Chemical constituents from Cicuta virosa Linnaeus and their reversal effects on doxorubicin-resistant human myelogenous leukemia (K562/A02) cells

Article abstract of DOI:10.1016/j.cclet.2016.03.039

Two new compounds, 11,11′-dimer of scopoletin (1) and 11-O-β-glucopyranosylhamaudol (2), together with seven known compounds were isolated and identified from the whole grass of Cicuta virosa. The chemical structures of the isolated compounds were elucidated using different spectroscopic methods. In addition, the chemical constituents were evaluated for multidrug resistance reversing activity towards doxorubicin-resistant K562/A02 cells. Compounds 1, 8, and 9 were endowed with remarkable MDR reversing effects.

Full text of DOI:10.1016/j.cclet.2016.03.039

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CCLET-3659; No. of Pages 4
Chinese Chemical Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Chemical constituents from Cicuta virosa Linnaeus and their reversal
effects on doxorubicin-resistant human myelogenous leukemia
(
K562/A02) cells
a
b
c
d
a,
Shu-Qi Wang , Qing-Wei Zhang , Xiao-Ling Wang , Xia-Xia Di , Xiao-Ning Wang *,
a,
Hong-Xiang Lou *
a
School of Pharmaceutical Science, Shandong University, Jinan 250012, China
b
Xintai Institute of Skin Diseases, Xintai 271200, China
c
The Second Hospital of Shandong University, Jinan 250033, China
d
Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, Iceland
A R T I C L E I N F O
A B S T R A C T
Two new compounds, 11,11 -dimer of scopoletin (1) and 11-O-b-glucopyranosylhamaudol (2), together
0
Article history:
Received 3 February 2016
Received in revised form 16 March 2016
Accepted 22 March 2016
Available online xxx
with seven known compounds were isolated and identified from the whole grass of Cicuta virosa. The
chemical structures of the isolated compounds were elucidated using different spectroscopic methods.
In addition, the chemical constituents were evaluated for multidrug resistance reversing activity
towards doxorubicin-resistant K562/A02 cells. Compounds 1, 8, and 9 were endowed with remarkable
MDR reversing effects.
Keywords:
Cicuta virosa
MDR
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
K562/A02
Doxorubicin
P-Glycoprotein
1
. Introduction
Multidrug resistance (MDR) has long been recognized as a
chemical constituents were evaluated for their multidrug resis-
tance reversing activity on human myelogenous leukemia cells.
serious problem in cancer treatment. One of the major mecha-
nisms of MDR in tumor cells is the over-expression of P-
glycoprotein (P-gp) [1]. Therefore, there is great clinical interest
in developing compounds that overcome resistances with lower
host toxicity [2]. Several types of compounds have been identified
as P-gp modulators, but most of them were reported to show
toxicity at the pharmacological dose required to achieve significant
MDR reversal [3,4]. Thus, P-gp inhibitors of plant origin have the
potential to be developed as MDR reversing agents.
In a previous study, we reported that a series of coumarins from
the methanol extract of Cicuta virosa L. possess potent multidrug
resistance reversing activity [5]. In connection with our interest in
this plant, two new compounds were isolated and identified,
together with seven known compounds (Fig. 1). In addition, the
2. Experimental
2.1. General
UV spectra were recorded in MeOH on a Agilent 8453E UV–vis
spectroscopy system. The IR spectra were measured in KBr on a
Thermo Nicolet NEXUS 470 FT-IR spectrometer. NMR spectra were
recorded on a Bruker AV 600 MHz NMR spectrometer with TMS as
an internal standard. HRESIMS data were obtained from Thermo-
Fisher Scientific LTQ-Orbitrap XL. HPLC was performed on Agilent
1260 HPLC system. Optical rotation data were measured by a
GYROMAT-HP polarimeter. The silica gel GF254 used for TLC was
supplied by the Qingdao Marine Chemical Co., Ltd., Qingdao, China.
Sephadex LH-20 and silica gel (200–300 mesh) used for column
chromatography were supplied by Pharmacia Biotech AB, Uppsala,
Sweden and Qingdao Marine Chemical Co., Ltd., Qingdao, China,
respectively. Spots of TLC were visualized within I
spraying with H SO /EtOH 1:9 followed by heating. All solvent
ratios are measured v/v.
2
vapor or by
*
Corresponding authors.
E-mail addresses: wangxn@sdu.edu.cn (X.-N. Wang),
2
4
louhongxiang@sdu.edu.cn (H.-X. Lou).
http://dx.doi.org/10.1016/j.cclet.2016.03.039
1
001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: S.-Q. Wang, et al., Chemical constituents from Cicuta virosa Linnaeus and their reversal effects on
doxorubicin-resistant human myelogenous leukemia (K562/A02) cells, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/
j.cclet.2016.03.039

G Model
CCLET-3659; No. of Pages 4
2
S.-Q. Wang et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
by semi-preparative HPLC eluted with (MeOH/H
2
O 50:50, 1.5 mL/
min) to obtain 7 (55.8 mg, t
R
12.4 min) and 9 (78.3 mg, t 14.7 min).
R
0
11,11 -Dimer of scopoletin (1): Amorphous colorless powder.
ꢁ1
UV (MeOH): 230 (3.92), 254 (3.34). IR (KBr, cm ): 3650, 1710,
1
13
1
620, 1511. H NMR (CDCl
3 3
, 600 MHz) and C NMR (CDCl ,
+
þ
150 MHz): see Table 1. HRESIMS: 383.0765 ([M + H] ; C20
H
15O ,
8
calcd. 383.0767).
1-O- -Glucopyranosyl-hamaudol (2): Amorphous colorless
powder. ½ ꢂ ꢁ63 (c 0.11, MeOH). CD (MeOH): De254 + 5.2,
1
b
2
D
0
a
De232 ꢁ 4.2. UV (MeOH): 230 (4.11), 252 (5.05). IR (KBr): 3499,
1
13
1
1
655, 1580. H NMR (CDCl
3
, 600 MHz) and C NMR (CDCl
3
þ
,
,
+
50 MHz): see Table 1. HRESIMS: 455.1547 ([M + H] ; C21
27
H O
11
calcd. 455.1553).
.4. Sugar identification.
2
D
-Glucose (60 mg) and
75 mg) were dissolved in pyridine (4 mL) and stirred at 60 8C for
.5 h, and then o-tolyl isothiocyanate (330 L) was added to the
mixture and heated at 60 8C for 1.5 h. Separation by HPLC on an C-
8 column eluted with H O (containing 0.2% TFA)–CH CN (70:30)
gave the derivative S-1. The HRESIMS of S-1 gave a quasi-molecular
L-cysteine methyl ester hydrochloride
(
1
Fig. 1. Structures of compounds 1,2,8, and 9 isolated from C. virosa.
m
1
2
3
2.2. Plant material
+
27 2 7 2
ion [M + H] peak at m/z 447.1246 (calcd. for C18H N O S ,
C. virosa Linnaeus was collected in July 2012 in Heilongjiang
447.1254), which was well consistent with our previous experi-
Province, China, and was identified by Prof. Xueshen Wen, School
of Pharmaceutical Sciences, Shandong University. A voucher
specimen (No. 201207CV) has been deposited at the Laboratory
of Natural Products Chemistry, School of Pharmaceutical Sciences,
Shandong University, China.
ment [6]. Compound 2 was hydrolyzed with HCl and extracted
with CH
LH-20 column and the eluate was concentrated. The residue was
dissolved in pyridine (0.4 mL) and stirred with -cysteine methyl
ester (10 mg) for 1.5 h at 60 8C, and then o-tolyl isothiocyanate
40 L) was added to the mixture and heated at 60 8C for 1.5 h. The
2 2
Cl . The aqueous layer was passed through a Sephadex
L
(
m
2.3. Extraction and isolation
reaction mixture was analyzed by HPLC and detected at 250 nm.
Analytical HPLC was performed on a Phenomenex C18 column
The air-dried powder of the plant material of C. virosa L. (3.0 kg)
was extracted with EtOH/H
2
O (3 ꢀ 3 L, 95:5, v/v) under condition
of reflux. The combined EtOH extracts were concentrated in
vacuum to yield the crude material (780 g), which was then
successively partitioned with petroleum ether (PE; 210 g), AcOEt
Table 1
1
13
1
13
H NMR and C NMR data of 1 and 2 (600 MHz for H NMR and 150 MHz for
C
NMR, in CDCl3,
d in ppm, J in Hz).
(140 g), and BuOH (240 g). The AcOEt fraction was chromato-
1
2
graphed over silica gel, eluted with a solvent gradient system (PE/
acetone 5:1–1:1) to produce fractions A–D. Fraction A (12 g) was
subjected to column chromatography on silica gel eluted by PE/
acetone (50:1–10:1), to give three sub-fractions (A1–A3). Sub-
fraction A2 (220 mg) was separated by semi-preparative HPLC
a
a
No.
d
H
d
C
No.
d
H
d
C
0
0
2/2
160.6
113.4
2
3
166.7
106.5
3/3
6.22 (d, 1H,
J = 9.0 Hz)
6.39 (s, 1H)
0
4/4
7.92 (d, 1H,
J = 9.6 Hz)
143.3
4
181.8
(MeOH/H
2
R
O 80:20, 1.5 mL/min,) to give 4 (38.1 mg, t 21.5 min)
and 5 (60.5 mg, t
separated via column chromatography on silica gel with PE/
acetone (30:1–10:1) to yield five sub-fractions (C1–C5). Sub-
R
24.2 min). Fraction C (345 mg) was further
5/5
6/6
0
0
0
0
0
7.23 (s, 1H)
107.5
144
5
6
159
158.6
94.3
155.1
104
7/7
8/8
9/9
1
149.7
103.2
150
7
6.78 (s, 1H)
4.54 (s, 2H)
8
6.53 (s, 1H)
fraction C3 (35 mg) was purified by Sephadex LH-20, using CH
3
Cl/
9
CH OH (1:1) to yield compound 1 (25 mg). Fraction D (23 g) was
3
0
0
0/10
111.5
69.2
10
11
103.7
65.1
further separated on column chromatography on silica gel with PE/
acetone (10:1–5:1) to yield six sub-fractions (D1–D6). Sub-fraction
11/11
4.71 (d, 1H, J = 15.6 Hz)
4.60 (d, 1H, J = 15.6 Hz)
0
2
78.9
66.5
24.8
D2 (80.4 mg) was purified by semi-preparative HPLC (MeOH/H
0:30, 1.5 mL/min) to give 3 (46.3 mg, t 18.5 min). The BuOH
extract was applied to column chromatography on silica gel eluted
by CH Cl /CH OH (200:1–1:1) in gradient to give five fractions (E–
I). Fraction E (18 g) was subjected to column chromatography on
silica gel using CH Cl /CH OH (50:1–10:1), to yield mixtures (E1–
E4). Sub-fractions E1 (150.0 mg) and E2 (95.7 mg) were purified by
semi-preparative HPLC (CH OH/H O 65:35, 1.5 mL/min) to give 2
35.2 mg, t 15.4 min) and 6 (43.1 mg, t 17.3 min), respectively.
Fraction G (12.5 g) was applied to column chromatography on
silica gel, with CH Cl /CH OH (20:1) as eluent to give two fractions
G1 and G2). Sub-fraction G2 (115 mg) was separated on a
Sephadex LH-20 column with CH Cl /CH OH (1:1), to yield
compound 8 (35.3 mg). Fraction H (520 mg) was further chroma-
tographed on Sephadex LH-20 (CHCl /MeOH 1:1) and then purified
2
O
0
0
3
3.71 (m, 1H)
7
R
4
2.79 (dd, 1H, J =4.8,
16.8 Hz)
2.48 (dd, 1H, J =4.8,
2
2
3
16.8 Hz)
0
5
1.29 (s, 3H)
25
2
2
3
0
6
1.27 (s, 3H)
21.1
102.3
73.2
76.4
69.9
76.9
60.9
00
1
4.30 (d, 1H, J = 7.8 Hz)
3.10 (m, 1H)
3
2
2
3
4
5
6
3.18 (m, 1H)
(
R
R
3.05 (m, 1H)
3.12 (m, 1H)
2
2
3
3.67 (dd,1H, J =5.6,
12.5 Hz)
(
3.44 (dd, 1H, J =2.5,
2
2
3
12.5 Hz)
a
3
Atom numbering as indicated in Fig. 2.
Please cite this article in press as: S.-Q. Wang, et al., Chemical constituents from Cicuta virosa Linnaeus and their reversal effects on
doxorubicin-resistant human myelogenous leukemia (K562/A02) cells, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/
j.cclet.2016.03.039

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S.-Q. Wang et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
3
Table 2
(
H
6
4.6 ꢀ 250 mm) at 25 8C using a gradient of CH
O: 0–25 min (32:68), 25–35 min (from 32:68 to 70:30), and 35–
0 min (70:30) as the mobile phase. Peaks were detected with an
Agilent DAD detector. -Glucose was identified as the sugar moiety
of 2 according to the same retention time (t 14.2 min).
3
CN:0.2%TFA in
Effects of compound 1–9 on doxorubicin (DOX) cytotoxicity in K562 cells and K562/
2
A02 cells.
Compounds
IC50
(
mmol/L)
RF (K562/A02)
D
R
K562
K562/A02
DOX
0.37 ꢃ 0.03
0.33 ꢃ 0.12
0.39 ꢃ 0.22
0.33 ꢃ 0.08
0.41 ꢃ 0.20
0.43 ꢃ 0.18
0.29 ꢃ 0.14
0.35 ꢃ 0.06
0.31 ꢃ 0.13
0.34 ꢃ 0.18
0.29 ꢃ 0.11
41.5 ꢃ 0.12
13.3 ꢃ 0.07
25.8 ꢃ 0.11
32.3 ꢃ 0.24
42.7 ꢃ 0.14
43.1 ꢃ 0.09
21.7 ꢃ 0.15
36.2 ꢃ 0.07
6.2 ꢃ 0.06
8.3 ꢃ 0.10
4.7 ꢃ 0.17
2
.5. Biological assays
*
DOX + 1
DOX + 2
DOX + 3
DOX + 4
DOX + 5
DOX + 6
DOX + 7
DOX + 8
DOX + 9
DOX + Verapamil
3.12
1.61
1.28
0.97
0.96
1.91
1.15
6.69
5.00
8.83
The human myelogenous leukemia cell line K562, and its
multidrug-resistant counterpart K562/A02 were obtained from the
Department of Pharmacology, the Institute of Hematology of the
Chinese Academy of Medical Sciences (Tianjin, China). K562/A02
cells were maintained in a complete RPMI-1640 medium contain-
*
*
*
*
*
*
*
ing 1
m
g/mL doxorubicin (DOX) (Pfizer Italia S.r.l.) at 378 in a
. The cells were cultured for two
**
humidified atmosphere of 5% CO
2
Verapamil was used as a positive control agent.
weeks in drug-free medium prior to their use in the experiments.
4
Data were expressed as means ꢃ SD of three independent experiments.
Cells were harvested and seeded into 96-well plates at 2 ꢀ 10
*
P < 0.05 vs. doxorubicin treatment alone.
cells/well. For cytotoxicity experiments, different concentrations
of compounds 1–9 were added into designated wells, and for MDR
reversal experiments, different concentrations of DOX were added
**
P < 0.01 vs. doxorubicin treatment alone.
into designated wells with or without compounds 1–9 (10
mmol/
L). After 48 h, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-
lium bromide (MTT) solution was added to each well, and the plate
was further incubated for 4 h. The medium was discarded, and
moiety, and 15 signals attributable to the aglycone moiety, which
was similar to those of hamaudol (Table 1) [11]. The signals at d
H
6.53 (s, 1H, H-8) and 6.39 (s, 1H, H-3) were characteristic for the
0
1
00
crystal. The absorbance in individual wells was determined at
70 nm. IC50 values for compounds 1–9 and doxorubicin
concentration resulting in 50% inhibition of cell growth) were
m
L of DMSO was added into each well to dissolve the formazan
chromone of 2. The signals at
and
d
H
2.79 (dd, 1H, J = 4.8, 16.8 Hz, H-4 a)
0
0
d
H
2.48 (dd, 1H, J = 4.8, 16.8 Hz, H-4 b), 3.71 (m, 1H, H-3 ), and
1.29, 1.27 (s, each 3H, H-5 ,6 ) can be assigned to a trisubstituted
pyran ring. In addition, the signal of anomeric H-atoms appeared at
4.30 (d, 1H, J = 7.8 Hz, H-1 ) with coupling constants
characteristic of a -configuration. After sugar analysis, the
presence of a -glucose was confirmed [6]. The glucose residue
in 2 was found to be linked to C-11 since the signal of anomeric
0
0
5
(
00
calculated from plotted results using untreated cells as 100%. The
reversal fold (RF) values, as potency of reversal, were obtained
from fitting the data to RF = IC50 of cytotoxic DOX alone/IC50 of
cytotoxic DOX in the presence of the tested compounds [7].
d
H
b
D
1
13
proton at
H
d 4.30 showed a H– C long range correlation with a
3
. Results and discussion
signal of the C-11 at
d
C
65.1, in the HMBC spectrum (Fig. 2). The
0
absolute configuration at C-3 of 2 was confirmed as S by
comparison of the circular dichrosim (CD) curve with those of
hamaudol [11]. The basis of the evidence obtained, compound 2
Compound 1 was obtained as colorless, amorphous powder.
The positive-ion-mode HRESIMS exhibited a quasi-molecular-ion
peak at m/z 383.0765 ([M + H] ; calcd. 383.0767) corresponding to
+
was assigned to 11-O-b-glucopyranosyl-hamaudol.
the molecular formula C20
H
14
O
8
. The NMR spectra of 1 indicated a
The seven known compounds were isobyakangelicin (3) [12],
psoralene (4) [13], angelicin (5) [14], prim-O-glucosylangelicain
(6) [15], apiosylskimmin (7) [16], rutin (8) [17], and quercetin-3-O-
dimeric structure with a total of 15 C-atoms signals observed in the
13
C NMR spectra (Table 1). The spectral data of 1 was very similar
1
3
to those of scopoletin with some notable differences [8,9]. The
NMR spectra of 1 closely resembled that of scopoletin, except for
the signal assignable to C-11. The C-11 signal at 69.2 showed a
downfield shift by 12.8 ppm. The downfield shift of the signal
assignable to H-11 was also observed in the H NMR spectra. The
C
b-D-rhamnoside (9) [18], respectively.
The in vitro cytotoxic activities of the isolated compounds were
d
C
evaluated against K562 and K562/A02. Compounds 1–9 possessed
very weak cytotoxic activities (Table 2). The MDR reversal effects of
compounds 1–9 were further investigated by using the revised 3-
(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide
(MTT) method as described in the Experimental Part. Compounds
1, 8, and 9 were most active and exhibited significant MDR reversal
effects on K562/A02 cell line, using verapamil as a reference
compound.
1
0
H-11 signal at
d
H
4.54 (s, 2H, H-11/11 ) showed a downfield shift by
0
1
.72 ppm. All of the above data indicated that 1 might be the
1,11 -dimer of scopoletin. It was also supported by the NMR data
0
of another coumarin dimer, diumancal, which was very similar to 1
0
[
10]. Therefore, compound 1 was elucidated as 11,11 -dimer of
scopoletin (Fig. 2).
Compound 2 was obtained as a colorless amorphous powder.
The HRESIMS exhibited the [M + H] peak at m/z 455.1547 (calcd.
4. Conclusion
+
4
55.1553), corresponding to the molecular formula C21
H
26
O
11. The
In conclusion, nine compounds, including two new compounds
(1 and 2), were isolated from the C. virosa. The present study about
the isolation and identification of nine compounds shows the
diversity of chemical constituents in C. virosa. In addition, some of
these compounds showed remarkable MDR reversing effects.
13
C NMR spectra exhibited six signals due to a
b-glucopyranosyl
O
OH
O
2'
O1' 3'
4'
4'
4
HO 3'
3
5
9
'
10'
Acknowledgments
2'
2
8
7
'
'
6'
1
O
O
1''O
2'' 4''
6
''
5'
O
5''
OH
OH
O
O
OH
6'
5'
8
11
1
9
10
8
7
6
HO
2
3
Financial supported from the National Natural Science Foun-
dation of China (Nos. 81202422, 21472113, and 31500280) and
the Natural Science Foundation of Shandong Province (No.
ZR2012HQ024) are acknowledged.
3''
HO
4
11' O
O 11
5
1
2
OH
1
1
Fig. 2. The selected H, H-COSY ( ) and HMBCs (H ! C) correlations of 1 and 2.
Please cite this article in press as: S.-Q. Wang, et al., Chemical constituents from Cicuta virosa Linnaeus and their reversal effects on
doxorubicin-resistant human myelogenous leukemia (K562/A02) cells, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/
j.cclet.2016.03.039

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[9] T. Iossifova, B. Vogler, I. Kostova, Escuside, a new coumarin-secoiridoid from
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Please cite this article in press as: S.-Q. Wang, et al., Chemical constituents from Cicuta virosa Linnaeus and their reversal effects on
doxorubicin-resistant human myelogenous leukemia (K562/A02) cells, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/
j.cclet.2016.03.039