Evaluation of biological activities, and exploration on mechanism of action of matrine–cholesterol derivatives

Article abstract of DOI:10.1016/j.bioorg.2019.103439

To develop new potential pesticides, a series of matrine–cholesterol derivatives were prepared by modifications of two non-food bioactive products matrine and cholesterol. Two N-phenylsulfonylmatrinic esters (5i and 5j) showed the most potent insecticidal

Full text of DOI:10.1016/j.bioorg.2019.103439

BioorganicChemistryxxx(xxxx)xxxx
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Evaluation of biological activities, and exploration on mechanism of action
of matrine–cholesterol derivatives
Jianwei Xua,1, Zhiqiang Suna,1, Meng Haoa, Min Lva,⁎, Hui Xua,b,⁎
a College of Plant Protection/Chemistry and Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China
b Research Center of Natural Products & Medicinal Chemistry, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang Province, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
To develop new potential pesticides, a series of matrine–cholesterol derivatives were prepared by modifications
of two non-food bioactive products matrine and cholesterol. Two N-phenylsulfonylmatrinic esters (5i and 5j)
showed the most potent insecticidal activity against Mythimna separata Walker. Two N-benzylmatrinic esters (5e
and 5g) exhibited the most promising aphicidal activity against Aphis citricola Van der Goot. Especially com-
pound 5e showed good control effects in the greenhouse against A. citricola. Some interesting results of their
structure-activity relationships were also observed. By reverse transcription polymerase chain reaction (RT-PCR)
and quantitative real-time polymerase chain reaction (qRT-PCR) analysis of HMG-CoA reductase in apterous
adults of A. citricola, it demonstrated that matrine and cholesterol may be the HMG-CoA reductase inhibitors,
and the hydroxyl of cholesterol or the lactam ring of matrine may be important for acting with HMG-CoA
reductase in A. citricola.
Sophora flavescens
Matrine
Pesticidal activity
qRT-PCR
Mechanism of action
1. Introduction
were tested against Aphis citricola Van der Goot and Mythimna separata
Walker. Furthermore, their mechanism of action against A. citricola was
Over the past decade, the repeat and massive use of synthetic pes-
investigated.
ticides
has led to negative effects on the
environment and
hu-
man health, and insect pests resistance and rerampancy [1,2]. To de-
velop new potential alternatives for efficient control insect pests,
recently, naturally non-food bioactive substances have received much
attention [3–5].
2. Materials and methods
2.1. Preparation of matrine–cholesterol derivatives (5a–n)
Matrine (1, Fig. 1) is an important plant secondary metabolite, ex-
tracted and isolated as a quinolizidine alkaloid from the roots of So-
phora flavescens (Kushen) distributed in Asia, Oceanica, and the Pacific
islands [6]. Matrine and its derivatives displayed a variety of medicinal
activities such as antiviral activity [7], anti-inflammatory activity [8],
anticancer activity [9], and so on. Additionally, although matrine and
its derivatives (registered as a botanical pesticide in China) showed
pesticidal activities for crop protection [10,11], their pesticidal activ-
ities are much lower in magnitude when compared with commercially
chemical pesticides. Previously, we found some cholesterol-based hy-
drazones exhibiting potent insecticidal activity after modification of
cholesterol (2, Fig. 1), a type of lipid molecule, which is transported in
the blood plasma of all animals [12]. Consequently, we prepared a
series of matrine–cholesterol derivatives (Fig. 1) by combining two
molecules, matrine and cholesterol together. Their biological activities
A mixture of compounds 4a–n (0.5 mmol), cholesterol (2,
0.6 mmol), DCC (0.5 mmol), and DMAP (0.1 mmol) in 5 mL of dry
dichloromethane was stirred at room temperature. After 48–96 h, the
mixture was diluted with 20 mL of dichloromethane. Then the solution
was washed with 0.1 M aq. HCl (10 mL), 5% aq. Na2CO3 (10 mL) and
brine (10 mL), dried over anhydrous Na2SO4, concentrated in vacuo,
and purified by preparative thin-layer chromatography (PTLC) to afford
target compounds 5a–n in 9–31% yields. Data for compound 5a: Yield:
21%, white solid; m.p. 146–148 °C; [α] 2D0 = −7 (c 2.4 mg/mL, CHCl3);
1H NMR (500 MHz, CDCl3) δ: 7.32–7.34 (m, 2H, Ph-H), 7.28–7.30 (m,
2H, Ph-H), 7.19–7.22 (m, 1H, Ph-H), 5.33 (s, 1H, –CH = C), 4.55–4.61
(m, 1H, –OCH), 4.10 (d, J = 14.0 Hz, 1H), 3.10 (d, J = 13.5 Hz, 1H),
2.82–2.86 (m, 2H), 2.77 (d, J = 11.0 Hz, 1H), 2.62 (t, J = 12.0 Hz,
1H), 2.31–2.34 (m, 1H), 2.24–2.26 (m, 4H), 1.90–2.03 (m, 5H),
1.80–1.84 (m, 5H), 1.65–1.74 (m, 5H), 1.47–1.60 (m, 9H), 1.34–1.44
⁎ Corresponding authors at: College of Plant Protection, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China.
E-mail addresses: lvmin@nwsuaf.edu.cn (M. Lv), orgxuhui@nwsuaf.edu.cn (H. Xu).
1 These authors contributed equally to this work.
https://doi.org/10.1016/j.bioorg.2019.103439
Received 28 September 2019; Received in revised form 6 November 2019; Accepted 12 November 2019
0045-2068/©2019ElsevierInc.Allrightsreserved.
Pleasecitethisarticleas:JianweiXu,etal.,BioorganicChemistry,https://doi.org/10.1016/j.bioorg.2019.103439

J. Xu, et al.
BioorganicChemistryxxx(xxxx)xxxx
H
H
H
H
HO
Cholesterol (2)
H
H
O
H
R1
H
H
H
H
H
N
H
N
O
H
O
H
H
Target compounds
N
N
Matrine (1)
Sophora flavescens
O
O
O
Cl
O
OH
N
N
N
O
O
O
NH
NO2
Fig. 1. Chemical structures of toosendanin, imidacloprid, matrine (1), cholesterol (2) and target compounds.
(m, 10H), 1.25 (s, 1H), 1.05–1.18 (m, 8H), 0.96 (s, 3H), 0.90–0.91 (m,
3. Results and discussion
3H), 0.85–0.87 (m, 6H), 0.67 (s, 3H).
3.1. Chemistry
2.2. Biological assay
In Scheme 1, first, N-benzylmatrinic methyl esters and N-phe-
nylsulfonylmatrinic methyl esters (3a–n) were obtained by reaction of
matrine (1) with 6 M aq. HCl, followed by MeOH, and benzyl bromides/
chlorides or phenylsulfonyl chlorides. Then hydrolysis of compounds
3a–n in the presence of NaOH or HCl gave N-benzylmatrinic acids and
N-phenylsulfonylmatrinic acids (4a–n). Finally, target compounds 5a–n
were obtained by reaction of compounds 4a–n with cholesterol (2) in
the presence of DCC and DMAP (Zhang et al., 2018). Their structures
were characterized by optical rotation, IR, 1H NMR, and mp (see
Supplementary data).
The biological activities of compounds 1, 2 and 5a–n were eval-
uated against M. separata and A. citricola, respectively [13,14].
2.3. Mechanisms of action against Aphis citricola
Acetone solutions of compounds 1, 2, and 5e were prepared at
1.076, 2.878, and 0.609 mg/mL, respectively. The solution of imida-
cloprid (a positive control) was prepared in acetone at 0.248 μg/mL.
The corresponding solution (0.04 µL) was added to the pronotum of
aphids (120 healthy and size-consistency apterous adults of A. citricola
for each compound). The aphids treated with acetone alone were used
3.2. Pesticidal activities
as CK. The experiment was carried out at 25
1 °C and 50
7%
3.2.1. Growth inhibitory activity of compounds 1, 2 and 5a–n against M.
separata
relative humidity (RH), and on 14 h/10 h (light/dark) photoperiod.
After 48 h, 30 alive aphids of each treatment were selected out. The
putative HMG-CoA reductase mRNAs of A. citricola were obtained from
National Center for Biotechnology Information (NCBI) (https://www.
ncbi.nlm.nih.gov/) and UniProt (https://www.uniprot.org/). The N-
terminal ligand-binding conserved domain and the transmembrane re-
gions (TM) were used by SMART program (http://smart.embl-
heidelberg.de/). The primers for qRT-PCR were design using primer 3
online (http://primer3.ut.ee/). The mechanism of action of compound
5e was explored through reverse transcription polymerase chain reac-
tion (RT-PCR) and quantitative real-time polymerase chain reaction
(qRT-PCR) analysis of the mRNAs expression in A. citricola [6,13].
As shown in the Table 1, the final mortality rates (FMRs) of these
derivatives against M. separata after 35 days were generally higher than
those after 10 or 20 days, so these derivatives displayed the delayed
insecticidal activity against M. separata. On the other hand, the symp-
toms for all treated M. separata were observed as the same as our pre-
vious papers [6,13,14]. For instance, the thin and wrinkled dead larvae
appeared at the larval stage (Fig. 2); some malformed and dead pupae
were observed at the pupation period (Fig. 3); some malformed moths
were found during the adult stage (Fig. 4). When compared with a
botanical insecticide toosendanin (Fig. 1), compounds 5d, 5g, 5i, 5j and
5n exhibited potent insecticidal activity against M. separata. The final
2

J. Xu, et al.
BioorganicChemistryxxx(xxxx)xxxx
R
N
H
H
H
COOH
For 3a-m
O
H
NaOH/MeOH
reflux/5 h
H
R
N
H
a) 6 M HCl/ reflux/6 h
b) MeOH/rt/3 h
N
H
H
H
H
N
H
86%-95%
4a-m
COOCH3
c) RCl or RBr/K2CO3
DCM/rt/6-12 h
95%
H
R
H
N
H
19%-64%
N
N
For 3n
COOH
THF/4 M HCl/50 o
C
1
3a-n
H
H
N
4n
H
H
H
H
4a-n
R
N
H
H
H
DCC/DMAP/DCM
H
H
H
H
O
O
HO
rt/48-96 h
9%-31%
2
H
N
5a-n
R =
OCH3
CH2
Br
F
Cl
C2H5
m
g
h
k
l
i
a
c
e
CH2
CH2
CH2
SO2
CH3
SO2
Br
SO2
F
CH3
Cl
n
j
f
d
b
Br
F
SO2
SO2
SO2
CH2
CH2
CH2
CH2
Scheme 1. Preparation of target compounds 5a–n.
mortality rates (FMRs) of compounds 5d, 5g, 5i, 5j and 5n were 51.7%,
51.7%, 58.6%, 55.1%, and 51.7%, respectively. Especially compounds
5i and 5j showed the most promising insecticidal activity; whereas the
FMRs of their lead compounds (matrine (1) and cholesterol (2)) were
only 24.1% and 20.7%, respectively (Table 1). To N-benzylmatrinic
esters (5a–h), compounds 5d (R = 4-methylbenzyl) and 5g (R = 4-
methoxybenzyl) showed potent insecticidal activity. It suggested that
compounds containing the electron-donating groups on their phenyl
usually exhibited more potent insecticidal activity than those con-
taining the electron-withdrawing ones. To N-phenylsulfonylmatrinic
esters (5i–n), compounds 5i (R = phenylsulfonyl), 5j (R = 4-methyl-
phenylsulfonyl) and 5n (R = 4-fluorophenylsulfonyl) displayed pro-
nounced insecticidal activity, however, the electron effect of the sub-
stituents R on the insecticidal activity was not obvious.
3.2.2. Aphicidal activity of compounds 1, 2 and 5a–n against Aphis
citricola
As described in Table 2, compounds 5c, 5e, 5g and 5h showed
potent aphicidal activity against A. citricola. The 48 mortality rates
(MRs) of compounds 5c, 5e, 5g and 5h were 48.8%, 56.9%, 50.5%, and
44.1%, respectively. Especially compound 5e (R = 4-fluorobenzyl)
displayed the most pronounced aphicidal activity with the 48 h MR of
56.9%; whereas the 48 h MRs of compounds 1 and 2 were only 31.8%
and 19.3%, respectively. In general, derivatives 5a–h (R as the (un)
substituted benzyl) exhibited more promising aphicidal activity than
5i–n (R as the (un)substituted phenylsulfonyl). To compounds 5a–h,
introduction of the fluorine atom at the 4-position on the phenyl was
important for the aphicidal activity (e.g., 5e (4-F) Vs. 5c (4-Br); 5e (4-F)
Vs. 5h (2-F)).
3

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Table 1
Growth inhibitory activity of compounds 1, 2 and 5a–n against M. separata at
1 mg/mL.
Compound
Corrected mortality rate (mean
SE, %)
10 days
20 days
35 days
1
6.7
3.3
3.3
3.3
6.6
6.6
3.3
6.6
6.6
16.6
13.3
13.3
3.3
3.3
3.3
24.1
20.7
34.5
27.6
44.8
51.7
48.2
44.8
51.7
48.2
58.6
55.1
44.8
44.8
34.5
51.7
48.2
3.3
6.6
6.6
5.7
8.8
8.8
5.7
3.3
3.3
5.7
5.7
8.8
3.3
8.8
3.3
6.6
5.7
2
3.3
5a
13.3
6.7
5b
6.7
6.6
5c
23.3
6.7
26.6
20.0
23.3
13.3
23.3
43.3
46.6
16.6
30.0
13.3
16.6
20.0
23.3
8.8
5.7
8.8
3.3
8.8
8.8
3.3
8.8
5d
5e
16.6
6.7
5f
5g
20.0
30.0
33.3
6.7
5.7
5h
5.7
6.6
5i
5j
3.3
5k
20.0
10.0
10.0
20.0
16.6
5.7
5.7
5.7
5.7
3.3
10.0
3.3
6.6
5.7
8.8
5l
5m
5n
toosendanin
Fig. 3. The representative malformed pupae pictures of compounds 5d (XJW-
21), 5g (XJW-23), 5l (XJW-24), 5j (XJW-25), 5k (XJW-30), 5f (XJW-31), and
5m (XJW-35) against M. separata during the pupation period (CK: blank control
group).
Fig. 4. The representative malformed moth pictures of compounds 5d (XJW-
21), 5g (XJW-23), 5j (XJW-25), 5i (XJW-26), 5e (XJW-27), 5n (XJW-28), and
5h (XJW-33) against M. separata during the adult emergence period (CK: blank
control group).
Fig. 2. The representative abnormal larvae pictures of compounds 5i (XJW-
26), 5k (XJW-30), 5h (XJW-33), 5g (XJW-23), 5n (XJW-28), 5c (XJW-32),
and 5m (XJW-35) against M. separata during the larval period (CK: blank
control group).
32.9%, and 34.4%, respectively. The pictures of control efficiency of
The 48 h LD50 values of some potent derivatives against A. citricola
were shown in Table 3. The LD50 values of 5c, 5e, 5g and 5h were
between 0.041 and 0.047 µg/larvae. Compounds 5e and 5g ex-
hibited > 2.4 folds more pronounced aphicidal activity than compound
1 (LD50 value: 0.101 µg/larvae), and compounds 5e and 5g ex-
hibited > 4.5-fold more potent aphicidal activity than compound 2
(LD50 value: 0.191 µg/larvae). Moreover, compounds 1 and 5e were
tested for their control effects against A. citricola at 1.0 mg/mL in the
greenhouse (Table 4). Compound 5e exhibited good control effects
when compared with that of compound 1. The control effects of com-
pound 5e on the 3rd, 5th and 7th day were 55.0%, 58.7%, and 59.1%,
respectively; whereas the control effects of compound 1 were 26.5%,
compounds 1 and 5e against A. citricola were shown in Fig. 5.
3.3. Mechanisms of action against A. citricola
HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A re-
ductase) is the rate-controlling enzyme for cholesterol biosynthesis
[15]. In insects pest, HMG-CoA reductase can regulate insect juvenile
hormones (JH) biosynthesis [16,17]. Cholesterol derivaties alone or in
combination with statin can be used as inhibitors reducing HMG-CoA
reductase protein accumulation in CHO-7 cells to treat cardiovascular
disease in mammals [18]. So compounds 1, 2, and 5e were investigated
targeting on HMG-CoA reductase of A. citricola. The primers of HMG-
4

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BioorganicChemistryxxx(xxxx)xxxx
Table 2
positive control) were tested by qRT-PCR and RT-PCR (Fig. 6b–c).
Compounds 1 and 2 down-regulated HMG-CoA reductase to 0.08 and
0.13 folds, respectively; whereas imidacloprid up-regulated HMG-CoA
reductase to 11.43 folds. It suggested that compounds 1 and 2 may be
inhibitors of HMG-CoA reductase. The result of compound 2 was the
same as the previous reports [18]. Interestingly, cholesterol-matrine
derivative 5e had no effect on the mRNA expression changes of HMG-
CoA reductase in A. citricola. That is, opening the lactam ring of com-
pound 1 or esterization of hydroxyl of compound 2 may lead to no
action with HMG-CoA reductase in A. citricola. It demonstrated the hy-
droxyl of compound 2 or the lactam ring of compound 1 may be ne-
cessary for acting with HMG-CoA reductase in A. citricola.
Aphicidal activity of compounds 1, 2 and 5a–n against apterous adults of A.
citricola treated at 0.04 µg/larvae aAt 0.8 ng/larvae.
Compound
Corrected mortality rate (mean
24 h
SE, %)
48 h
1
13.4
6.7
2.9
31.8
19.3
27.0
29.4
48.8
35.2
56.9
34.1
50.5
44.1
32.5
32.9
19.7
37.6
31.3
29.0
88.6
5.0
2.9
2.9
1.9
4.0
2.9
2.9
2.9
3.8
1.9
1.1
3.3
1.9
4.0
2.9
2.2
1.1
2
1.1
5a
8.0
1.1
0
5b
3.5
5c
25.0
6.9
1.9
5d
1.9
2.2
1.1
1.9
4.0
1.1
2.9
5e
13.6
9.2
5f
5g
13.7
19.3
3.4
4. Conclusion
5h
5i
A series of matrine–cholesterol derivatives were prepared by mod-
ifications of two non-food bioactive products, matrine and cholesterol.
Especially two N-phenylsulfonylmatrinic esters (5i and 5j) showed the
most promising insecticidal activity against M. separata. Two N-ben-
zylmatrinic esters (5e and 5g) exhibited the most pronounced aphicidal
activity against A. citricola. It demonstrated that N-benzylmatrinic es-
ters generally showed more promising aphicidal activity than N-phe-
nylsulfonylmatrinic ones; on the contrary, N-phenylsulfonylmatrinic
esters generally exhibited more potent insecticidal activity than N-
benzylmatrinic ones. Compound 5e displayed good control effects
against A. citricola. By RT-PCR and qRT-PCR analysis of HMG-CoA re-
ductase in apterous adults of A. citricola, it suggested that compounds 1
5j
14.9
8.0
5k
1.9
5l
11.4
11.3
6.8
2.9
3.8
5m
5n
1.1
imidacloprida
64.0
1.1
CoA reductase gene of A. citricola used for qRT-PCR were described in
Table 5, and the schematic diagram of HMG-CoA reductase in A. citricola
was shown in Fig. 6a. The mRNA expressions changes of HMG-CoA
reductase in A. citricola against compounds 1, 2, 5e and imidacloprid (a
Table 3
LD50 values of some compounds at 48 h against A. citricola.a
Compound
Regression equation
LD50 (µg/larvae)
Confidence interval
95% (µg/larvae)
r
1
Y = 1.411 + 1.417X
Y = 1.711 + 2.381X
Y = 4.181 + 3.102X
Y = 3.254 + 2.342X
Y = 3.926 + 2.848X
Y = 2.980 + 2.247X
Y = 3.822 + 0.869X
0.101
0.191
0.045
0.041
0.042
0.047
0.00004
0.079–0.159
0.168–0.229
0.041–0.050
0.036–0.047
0.038–0.047
0.041–0.057
0.000026–0.000062
0.979
0.944
0.988
0.987
0.987
0.990
0.972
2
5c
5e
5g
5h
imidacloprid
a
Regression analysis by IBM SPSS Statistics 23.0, P < 0.05.
Table 4
Control efficiency of compounds 1 and 5e against A. citricola in greenhouse tested at 1.0 mg/mL.
Compound
Control efficiency (mean
SE, %)
1st day
3rd day
5th day
7th day
1
7.7
1.6
1.2
1.6
26.5
55.0
98.0
1.4
1.6
0.4
32.9
58.7
99.4
1.7
1.7
0.4
34.4
59.1
100.0
1.2
2.6
0
5e
11.0
68.2
Imidacloprida
a
At 10 mg/L.
5

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BioorganicChemistryxxx(xxxx)xxxx
Fig. 5. Pictures of control efficiency of matrine (1), and compound 5e (XJW-27) against Aphis citricola in the greenhouse.
Table 5
Primers of HMG-CoA reductase of A. citricola used for qRT-PCR.
Gene
Sequence (5′–3′)b
Annealing
Product size
(bp)
temperature (°C)
Ef1-α
F-agcctggtatggttgtcgtt
R-ctgtgaaatcagcagctccc
F-cagagaggggtgttggtctt
R-gtccagcaactccaacaggt
60
60
207
165
HMG-CoA
reductasea
a
HMG-CoA reductase: 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. bF: forward primer; R: reverse primer.
6

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BioorganicChemistryxxx(xxxx)xxxx
Fig. 6. The expression patterns of HMG-CoA
reductase in apterous adults of A. citricola
collected 48 h post-treatment with matrine
(43.04 ng/larvae), cholesterol (115.12 ng/
larvae), compound 5e (24.36 ng/larvae),
and imidacloprid (0.00992 ng/larvae), re-
spectively. (a): The schematic diagram of
the HMG-CoA reductase in A. citricola. TM:
the transmembrane regions. (b): The HMG-
CoA reductase mRNA expressions were
evaluated by qRT-PCR. HMG-CoA reductase
mRNA expressions were normalized to ef1-α
TM1
TM3
TM5
a
HMG-CoA reductase
TM2
TM4
TM6
250
60
350 aa
16
15
14
13
12
11
10
9
b
CK
Compd.
**
expression (mean
SD, n = 3). Asterisks
indicate significant differences (*P < 0.05;
**P < 0.01) compared with CK. CK: blank
control group. (c): HMG-CoA reductase was
evaluated through RT-PCR.
8
7
6
5
4
3
2
1
*
*
0
Matrine
Cholesterol
5e
Imidacloprid
CK matrine cholesterol 5e imidacloprid
43.04 115.12 24.36 0.00992 (ng/per aphid)
c
0
HMG-CoA reductase
ef1-
and 2 may be the HMG-CoA reductase inhibitors, and hydroxyl of
compound 2 or the lactam ring of compound 1 may be necessary for
acting with HMG-CoA reductase in A. citricola.
[2] Z. Sun, M. Lv, X. Yu, H. Xu, A.C.S. Sust, Chem. Eng. 5 (2017) 3945.
[3] J.N. Seiber, J. Coats, S.O. Duke, A.D. Gross, J. Agric. Food Chem. 62 (2014) 11613.
[4] X. Yu, Z. Che, H. Xu, Chem. Eur. J. 23 (2017) 4467.
[5] Y. Zuo, Q. Wu, S. Su, C. Niu, Z. Xi, G. Yang, J. Agric. Food Chem. 64 (2016) 552.
[6] B. Zhang, Z. Sun, M. Lv, H. Xu, J. Agric. Food Chem. 66 (2018) 12898.
[7] Y. Ding, N. Li, J. Sun, L. Zhang, J. Guo, X. Hao, Y. Sun, Virol. Sin. 34 (2019) 78.
[8] P. Dong, X. Ji, W. Han, H. Han, Inter. Immunopharm. 74 (2019) 105686.
[9] Y.Y. Jung, M.K. Shanmugam, A.S. Narula, C. Kim, J.H. Lee, O.A. Namjoshi,
B.E. Blough, G. Sethi, K.S. Ahn, Cancers 11 (2019) 49.
Acknowledgements
The work was supported by National Natural Science Foundation of
China (No. 21877090), and Special Funds of Central Colleges Basic
Scientific Research Operating Expenses, Northwest A&F University (No.
2452018110).
[10] Z.Z. Odimar, D.P.R. Leandro, F.A. Thiago, S.S. Monica, P.B. Gabriela, T.Y. Pedro,
D.V. Jose, Crop Prot. 67 (2015) 160.
[11] B.Z. Zhong, C.J. Lu, X.D. Sun, W.Q. Qin, Z.Q. Peng, Agrochemicals 49 (2010) 924.
[12] C. Yang, Y. Shao, X. Zhi, H. Qu, X. Yu, X. Yao, H. Xu, Bioorg. Med. Chem. Lett. 23
(2013) 4806.
[13] S. Li, Z. Sun, B. Zhaung, M. Lv, H. Xu, Ind. Crop Prod. 131 (2019) 134.
[14] M. Lv, G. Liu, M. Jia, H. Xu, Bioorg. Chem. 81 (2018) 88.
[15] L.A. Schuler, M.E. Toaff, J.F. Strauss, Endocrinology 108 (1981) 1476.
[16] E.S. Istvan, J. Deisenhofer, Science 292 (2001) 1160.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bioorg.2019.103439.
[17] D.J. Monger, W.A. Lim, F.J. Kézdy, J.H. Law, Biochem. Bioph. Res. Co. 105 (1982)
1374.
[18] S. Jiang, H. Li, J. Tang, J. Wang, J. Luo, B. Liu, J. Wang, X. Shi, H. Cui, J. Tang,
F. Yang, W. Qi, W. Qiu, B. Song, Nat. Commun. 9 (2018) 5138.
References
[1] F. Gould, Z.S. Brown, J. Kuzma, Science 360 (2018) 728.
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