeated a
minimum of three times.
2.3.3
|
DPPH radical scavenging activity
The scavenging activity of E-DRS on 1,1-diphenyl-2-picrylhydrazyl
(DPPH) radicals was performed as described previously with minor
modifications (Shimamura et al., 2014). Briefly, 200 μl of increasing
concentration of sample solution (7.8, 15.6, 31.3, 62.5, 125, 250,
500 μg/ml), 800 μl of 0.1 M Tris–HCl buffer (pH 7.4), and 1 ml of
0.2 mM DPPH-ethanol solution was added into a test tube and mixed
for 10 s quickly. The reaction mixture was then incubated for 30 min at
room temperature in the dark. 200 μl of ethanol instead of the sample
was used as blank control. The absorbance was measured at 517 nm,
and the inhibition ratio was calculated using the following equation:
ÈÀ
Á
É
Inhibition ratioð%Þ = Acon −Asample =Acon × 100:
Here, Asample represents the absorbance of the sample group,
while Acon represents the absorbance of the control group. IC50 was
used to measure the DPPH scavenging activity level. Each sample was
assayed at least three times.
2.4
|
Antioxidant activity assessment in vivo
| Animal experiment
2.4.1
The animal research protocol was approved by the animal ethics com-
mittee of the University of South China. After institutional ethical
clearance for the study was acquired, 70 Kunming male mice weighing
20–25 g were purchased from the Laboratory Animal Centere of Uni-
versity of South China (Certificate No. SCXK 2015-0002). The mice
were housed under standard environmental conditions (22
2
ꢀC,
12 hr light, and 12 hr dark cycle) and fed a standard commercial pellet
diet and water ad libitum. The animals were acclimatized for 1 week
and then randomly divided into 7 groups with 10 animals each. Vit C
and RES were used as positive control drugs for economic reasons.
Mice were pre-treated with E-DRS (5, 25, or 125 mg/kg body weight),
ascorbic acid (7.5 mg/kg body weight), RES (25 mg/kg body weight),
or the same volume of saline (0.5 ml, n = 20, 10 mice for the blank
FIGURE 2 Antioxidant activities of E-DRS in vitro (a) Total
antioxidant capacity (TAC) of E-DRS measured by the FRAP method.
All compounds were prepared at the same test concentration of
0.125 mg/ml. (b,c) Superoxide anion scavenging ability (b) and DPPH
radical scavenging activity (c) are reported in terms of IC50 (μmol).
Data are expressed as mean S.E.M. (n = 9 from 3 separate
experiments), **p < .01, ***p < .001 versus E-DRS group, #p > .05
versus SAA group, †p > .05 versus E-DRS group

QIU ET AL.
5
group were injected with an equal volume of olive oil. Two hours later,
all mice were allowed to drink water ad libitum but fasted strictly.
Twenty four hours after the last treatment, mice were all anesthe-
tized using diethyl ether. Then liver tissues were removed and washed
with ice-cold saline immediately. About 0.2 g liver were homogenized
with the corresponding buffer according to the protocols of commer-
cially available kits. The tissue lysates were centrifuged at 2,500 rpm
for 20 min at 4 ꢀC, and the supernatant was used for assaying the
levels of MDA, CAT, SOD, and GSH following the manufacturer's
instructions.
relationship between the imine moiety and its antioxidant activity pre-
liminarily. Our result showed that the scavenging efficiency improved
nearly threefold from average 25.7–66.7% when the C-N double
bond in compound III was reduced to the C–N single bond in com-
pound IV. Compound IV was then used throughout this study and
named E-DRS. Figure 1 shows the chemical structure and differences
between E-DRS and SAA.
Next, the total antioxidant capacity (TAC) and free radical (includ-
−
ing •O2 and DPPH•) scavenging ability experiments were used to
compare the antioxidant activities of E-DRS, RES, and SAA in vitro.
Rutin and ascorbic acid (Vit C) were used as positive control antioxi-
dants throughout this study. The results are shown in Figure 2.
According to the TAC assay, all compounds exerted good antioxi-
dant activity at the same test concentration (0.125 mg/ml). The effect
of E-DRS is weaker than that of Vit C but stronger than that of rutin,
SAA, and RES significantly (all p < .01). The relative antioxidant capaci-
ties of the compounds were in the order: Vit C > E-DRS > SAA ≥ rutin
> RES (Figure 2(a)).
2.5
|
Statistical analysis
All experiments were repeated at least three times, and results were
expressed as the means S.E.M. Statistical analysis was performed
using one-way ANOVA and comparisons between means were carried
out according to Bonferroni post hoc test. p < .05 was considered sta-
tistically significant.
According to the pyrogallol autoxidation method, the superoxide
anion scavenging ability of E-DRS was also obviously higher than that
of RES, SAA, and rutin, but weaker than that of Vit C (all p < .05). The
mean IC50 value for E-DRS was 35.79 5.40 μg/ml, which is approxi-
mately 1.5-fold more potent than that for SAA (59.12 5.38 μg/ml)
and rutin (63.17 7.97 μg/ml) and approximately threefold more
potent than RES (116.7 10.36 μg/ml). The relative potency of the
compounds was in the order: Vit C > E-DRS > SAA ≥ rutin > RES (Fig-
ure 2(b)).
3
|
RESULTS AND DISCUSSION
| Chemistry (structure elucidation)
3.1
The synthesis of E-DRS, a kind of SAA analog, was accomplished by
esterification, acylation, and aldimine condensing reaction according
to the pathway illustrated in Scheme 1. Compound II was synthesized
from RES (compound I) via Vilsmeier formylation reaction according
to the report previously (Huang et al., 2007; Kataria & Khatkar, 2019).
It was then condensed with methyldopa in methanol to form the
Schiff bases (compound III), which was further purified by column
chromatography. Finally, compound III was reduced by NaBH4, and a
more stable saturated alkylamine (compound IV) was obtained.
In the DPPH assay, the free radical scavenging ability of E-DRS is
similar to that of Vit C, higher than that of RES and SAA, but weaker
than that of rutin. The relative potency of the compounds was in the
order: rutin > E-DRS ≥ Vit C > SAA > RES (Figure 2(c)).
All these results demonstrated clearly that E-DRS has consider-
able antioxidant activities in vitro.
3.3
|
Hepatoprotective activity of E-DRS
3.2
|
Antioxidant activities of E-DRS in vitro
Intraperitoneal administration of carbon tetrachloride (CCl4) is a clas-
sic method to induce free radical generation. It had been extensively
used for the evaluation of antioxidant agents in vivo (Li et al., 2016).
At first, we used the DPPH method to measure the free radical scav-
enging activity of compounds III and IV, in order to explore the
TABLE 1 Effects of E-DRS on hepatic MDA, GSH contents, and CAT and SOD-like activities in CCl4-treated mice
Group
Control
Model
MDAa (nmol/mg protein)
GSHa (U/g protein)
CATa (U/g protein)
SODa (U/g protein)
21.97 1.14
0.083 0.002
14.82 0.62
852.2 26.87
0.103 0.002##
0.091 0.001**
0.083 0.002**
0.081 0.005**
0.092 0.001**,†
0.082 0.001**
8.12 0.26##
9.49 0.69**
724.2 53.53##
783.3 21.86**
809.0 12.14**
875.0 18.03**
762.3 41.37**,†
829.5 9.7**,†
10.24 0.66##
13.37 1.65**
13.58 1.75**
18.26 1.05**
12.90 0.86**,†
15.65 0.81**,†
b
E-DRSL
10.86 0.64**
12.88 0.75**
9.06 0.68*,†
10.01 0.62**,†
b
E-DRSM
b
E-DRSH
Vit C
RES
aData are expressed as mean S.E.M., n = 10. ##p < .01 versus control group, *p < .05, **p < .01 versus model group, †p < .05 versus E-DRSH group.
bE-DRSL, E-DRSM, and E-DRSH represent 5, 25, or 125 mg/kg day of E-DRS p.o., respectively.

6
QIU ET AL.
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Bonnefont-Rousselot, D. (2016). Resveratrol and cardiovascular diseases.
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In accordance with those in vitro antioxidant effects, the
hepatoprotective activity of E-DRS in mice was also used here to eval-
uate its antioxidant capacity in vivo. As SAA is more expensive, we
selected vitamin C and resveratrol as positive drugs for economic rea-
sons in this part. The results are shown in Table 1.
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oxidative stress, in CCl4-treated mice increased remarkably, indicating
increased lipid peroxidation and oxidative stress in the liver. Oral
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CCl4-induced oxidative stress as evidenced by reduced MDA con-
tents, increased GSH level, and elevated CAT and SOD-like activities
in mice liver (all p < .05). It should be noted that E-DRS can protect
the liver against CCl4-induced oxidative damage even at a low con-
centration (10 μmol/kg day, E-DRSL group) in the present study. In
addition, the protective effect of E-DRS at high doses (100 μmol/
kg day, E-DRSH group) is obviously better than that of Vit C
(100 μmol/kg day) and RES (100 μmol/kg day) (p < .05), suggesting a
potent antioxidant effect of E-DRS in vivo.
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4
|
CONCLUSION
In this study, we successfully designed and synthesized a new SAA
analog, E-EDRS, which uses RES structure and an amine group to
replace the 30,40-dihydroxy-trans-stilbene group, and the ester struc-
ture of SAA, respectively. E-DRS exhibited powerful antioxidant activ-
ities both in vitro and in vivo, and its antioxidant activity in vitro was
stronger than SAA significantly. The mechanism includes direct scav-
enging effects on free radical species as well as indirect antioxidant
capacities via promoting the activities of the antioxidant enzyme, such
as CAT and SOD. The new SAA analog could be used as a new power-
ful antioxidant resource after further optimization and evaluation.
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& Vemuganti, R. (2015). Resveratrol
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ACKNOWLEDGMENTS
This work was supported by Education Department General Project
of Hunan Province (Grant No. 09C830), Hunan Provincial Innovation
Foundation for Postgraduate (Grant No. CX20190748), Natural Sci-
ence Foundation of Hunan Province (Grant No. 2019JJ40251), and
Undergraduate Training Program for Innovation and Entrepreneurship
of Hunan Province (Grant No. 2324).
CONFLICT OF INTEREST
Tang, H. J., Zhang, X. W., Yang, L., Li, W., Li, J. H., Wang, J. X., & Chen, J.
(2016). Synthesis and evaluation of xanthine oxidase inhibitory and
antioxidant activities of 2-arylbenzo[b]furan derivatives based on
salvianolic acid C. European Journal of Medicinal Chemistry, 124,
637–648.
The authors declare no conflicts of interest.
ORCID
Zhi-Zhong Xie
https://orcid.org/0000-0003-3365-0379
Teixeira, J., Chavarria, D., Borges, F., Wojtczak, L., Wieckowski, M. R.,
Karkucinska-Wieckowska, A., & Oliveira, P. J. (2019). Dietary polyphe-
nols and mitochondrial function: Role in health and disease. Current
Medicinal Chemistry, 26(19), 3376–3406.
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How to cite this article: Qiu J-M, Qin C-F, Wu S-G, et al. A
novel salvianolic acid A analog with resveratrol structure and
its antioxidant activities in vitro and in vivo. Drug Dev Res.
2020;1–8. https://doi.org/10.1002/ddr.21734

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