Design, synthesis, and vasorelaxation activity of novel imperatorin derivatives

Article abstract of DOI:10.1080/10286020.2013.790378

In this study, a series of novel imperatorin derivatives 7a-7e were designed and synthesized. Their vasorelaxation activities were evaluated by the pharmacological experiments in vitro. Most of the tested compounds exhibited better water solubility and vasorelaxation activity in different degrees, especially 7b and 7c with EC50 values of 2.29 and 2.63 μM, respectively on mesenteric artery, 7d and 7e with EC50 values of 1.04 and 2.65 μM, respectively on brain artery. The results indicated that these novel compounds have a potential interest for the development of novel and potent vasorelaxant agents for different kinds of arteries.

Full text of DOI:10.1080/10286020.2013.790378

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Design, synthesis, and vasorelaxation
activity of novel imperatorin
derivatives
a
a
a
a
Nan Zhou , Jian-Yu He , Tao Wang , Jie Zhang & Huai-Zhen
a
He
a
School of Medicine, Xi'an Jiaotong University , Xi'an , 710061 ,
China
Published online: 10 May 2013.
To cite this article: Nan Zhou , Jian-Yu He , Tao Wang , Jie Zhang & Huai-Zhen He (2013): Design,
synthesis, and vasorelaxation activity of novel imperatorin derivatives, Journal of Asian Natural
Products Research, 15:6, 650-657
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Journal of Asian Natural Products Research, 2013
Vol. 15, No. 6, 650–657, http://dx.doi.org/10.1080/10286020.2013.790378
Design, synthesis, and vasorelaxation activity of novel imperatorin
derivatives
Nan Zhou, Jian-Yu He, Tao Wang, Jie Zhang and Huai-Zhen He*
School of Medicine, Xi’an Jiaotong University, Xi’an 710061, China
(
Received 18 December 2012; final version received 25 March 2013)
In this study, a series of novel imperatorin derivatives 7a–7e were designed and
synthesized. Their vasorelaxation activities were evaluated by the pharmacological
experiments in vitro. Most of the tested compounds exhibited better water solubility
and vasorelaxation activity in different degrees, especially 7b and 7c with EC50 values
of 2.29 and 2.63 mM, respectively on mesenteric artery, 7d and 7e with EC50 values of
1.04 and 2.65 mM, respectively on brain artery. The results indicated that these novel
compounds have a potential interest for the development of novel and potent
vasorelaxant agents for different kinds of arteries.
Keywords: hypertension; imperatorin; xanthotoxol; vasorelaxation activity; synthesis
1
.
Introduction
previous work, we have found that
imperatorin may exert a vasodilatory
effect via the method of vascular smooth
muscle/cell membrane chromatography
Hypertension is one of the most important
public health problems worldwide and
has been recognized as an important
cardiovascular disorder since the dawn of
the twentieth century [1]. It is also a
major risk for accelerated atherogenesis
and cardiovascular morbidity [2]. Cur-
rently, several types of agents to lower
blood pressure are either new or investi-
gational. The most effective treatment for
hypertension can be taking vasorelaxant
agents, which can cause arterial vasodila-
tion in selected arterial beds [3–6].
Therefore, the development of novel
vasorelaxant agents causes wide interest
of researchers.
[
13,14]. However, due to the poor
solubility, the druggability of imperatorin
is subject to a certain restriction.
In this study, in an attempt to develop
novel imperatorin derivatives with
improved solubility, we retained the
furanocoumarin, saturated the double
bond, and then introduced a nitrogen
atom in the side chain (Figure 1). Thus,
five new imperatorin derivatives have been
designed, synthesized, and evaluated for
the first time as vasorelaxant agents in
different isolated arteries of rat.
Imperatorin, which is a naturally
occurring furocoumarin compound, can
be isolated from the roots of Angelica
dahurica and fruits of Angelica arch-
angelica [7–9]. It exhibits a wide range of
biological properties, such as antioxidative
activity [10], central nervous system
activity [11], hepatoprotective activity,
and antibacterial activity [12]. In the
2
.
Results and discussion
2
.1 Structure analysis
The main structural feature of imperatorin
from other vasodilator agents is the special
furocoumarin. However, the large con-
jugated system of imperatorin leads to the
poor water solubility. Through the struc-
*Corresponding author. Email: hehuaizhen@mail.xjtu.edu.cn
q 2013 Taylor & Francis

Journal of Asian Natural Products Research
651
Figure 1. Design of the novel imperatorin derivatives.
ture analysis of traditional vasodilators
such as dihydropyridine and phenylalk-
ylamine [15], there is always a nitrogen
atom in the molecule. In fact, it is easy to
form a salt with the existence of nitrogen
atom in the molecular structure. Therefore,
the incorporation of nitrogen atom in the
side chain will not affect the bone structure
of furocoumarin but can increase the
possibility of forming salt. In these
imperatorin derivatives, the water solubility
order is 7d (1.83 g) . 7c (0.22 g) . 7e
23
24
(1.18 £ 10 g) . 7b (7.00 £ 10 g). 7a
24
25
(1.50 £ 10 g) . imperatorin (8.00 £ 10 g).
All the data were measurements obtained
in 10 ml of water. The new compounds
7a–7e were synthesized according to
Scheme 1. N-(2-chloroethyl) nicotina-
mide, a key intermediate for the synthesis
of 7d, was prepared following Scheme 2.
O
O
O
O
NH
Br
amine, DMF
O80˚C ,12h
Br
7a
DMF, 80˚C
O
O
O
Br
6
O
O
O
BBr ,CH Cl
3
2
2
O
N
0˚C ,4h
O
O
O
O
O
O
O
O
OH
O
O
O
7b
O
N
4
5
7c
organic amine
salt, acetone
65˚C ,12h
O
O
O
O
O
NH
7d
N
O
O
O
N
7e
Scheme 1. General routes for the synthesis of target compounds (7a–7e).

6
52
N. Zhou et al.
O
O
O
Cl
OH SOCl2
0˚C , 4h
Cl H2O / CH2Cl2
N
H
4
Cl
HCl
N
N
H N
N
2
·
Scheme 2. Synthesis of N-(2-chloroethyl) nicotinamide.
.2 Vasorelaxation activity
2
all the tested compounds exhibited similar
relaxation activity with imperatorin on
renal artery. The analysis results suggested
that the incorporation of nitrogen atom not
only improved the water solubility but also
enhanced the pharmacological activity in
different degrees. Therefore, these new
compounds could be considered to
develop good vasorelaxant agents for
different kinds of arteries.
The vasorelaxation activity of imperatorin
derivatives was evaluated on isolated rat
mesenteric artery, basilar artery and renal
artery. Imperatorin was used as the positive
control. The results were expressed by their
potency (EC , pEC ) and efficacy (Emax).
5
0
50
Therein, the data of EC50 was defined as the
concentration of the tested compounds that
induced 50% of maximum relaxation from
þ
the contraction elicited by a K -rich Krebs
3
.
Experimental
or U46619 solution. The pEC50 was the
logarithm of half maximum effective
concentration. The Emax% was the maxi-
mal relaxation.
3.1 General experimental procedures
The melting points were measured on an
XT-4 instrument without correction
Through analysis of the data shown in
Tables 1–3 and Figure 2, we found that all
the tested compounds promoted relaxation
in a dose-dependent manner and their
maximal effects were observed at 100 mM.
Therein, 7b and 7c showed excellent
half maximum effective concentration
(
Henan, China). The infrared (IR) spectra
were recorded on a Shimadzu Fourier
transform (FT)-IR 440 spectrometer in the
2
000–500 cm range (Shimadzu, Kyoto,
1
4
1
Japan). H NMR spectra were recorded on
a Bruker AVANCF 400 MHZ instrument
in CDCl (Bruker, Zurich, Switzerland).
3
(
EC50 ¼ 2.29, 2.63) compared with that
The chemicals shifts (d values) are given
in parts per million downfield from
tetramethylsilane as the internal reference.
The molecular weights were performed on
a Shimadzu GC-MS-QP2010 instrument
(Shimadzu). All the solvents and chemi-
cals were obtained from commercial
sources and were used without further
of imperatorin (EC ¼ 6.31) and could
50
induce maximal relaxation (E %) more
max
than 95% on mesenteric artery. Com-
pounds 7c, 7d, and 7e showed excellent
EC50 (3.16, 1.04, and 2.45) compared with
that of imperatorin (7.41) and could induce
better Emax% on basilar artery. However,
Table 1. Vasorelaxation activities of imperatorin derivatives on mesenteric artery rings.
Compounds
Imperatorin
n
p EC50
EC50 (mM)
Emax%
7
7
7
7
7
7
5.20 ^ 0.09
5.30 ^ 0.06
5.64 ^ 0.10
5.58 ^ 0.03
4.39 ^ 0.06
5.36 ^ 0.08
6.31
5.01
2.29
2.63
40.74
4.37
96.00 ^ 1.00
87.33 ^ 0.42
98.44 ^ 0.98
98.44 ^ 0.98
34.18 ^ 6.96
97.64 ^ 2.09
7
7
7
7
7
a
b
c
d
e

Journal of Asian Natural Products Research
653
Table 2. Vasorelaxation activities of imperatorin derivatives on basilar artery rings.
Compounds
Imperatorin
n
p EC50
EC50 (mM)
max
E %
6
6
6
6
6
6
5.13 ^ 0.25
5.07 ^ 0.14
4.81 ^ 0.02
5.50 ^ 0.21
5.98 ^ 0.23
5.61 ^ 0.43
7.41
8.51
15.49
3.16
1.04
2.45
53.12 ^ 2.986
64.70 ^ 4.35
108.5 ^ 8.55
62.47 ^ 4.81
84.76 ^ 8.15
63.79 ^ 6.13
7
7
7
7
7
a
b
c
d
e
purification unless otherwise stated. The
synthetic procedure was controlled by the
method of thin-layer chromatography on
J ¼ 2.4 Hz, CHvHCZO), 7.42 (1H, s,
ArZH), 8.04 (1H, d, J ¼ 2.4 Hz,
CHvHCZO), 8.07 (1H, d, J ¼ 9.6 Hz,
þ
0
.25 mm silica gel plates (60 GF-254) and
CHvHCZCvO). EI-MS:m/z 201.9[M] .
visualized by UV light. The products were
purified by recrystallization or flash
chromatograph.
3.3 9-(2-Bromoethoxy)-7H-furo[3,2-
g]chromen-7-one (6)
Xanthotoxol (2.02 g, 10.00 mmol) was
dissolved in anhydrous N,N-dimethylfor-
mamide (10 ml). Anhydrous K CO
3
.2 Synthesis of xanthotoxol (5)
Boron tribromide (3.50 ml) in 15 ml
CH Cl was added dropwise to a solution
of xanthotoxin (2.16 g, 10.00 mmol) in
2
3
(1.66 g, 12.00 mmol) was added and the
reaction mixture was stirred under nitro-
gen atmosphere for 30 min at room
temperature. Then, 1,2-dibromoethane
(5 ml) was added and the reaction mixture
was stirred at 808C for another 12 h under
nitrogen atmosphere. After the reaction,
the mixture was cooled and poured into
cold water (100 ml). Then, the mixture was
extracted with EtOAc (3 £ 50 ml) and the
dried (Na SO ) organic layer was evapor-
2
2
3
0
0
0 ml anhydrous CH Cl under nitrogen at
2 2
8C. The reaction mixture was stirred at
8C for 4 h. Then, the reaction mixture was
poured slowly into a stirred solution of
saturated aqueous sodium bicarbonate
(100 ml) and stirred for another 1 h. The
precipitate was removed by filtration, and
the filtrate was treated with 2 M HCl for
further product. The product was purified
by column chromatography (EtOAc:petro-
leum ether ¼ 1:1) to afford 1.62 g (81%)
isolated yield light yellow solid with
mp 251–2538C (lit. [16] 2478C). IR (KBr)
2
4
ated in vacuo. The oil residue was purified
by column chromatography (EtOAc:pe-
troleum ether ¼ 1:2) to give the product as
a white solid (2.63 g, 85%), mp 148–
21
1
21
ymax (cm ): 3294 (OH), 1697 (CvO). H
NMR (CDCl , 400 MHz): d 6.35 (1H, d,
1498C. IR (KBr) y
(cm ): 1697
max
1
(CvO). H NMR (CDCl , 400 MHz): d
3
3
J ¼ 9.6 Hz, CHvHCZCvO), 7.01 (1H, d,
3.75 (2H, t, J ¼ 6.4 Hz, CH ZCH ZBr),
2
2
Table 3. Vasorelaxation activities of imperatorin derivatives on renal artery rings.
Compounds
Imperatorin
n
p EC50
EC50 (mM)
Emax%
6
6
6
6
6
6
4.76 ^ 0.02
4.76 ^ 0.04
4.86 ^ 0.21
4.34 ^ 0.05
4.61 ^ 0.16
4.53 ^ 0.02
17.38
17.38
13.80
45.70
24.54
29.51
99.16 ^ 2.479
97.93 ^ 6.25
67.21 ^ 5.99
50.92 ^ 9.22
32.66 ^ 8.47
83.70 ^ 3.20
7
7
7
7
7
a
b
c
d
e

6
54
N. Zhou et al.
Figure 2. Effects of imperatorin derivatives 7a, 7b, 7c, 7d, and 7e on relaxation in mesenteric
artery (MA), basilar artery (BA), and renal artery (RA), compared with imperatorin (IMP).
4
6
6
.76 (2H, t, J ¼ 6.4 Hz, CH ZCH ZBr),
anhydrous CH Cl and added dropwise.
2 2
2
2
.39 (1H, d, J ¼ 9.6 Hz, CHvHCZCvO),
The reaction mixture was stirred overnight
at room temperature. After the reaction,
the mixture was neutralized with saturated
aqueous sodium bicarbonate and extracted
with CH Cl (4 £ 50 ml). The dried
.84 (1H, s, CHvHCZO), 7.41 (1H, s,
ArZH), 7.72 (1H, s, CHvHCZO), 7.78
(
1H, d, J ¼ 9.6 Hz, CHvHCZCvO). EI-
þ
MS m/z: 307.9 [M] .
2
2
(
Na SO ) organic layer was evaporated
2 4
in vacuo and the residue was purified by
column chromatography (EtOAc:methanol
¼ 10:1) to give the product as a white solid
(1.17 g, 64%), mp 87–888C (lit. [17] 89–
3
.4 Synthesis of nicotinoyl chloride
Nicotinic acid (1.23 g, 10.00 mmol) was
dissolved in SOCl (10 ml). Three drops of
2
2
1
triethylamine were added to the mixture by
stirring. Then, the reaction mixture was
stirredat408C for4 h. Afterthereaction, the
918C). IR (KBr) ymax (cm ): 3425, 3263
1
(NZH), 1666 (CvO). H NMR (CDCl ,
3
400 MHz): d 3.77 (2H, t, J ¼ 5.2 Hz,
CH ZCH ZCl), 3.84 (2H, t, J ¼ 5.2 Hz,
excess SOCl was removed by evaporating
2
2
2
in vacuo. The crude white product was used
directly without further purification.
CH ZCH ZCl), 6.64 (1H, s, pyridine-
2 2
CH), 7.42 (1H, s, pyridine-CH), 8.13 (1H,
s, pyridine-CH), 8.76 (1H, s, pyridine-CH),
9
1
.02 (1H, s, HNZCvO). EI-MS: m/z
þ
3.5 Synthesis of N-(2-chloroethyl)
nicotinamide
84.0 [M] .
2
1
-Chloroethylamine hydrochloride (1.38 g,
2.00 mmol) was dissolved in 10 ml H O
3.6 General procedure for imperatorin
derivatives 7a and 7b
2
and 20 ml CH Cl . Then, the mixture was
2
2
treated with 7 ml 2 M NaOH to pH 8 and
kept at 08C for 20 min. After that, crude
nicotinoyl chloride was dissolved in 40 ml
Compound 6 (3.08 g, 10.00 mmol), anhy-
drous K CO (1.66 g, 12.00 mmol) and
amine (12.00 mmol) were dissolved in
2
3

Journal of Asian Natural Products Research
655
anhydrous N,N-dimethylformamide (10 ml).
Then, the reaction mixture was stirred at
was added and the reaction mixture was
stirred under nitrogen atmosphere for
30min at room temperature. Then, different
organic amine salt (12.00mmol) was added
respectively and the reaction mixture was
stirred at 658C for another 8 h under
nitrogen atmosphere. After the reaction,
the mixture was cooled and concentrated in
vacuo. The residue was dissolved in water
and extracted with EtOAc or CHCl3
(3 £ 50ml). The combined organic layers
were dried over Na SO and concentrated
8
08C for 12 h under nitrogen atmosphere.
After the reaction, the mixture was cooled
and poured into cold water (100 ml) and
the aqueous layer was extracted with
EtOAc (3 £ 50 ml). The combined organic
layers were dried over Na SO and
2
4
concentrated in vacuo. The crude product
was purified by column chromatography.
Both 7a and 7b were chromatographed on
silica gel (EtOAc:petroleum ether ¼ 1:1).
2
4
in vacuo. The product was purified by
column chromatography. Therein, 7c was
chromatographed on silica gel (CHCl3:
MeOH ¼ 5:1), 7d was chromatographed
on silica gel (EtOAc:MeOH ¼ 30:1) and 7e
was chromatographed on silica gel
(EtOAc:MeOH ¼ 5:1).
3
.6.1 9-(2-(Benzylamino)ethoxy)-7H-
furo[3,2-g]chromen-7-one (7a)
.40g (72% yield) isolated as a pale white
solid, mp 225–2268C. IR (KBr) y
2
max
1
21
(cm ): 3425 (NZH), 1620 (CvO). H
NMR (CDCl , 400 MHz): d 4.42 (4H, s,
3
CH ZCH ZNH, NHZCH ZAr), 4.61
2
2
2
3.7.1 9-(2-(Pyrrolidin-1-yl)ethoxy)-7H-
furo[3,2-g]chromen-7-one (7c)
(
(
2H, t, J ¼ 4.4 Hz, CH ZCH ZNH), 6.54
2
2
1H, s, CHvHCZCvO), 6.60 (1H, s,
CHvHCZO), 6.68 (2H, s, ArZH), 7.36
1.72g (58% yield) isolated as a white solid,
mp 225–2268C. IR (KBr) y
2
1
(
(
2H, s, ArZH), 7.57 (2H, s, ArZH), 7.88
1H, s, CHvHCZO), 7.93 (1H, s,
(cm ):
max
1
1635 (CvO). H NMR (400MHz, CDCl ):
3
þ
CHvHCZCvO). EI-MS: m/z 335.1 [M] .
d 2.30 (4H, s, CH ZCH ZN), 3.64 (6H, m,
2
2
CH ZCH ZO, CH ZCH ZN), 5.03 (2H,
2
2
2
2
t, J ¼ 3.8 Hz, CH ZO), 6.40 (1H, d,
2
3
7
.6.2 9-(2-(Diisopropylamino)ethoxy)-
H-furo[3,2-g]chromen-7-one (7b)
J ¼ 9.6 Hz, CHvHCZCvO), 6.85 (1H,
s, CHvHCZO), 7.45 (1H, s, ArZH), 7.73
(1H, s, CHvHCZO), 7.81 (1H, d,
J ¼ 9.6 Hz, CHvHCZCvO). EI-MS:
1.77 g (54% yield) isolated as a white solid,
mp 129–1308C. IR (KBr) y
1
d 2.60 (12H, s, CH ), 3.96 (2H, s,
2
(cm ):
1
max
1
716 (CvO). H NMR (400 MHz, CDCl ):
þ
m/z 299.1 [M] .
3
3
CHZ(CH ) ), 4.60 (2H, s, CH ZCH
2-
3
2
2
3
.7.2 N-(2-((7-oxo-7H-furo[3,2-
g]chromen-9-yl)oxy)ethyl)nicotinamide
7d)
ZCH), 5.00 (2H, s, CH ZO), 6.40 (1H, d,
2
J ¼ 9.0 Hz, CHvHCZCvO), 6.85 (1H, s,
(
CHvHCZO), 7.42 (1H, s, ArZH), 7.70
(
1H, s, CHvHCZO), 7.80 (1H, d,
J ¼ 9.0 Hz, CHvHCZCvO). EI-MS:
2.18 g (62% yield) isolated as a pale
white solid, mp 157–1588C. IR (KBr)
þ
21
ymax (cm ): 3440 (NZH), 1720, 1599
m/z 329.1 [M] .
1
CvO). H NMR (400 MHz, CDCl ): d
(
3
3
.90 (2H, t, J ¼ 4.6 Hz, OZCH ZCH
2
2-
3.7 General procedure for other
imperatorin derivatives (7c–7e)
ZNZCvO), 4.64 (2H, t, J ¼ 4.6 Hz,
OZCH ZCH ZNZCvO), 6.40 (1H, d,
2
2
Xanthotoxol (2.02 g, 10.00 mmol) was
dissolved in anhydrous acetone (50 ml).
Anhydrous K CO (1.66g, 12.00 mmol)
J ¼ 10.4 Hz, CHvHCZO), 6.85 (1H, s,
CHvHCZCvO), 7.40 (1H, s, ArZH),
7.44 (1H, d, J ¼ 10.4 Hz, CHvHCZO),
2
3

6
7
56
N. Zhou et al.
.38 (1H, dd, J ¼ 4.8 Hz, J ¼ 7.9 Hz,
and renal artery) was tested by exposure to
þ
1
2
pyridine-CH), 7.81 (1H, s, CHvHCZCv
O), 8.25 (1H, d, J ¼ 7.9 Hz, pyridine-CH),
a K -rich Krebs solution (with 60 mM
KCl), in which NaCl was exchanged for an
equimolar concentration of KCl. While,
U46619 (1 mM) was used for basilar artery
segments. When two reproducible con-
tractions have been achieved, the vessels
could be used for further experiments.
After equilibration, segments were pre-
contracted. Once the sustained tension was
obtained, the new imperatorin derivatives
(0.1 mM to 0.1 mM) were added cumulat-
ively to the baths, and the concentration–
response curves to the new imperatorin
derivatives were constructed. Control
tissues were subjected to the same
procedures simultaneously, but omitting
the compounds and adding the vehicle.
The data of logarithm of half maximum
effective concentration ( pEC ) and the
8
9
3
.73 (1H, d, J ¼ 4.8 Hz, pyridine-CH),
.17 (1H, s, pyridine-CH). EI-MS: m/z
50.0 [M] .
þ
3.7.3 9-(2-(Diethylamino)ethoxy)-7H-
furo[3,2-g]chromen-7-one (7e)
2.48 g (83% yield) isolated as a white solid,
mp 79–808C. IR (KBr) y
2
1
(cm ): 1720
CvO). H NMR (400 MHz, CDCl3):
max
1
(
d 1.11 (6H, t, J ¼ 7.1 Hz, CH ), 2.77
3
(
(
(
(
4H, q, J ¼ 7.1 Hz, NZCH ZCH ), 3.02
2 2
2
3
2H, t, J ¼ 6.4 Hz, OZCH ZCH ), 4.63
2H, t, J ¼ 6.4 Hz, OZCH ZCH ), 6.38
2
2
1H, d, J ¼ 9.6 Hz, CHvHCZCvO),
.79 (1H, s, CHvHCZO), 7.40 (1H, s,
ArZH), 7.70 (1H, s, CHvHCZO), 7.76
6
5
0
(
1H, d, J ¼ 9.6 Hz, CHvHCZCvO). EI-
maximal relaxation (Emax) in artery rings
were expressed as mean ^ SEM.
þ
MS: m/z 301.1 [M] .
3
.8 Vasodilatory effect assay
4. Conclusions
The vasodilatory activity was evaluated on
rat mesenteric artery, basilar artery, and
renal artery according to the literatures
In conclusion, we have synthesized a
series of novel imperatorin derivatives via
introducing a nitrogen atom in the side
chain of the furocoumarin and evaluated
the vasorelaxation activity of the new
compounds on different arteries. Gener-
ally, most of the new compounds dis-
played better vasorelaxation activity and
water solubility than imperatorin itself on
mesenteric artery and basilar artery, but
the similar vasorelaxation activity as
imperatorin on renal artery. The structure
analysis was also discussed in this study.
In particular, according to the different
vasorelaxation activity, 7b and 7c can be
used to develop a new kind of vasodilator
agent for mesenteric artery, while 7d and
7e can be used to develop a new kind of
vasodilator agent for basilar artery. In
addition, since all the tested compounds
are the imperatorin derivatives, we
hypothesized that the novel derivatives
have the similar mechanism of actions
with the imperatorin [20]. The further
[
18,19]. Sprague-Dawley rats weighing
50–300 g were anesthetized and sacri-
2
ficed by decapitation. For instance, small
mesenteric arteries (2 mm segments of
second order branch of the superior
mesenteric artery) were dissected free of
fat and connective tissue and mounted in
Multi-wire myograph system (Danish Myo
Technology A/S, Inc., Skejbyparken, Den-
mark). Vessels were maintained at 378C in
physiological Krebs buffer that was
bubbled with a carbogen (95% O , 5%
2
CO ) to maintain the buffer at pH 7.4.
2
After a 30 min equilibration period, vessel
tension was increased to 3 mN on mesen-
teric artery and renal artery, 1 mN on
basilar artery. That was equilibrated for
another 1.5 h before the experiments were
started. After equilibration, segments were
pre-contracted. The contractile capacity of
each vessel segment (mesenteric artery

Journal of Asian Natural Products Research
657
research on the mechanism of actions of
the new compounds needed more in-depth
research and the result will be reported in
the near future.
[8] P.M. Kearney, M. Whelton, K. Reynolds,
P. Muntner, P.K. Whelton, and J. He,
Lancet 365, 217 (2005).
[
9] S.M. Lang, G. Wolfram, R. Gerzer, and H.
Schiffl, Perit. Dial. Int. 19, 143 (1999).
[
10] E.M. Murphy, L. Nahar, M. Byres, M.
Shoeb, M. Siakalima, M.M. Rahman, A.I.
Gray, and S.D. Sarker, Biochem. Syst.
Ecol. 32, 203 (2004).
Acknowledgments
This work was financially supported by the
National Natural Science Foundation of China
[
11] M.B. Murphy, C. Murray, and G.D.
Shorten, New Engl. J. Med. 345, 1548
(
Nos 81202494, 30730110). We are grateful to
(
2001).
12] T.B. Ng, F. Liu, and Z.T. Wang, Life Sci.
6, 709 (2000).
Prof. Zongru Guo for practical guidance during
the course of this project.
[
[
6
13] O.P. Sethi, K.K. Anand, and O.D. Gulati,
J. Ethnopharmacol. 36, 239 (1992).
References
[
[
[
[
1] H.S. Ban, S.S. Lim, K. Suzuki, S.H. Jung,
S. Lee, Y.S. Lee, K.H. Shin, and K.
Ohuchi, Planta Med. 69, 408 (2003).
2] X.W. Dong, T. Liu, J.Y. Yan, P. Wu, J.
Chen, and Y.Z. Hu, Bioorg. Med. Chem.
[14] D.J. Triggle, Biochem. Pharmacol. 74, 1
(2007).
[15] Y. Wei, T.Y. Zhang, and Y. Ito,
J. Chromatogr. A 1033, 373 (2004).
[
16] S. Harkar, T.K. Razdan, and E.S. Waight,
Phytochemistry 23, 419 (1984).
17, 716 (2009).
3] X.W. Dong, L.L. Qi, C.Y. Jiang, J. Chen,
E.Q. Wei, and Y.Z. Hu, Bioorg. Med.
Chem. Lett. 19, 3196 (2009).
4] F. Fusi, S. Saponara, F. Pessina, B.
Gorelli, and G. Sgaragli, Eur. J. Nutr. 42,
[
17] T. Kniess, H. Spies, W. Brandau, and B.
Johannsen, J. Labelled Compd. Radio-
pharm. 41, 608 (1998).
[
18] J. Widelski, M. Popova, K. Graikou, K.
Glowniak, and I. Chinou, Molecules 14,
10 (2003).
2
729 (2009).
[
5] J.Y. He, W. Zhang, L.C. He, and Y.X.
Cao, Eur. J. Pharmacol. 573, 170 (2007).
6] Y.C. Zhang, J.P. Zhou, W.H. Pan, X.M.
Wu, and S. Wang, Lett. Drug. Des.
Discov. 7, 18 (2010).
[
19] Y.C. Xu, S.W.S. Leung, D.K.Y. Yeung,
L.H. Hu, G.H. Chen, C.M. Che, and
R.Y.K. Man, Phytochemistry 68, 1179
[
(
2007).
[
20] Y. Zhang, Y.J. Cao, Q.L. Wang, L. Zheng,
J. Zhang, and L.C. He, Fitoterapia 82, 988
(2011).
[
7] X.F. Hou, M.Z. Zhou, Q. Jiang, S.C.
Wang, and L.C. He, J. Chromatogr. A
1216, 7081 (2009).