Design, synthesis, and evaluation of new series of Imperatorin analogs with potential vasodilatory activity

Article abstract of DOI:10.1080/10286020.2017.1391228

Two series of imperatorin analogs were synthesized based on our previous research and evaluated for their vasodilatation activities on in vitro rat mesenteric artery, basilar artery, and renal artery ring models. Target compounds were characterized by infrared, ¹H NMR, and mass spectra. Most derivatives possessed significant vasodilatory activity on the mesenteric artery, and compound 3a exhibited favorable and broad vasodilatation activities on three kinds of rat artery ring models. The pharmacological results indicated that introducing nitrogen-contained ring in side chain or large steric hindrance at the distal end could increase the vasodilatory activity. Further, replacement of oxygen atom (–O–) in the skeleton of furocoumarin derivatives with nitrogen (–NH–) could cause the decrease of vasodilatory activity. The molecular docking also indicated that compound 3a showed a best affinity with α-1C receptor (PDB ID: 3G43). All these results suggested compound 3a would be a potential vasodilatory agent for hypertension.

Full text of DOI:10.1080/10286020.2017.1391228

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: http://www.tandfonline.com/loi/ganp20
Design, synthesis, and evaluation of new series of
Imperatorin analogs with potential vasodilatory
activity
Ya-Jing Hou, Cheng Wang, Tao Wang, Li-Min Huang, Yuan-Yuan Lin & Huai-
Zhen He
To cite this article: Ya-Jing Hou, Cheng Wang, Tao Wang, Li-Min Huang, Yuan-Yuan Lin
& Huai-Zhen He (2017): Design, synthesis, and evaluation of new series of Imperatorin
analogs with potential vasodilatory activity, Journal of Asian Natural Products Research, DOI:
10.1080/10286020.2017.1391228
To link to this article: http://dx.doi.org/10.1080/10286020.2017.1391228
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Date: 30 October 2017, At: 23:36

Journal of asian natural Products research, 2017
https://doi.org/10.1080/10286020.2017.1391228
Design, synthesis, and evaluation of new series of Imperatorin
analogs with potential vasodilatory activity
Ya-Jing Houa, Cheng Wanga, Tao Wangb, Li-Min Huanga, Yuan-Yuan Lina and
Huai-Zhen Hea
aschool of Pharmacy, Xi’an Jiaotong university, Xi’an 710061, china; bdepartment of food, Xi’an institute for
food and drug control, Xi’an 710054, china
ABSTRACT
ARTICLE HISTORY
received 20 april 2017
accepted 25 september 2017
Two series of imperatorin analogs were synthesized based on our
previous research and evaluated for their vasodilatation activities on in
vitro rat mesenteric artery, basilar artery, and renal artery ring models.
Target compounds were characterized by infrared, 1H NMR, and mass
spectra. Most derivatives possessed significant vasodilatory activity
on the mesenteric artery, and compound 3a exhibited favorable and
broad vasodilatation activities on three kinds of rat artery ring models.
The pharmacological results indicated that introducing nitrogen-
contained ring in side chain or large steric hindrance at the distal
end could increase the vasodilatory activity. Further, replacement of
oxygen atom (–O–) in the skeleton of furocoumarin derivatives with
nitrogen (–NH–) could cause the decrease of vasodilatory activity.
The molecular docking also indicated that compound 3a showed
a best affinity with α-1C receptor (PDB ID: 3G43). All these results
suggested compound 3a would be a potential vasodilatory agent
for hypertension.
KEYWORDS
imperatorin; furocoumarin;
pyrrolocoumarin;
vasodilatation; synthesis
CONTACT huai-Zhen he
hehuaizhen@mail.xjtu.edu.cn
school of Medicine, Xi’an Jiaotong university, Yanta
road, Xi’an 710061, People’s republic of china.
© 2017 informa uK limited, trading as taylor & francis Group

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Y.-J. HOU ET AL.
1. Introduction
Hypertension is the most common cardiovascular disease [1, 2], findings from serial surveys
indicate an increasing prevalence of hypertension in developing countries due to the urban-
ization, population ageing, changes in dietary habits, and social stress [3]. Hypertension is
associated with impaired vascular, which could result in the damnification of vasodilatory
capacity [4]. Furthermore, vascular damage has been recognized as one of the leading risk
factors for coronary artery disease, heart failure, and renal failure [5]. erefore, vascular
studies have got much attention [6, 7], and a great deal of novel agents have been put forward
for the treatment of hypertension [8, 9]. Even so, hypertension is still an incurable disease
and greatly threaten human beings’ health [10].
Imperatorin, a natural linear furocoumarin, is isolated from roots of Angelica dahurica
and fruits of Angelica archangelica [11]. Modern researches have certified that it plays a
significant role in pharmacological effects such as anti-inflammatory, antitumor, anticon-
vulsant, and so on [12–15]. In previous studies, we also found that imperatorin could induce
vasodilatation via inhibiting voltage-dependent calcium channels and receptor mediated
Ca2+ influx and release [16, 17]. However, the shortcomings such as its poor solubility and
low bioavailability have limited its clinical application to a certain restriction [18, 19]. In
order to improve its solubility and increase the structural diversity, our previous studies
constructed a novel pyrrolecoumarin structure, which maintained the skeleton of impera-
torin and replaced the oxygen of the furan-ring with NH [20].
In this study, six new imperatorin derivatives have been designed, synthesized (Scheme
1), and evaluated for the first time as vasorelaxant agents by isolated rat mesenteric artery
(MA), basilar artery (BA), and renal artery (RA) rings models. Further, Molecule docking
was performed to investigate the binding mode of these compounds with their receptor.
2. Results and discussion
2.1. Chemistry
e synthesis of compounds 1 and 2 was based on the references [20, 21]. e target com-
pounds were prepared by Williamson reaction, the most common way of etherification
Scheme 1. design strategy of target compounds.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
reaction, which can obtain hydrocarbyloxy derivatives. e optimization of reaction con-
ditions is the key point of this reaction. erefore, the effect of solvent, alkali, reaction
time, and temperature was studied. At first, DMF was chosen as the solvent due to its good
solubility of imperatorin intermediates, anhydrous K2CO3 was chosen as the acid-binding
agent, and the reaction performed at 80 °C for 12 h to obtain the target product. Under this
condition, the halogenated compounds will probably react with itself or the products, which
resulting in an increase of by-products. In addition, DMF was difficult to remove. ese
all go against the yield and purification of the target compounds. For this reason, acetone
is finally used as the solvent instead of DMF. With this kind of solvent, the by-products
are less and crude products can be directly recrystallized from petroleum to get the target
compounds (Scheme 2).
Besides, 8-hydroxypsoralen is suitable for using weak alkaline (such as K2CO3, Na2CO3)
as a binding agent for the reaction rather than strong alkali (such as NaOH), which will
easily lead to the degradation of pyrone. Furthermore, 9-hydroxy-8H-pyrano [3,2-f] indol-
2-one is susceptibly photocatalytic in organic solvents and easily oxidized by acid or alkali,
which could affect the further derivatization reaction.
Up to this point, the conditions of the Williamson reaction are summarized. e reaction
conditions for compounds 3a and 3b are: acetone as the reaction solvent, n (compound
1): n (chlorinated organic amine salt): n (K2CO3) = 1:1.2–1.5:1.5–3, reaction at 68 °C for
8–24 h and the yield is 54–72%. e reaction conditions for compounds 4a~4d are: acetone
as the reaction solvent, n (compound 2): n (chlorinated organic amine salt): n (K2CO3) =
1:1.5:3, reaction at 68 °C for 8–24 h avoiding light and oxygen, and the yield is 45–70%.
2.2. Pharmacology
At present, there are many ways to evaluate cardiovascular activity, in which the vascular
ring model is a generally accepted method [22, 23]. To this end, we selected three different
susceptible parts of cardiovascular disease, i.e. rat mesenteric artery (MA), renal artery
(RA), and brain basilar artery (BA) as the research objects, using the vascular ring tension
measurement method, to evaluate the vasodilatory activity of these six compounds. e
results are displayed in Table 1.
Scheme 2. synthesis route of target compounds. reagents and conditions: (a) ch2cl2, Bf3, −5~0 °c, 4 h;
(b) the reagents and conditions of b were according to the literature [21]; (c) K2co3, acetone, 68 °c,
8–24 h, reflux.

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Y.-J. HOU ET AL.
Table 1. Vasodilatory activity in ra, Ba, and Ma.
MA
BA
RA
Compounds
pEC50
Emax (%)
pEC50
Emax (%)
pEC50
Emax (%)
imperatorin
4.95 0.14
6.30 0.12
5.79 0.06
6.00 0.14
5.01 0.14
4.31 0.02
4.78 0.34
85.6 4.0
101.1 0.67
105.5 4.31
101.75 4.47
102.3 0.21
98.54 5.12
97.0 0.94
5.26 0.15
5.93 0.00
4.65 0.07
4.90 0.26
4.84 0.07
4.60 0.20
4.45 0.04
65.0 4.2
103.6 4.70
97.9 3.89
106.90 9.38
100.3 2.77
93.30 8.20
31.0 7.52
5.20 0.09
5.31 0.02
4.79 0.19
5.04 0.20
5.14 0.12
4.98 0.04
4.86 0.40
96.0 1.0
103.7 4.49
102.0 2.79
93.70 6.67
101.9 0.52
100.70 0.44
103.4 1.65
3a
3b
4a
4b
4c
4d
Introduction of the nitrogen-contained ring in side chain or large steric hindrance at the
distal end is beneficial to enhance the vasodilatory activity, and it will show the best activity
when the side chain ends at a diphenyl piperazine, such as compound 3a (pEC50 = 6.30)
and compound 4a (pEC50 = 6.00). On the other hand, comparison between furocoumarin
derivatives and pyrrolocoumarin derivatives with a same side chain, such as 3a with 4a,
shows the decrease of vasodilatory activity, and comparison between 3b with 4b also shows
the same tendency in MA, but a slight increase in BA and RA. Generally speaking, when
the oxygen atom (–O–) in the nucleus of the furocoumarin derivatives is replaced with
nitrogen (–NH–), it could cause the decrease of vasodilatory activity. Furthermore, most
of the derivatives can exhibit significant vasodilatory activity in the MA, but in the RA and
BA, most of the compounds are slightly lower or comparable than that of imperatorin. e
reason may be related to the difference of three vascular tissues, i.e. vascular personality,
which displays different or even opposite results for the same stimulus in different organs,
tissues, or area.
2.3. Docking
e previous studies indicate that imperatorin acts on the subunits E and F of α-1C receptor
in voltage-dependent L-calcium channel for its antihypertensive effect. In order to explain
the different activities of the target compounds and guide further SAR studies, we pro-
ceeded to examine the interaction of compounds 3a and 4a with L-calcium channel (PDB
code: 3G43). Molecular docking studies were conducted using the Sulflex-Dock Mode of
Sybyl-X program package (New Tripos International, St. Louis, USA), and the results are
shown in Figure 1.
In general, compounds 3a and 4a separately formed five and four hydrogen bonds.
Oxygens in pyrone of two compounds both can form hydrogen bonds with r110 and
His107 with distances of 2.25 Å and 1.99 Å for 3a, 2.02 Å and 2.12 Å for 4a. Afer -O- change
in -NH-, the H-bond donor, Lys94 was replaced with Ser81, a H-bond acceptor. And the
lengths were 2.08 Å and 2.65 Å, respectively. Besides, the bonding conditions of the oxygen
atom of the side chain also changed, 3a formed two bonds with Lys94 and His107 with
the distances of 2.25 Å and 1.99 Å, while 4a formed only one with His107, and the length
was 2.18 Å.
e results indicate that when the –O– in compound 3a is replaced with -NH-, the
numbers and lengths of bonds are both different, that may attribute to the changes of the
electric field distribution. As a result, the dominant conformation is changed and the side

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
Figure 1. Binding mode of compounds 3a (a) and 4a (b) to l-calcium channel (PdB code: 3G43).
chain in compound 4a cannot react with the activity cavity well. Overall, compound 3a
shows a better affinity with α-1C receptor (PDB ID: 3G43).
3. Experimental
3.1. General experimental procedures
Melting points were determined on an X-4 microscope melting point apparatus (Henan,
China) and are uncorrected. IR spectra were recorded on a Shimadzu Fourier transform
(FT)-IR 440 spectrometer in the 4000–500 cm−1 range (Shimadzu, Kyoto, Japan). NMR
spectra were recorded on a Bruker AVANCE 400 MHz spectrometer in CDCl3 solution
with TMS as internal standard (Bruker, Zurich, Switzerland). e HR-ESI-MS data were
obtained on a Bruker microTOF-Q II spectrometer (Bruker, Karlsruhe, Germany). All the
materials used for experiments were obtained from commercial suppliers without further
purification unless otherwise stated. All of the solvents used were of analytical reagent grade.
Water was deionized. e synthetic procedure was controlled by the method of thin-layer
chromatography on 0.25 mm silica gel plates (60 GF-254) and visualized with UV light. e
products were purified by recrystallization or flash chromatography. Column chromatog-
raphy was carried out on silica gel (300–400 mesh). All other reagents were commercially
available and used as received.
3.2. General procedure for the synthesis of (3a-3b, 4a-4d)
Compound 1 (2.02 g, 10.00 mmol) and compound 2 (2.81 g, 10.00 mmol) were separately
dissolved in dry acetone (150 ml), followed by adding anhydrous K2CO3 (12.00 mmol for
3a-3b, 30.00 mmol for 4a-4d). e reaction mixture was stirred under nitrogen atmosphere

6
Y.-J. HOU ET AL.
for 30 min at room temperature. en, various organic amine salts (12.00 mmol for 3a-3b,
15.00 mmol for 4a-4d) were added, respectively. e reaction mixture was stirred at 68 °C
for 8–24 h under nitrogen atmosphere and away from light. Afer cooling, the mixture was
concentrated in vacuum. e residue was dissolved with water and extracted with EtOAc
or CHCl3 (3 × 50 ml). e collected organic layer was washed by water (2 × 50 ml) and
saturated saline (2 × 50 ml) successively, dried over Na2SO4, and purified by column chro-
matography afer concentrated.
3.2.1. Compound 3a
Yield: 93%, Light yellow solid. m.p.: 77–79 °C; IR (KBr): υmax 3149.5 (furan-CH), 3058.9
(ArH), 2812.0 (–CH2–), 1730.0 (–C=O), 1587.3 (–C=C–), 1490.9 (–C=C–), 1149.5 (–C–
1
O–C–) cm−1; H-NMR (400 MHz, CDCl3): δ 7.77 (d, J = 9.6 Hz, 1H, H-pyrano), 7.67
(s, 1H, H-furan), 7.43 (d, J = 7.6 Hz, 4H, ArH), 7.37 (s, 1H, ArH), 7.30–7.26 (m, 4H,
ArH), 7.17–7.21 (m, 2H, ArH), 6.82 (s, 1H, H-furan), 6.37 (d, J = 9.6 Hz, 1H, H-pyrano),
4.61 (t, J = 5.6 Hz, 2H, –OCH2CH2 N), 4.23 (s, 1H, –N(CH2CH2)2NCH(Ph)2), 2.94
(t, J = 5.4 Hz, 2H, –OCH2CH2 N), 2.66 (s, 4H, –N(CH2CH2)2NCH(Ph)2), 2.43 (s, 4H,
–N(CH2CH2)2NCH(Ph)2); EI-MS (m/z): 479.0 [M]+.
3.2.2. Compound 3b
Yield: 56%, White solid. m.p.: 90–91 °C; IR (KBr): υmax 3149.5 (furan-CH), 3064.7 (ArH),
2810.7 (–CH2–),1714.6 (–C=O), 1587.3 (–C=C–), 1508.2 (–C=C–), 1151.4 (–C–O–C–)
cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.76 (d, J = 9.6 Hz, 1H, H-pyrano), 7.67 (d, J = 1.6 Hz,
1H, H-furan), 7.36 (s, 1H, ArH),7.29–7.25 (m, 2H, ArH), 7.01–6.97 (m, 2H, ArH), 6.81
(d, J = 1.6 Hz, 1H, H-furan), 6.36 (d, J = 9.6 Hz, 1H, H-pyrano), 4.60 (t, J = 5.6 Hz, 2H, –
OCH2CH2 N), 3.47 (s, 2H, –N(CH2CH2)2NCH2Ph-F), 2.91 (t, J = 5.6 Hz, 2H, –OCH2CH2 N),
2.64 (s, 4H, –N(CH2CH2)2NCH2Ph-F), 2.45 (s, 4H, –N(CH2CH2)2NCH2Ph-F); HR-ESI-MS
(m/z): 423.1 [M + H]+.
3.2.3. Compound 4a
Yield: 42%, White solid. m.p.: 83–85 °C; IR (KBr): υmax 3103.3 (pyrrole-CH), 3028.0 (ArH),
2810.1 (–CH2–), 1770.5 (–C=O), 1652.9 (–C=C–), 1498.6 (–C=C–), 1188.1 (–C–O–C–)
cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.40–7.38 (m, 4H, ArH), 7.28–7.24 (m, 4H, ArH),7.19–
7.15 (m, 2H, ArH), 7.07 (s, 1H, ArH), 7.05 (d, J = 5.4 Hz, 1H, H-pyrrol), 6.69 (d, J = 9.4 Hz,
1H, H-pyrano), 6.29 (d, J = 5.4 Hz, 1H, H-pyrrol), 6.13 (s, 1H, NH), 5.68 (d, J = 9.6 Hz,
1H, H-pyrano), 4.37 (s, 2H, –OCH2CH2 N), 4.20 (s, 1H,-N(CH2CH2)2 NCH(Ph)2),
2.70 (s, 2H, –OCH2CH2 N), 2.53 (s, 4H, –CH2 N(CH2CH2)2NCH–), 2.40 (s, 4H, –
CH2N(CH2CH2)2NCH–); EI-MS (m/z): 479.0 [M]+.
3.2.4. Compound 4b
Yield: 51%, Light brown solid. m.p. :172–173 °C; IR (KBr): υmax 3178.5 (pyrrole-CH), 3049.3
(ArH), 2813.9 (–CH2–), 1768.6 (–C=O), 1654.8 (–C=C–), 1510.2 (–C=C–), 1218.9 (–C–
O–C–) cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.28–7.25 (m, 2H, ArH), 7.08–7.07 (m, 1H,
ArH), 7.06 (d, J = 5.6 Hz, 1H, H-pyrrol), 7.01–6.97 (m, 2H, ArH), 6.70 (d, J = 9.6 Hz, 1H,
H-pyrano), 6.30 (d, J = 5.6 Hz, 1H, H-pyrrol), 6.15–6.14 (m, 1H, NH), 5.68 (d, J = 9.6 Hz,
1H, H-pyrano), 4.43–4.30 (m, 2H, –OCH2CH2 N), 3.46 (s, 2H, –N(CH2CH2)2NCH2Ph-F),

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
2.68 (t, J = 6.4 Hz, 2H, –OCH2CH2 N), 2.51 (s, 4H, –N(CH2CH2)2NCH2Ph-F), 2.42 (s, 4H,
–N(CH2CH2)2NCH2Ph-F); HR-ESI-MS (m/z): 422.1 [M + H]+.
3.2.5. Compound 4c
Yield: 43%, Light brown viscous liquid. IR (KBr): υmax 3176.5 (pyrrole-CH), 3105.2 (ArH),
2852.5 (–CH2–), 1764.7 (–C=O), 1596.5 (–C=C–), 1500.5 (–C=C–), 1188.1 (–C–O–C–)
1
cm−1; H-NMR (400 MHz, CDCl3): δ 7.11–7.10 (m, 1H, ArH), 7.08 (d, J = 5.6 Hz, 1H,
H-pyrrol), 6.71 (d, J = 9.2 Hz, 1H, H-pyrano), 6.30 (d, J = 5.6 Hz, 1H, H-pyrrol), 6.15 (s, 1H,
ArH), 5.68 (d, J = 9.2 Hz, 1H, H-pyrano), 4.37 (t, J = 6.8 Hz, 2H, –OCH2CH2 N), 2.66–2.58
(m, 2H, –OCH2CH2 N), 2.42–2.41 (m, 4H, –N(CH2CH2)2 CH2), 1.57–1.51 (m, 4H, –N(CH2
CH2)2CH2), 1.43–1.41 (m, 2H, –N(CH2CH2) 2CH2); EI-MS (m/z): 312.0 [M]+.
3.2.6. Compound 4d
Yield: 34%, Light brown viscous liquid. IR (KBr): υmax 3178.5 (pyrrole-CH), 3105.2 (ArH),
2875.7 (–CH2–), 1770.5 (–C=O), 1652.9 (–C=C–), 1500.5 (–C=C–), 1190.0 (–C–O–C–)
cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.10 (s, 1H, ArH), 7.07 (d, J = 5.6 Hz, 1H, H-pyrrol),
6.71 (d, J = 9.2 Hz, 1H, H-pyrano), 6.30 (d, J = 5.2 Hz, 1H, H-pyrrol), 6.16–6.15 (m, 1H,
NH), 5.69 (d, J = 9.6 Hz, 1H, H-pyrano), 4.38 (t, J = 6.8 Hz, 2H, –OCH2CH2 N), 2.81 (t,
J = 6.8 Hz, 2H, –OCH2CH2 N), 2.59–2.46 (m, 4H, –N(CH2CH2)2), 1.82–1.67 (m, 4H,
–N(CH2CH2)2); EI-MS (m/z): 298.0 [M]+.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
is work was financially supported by the Natural Science Basic Research Plan in Shaanxi Province
of China [grant number 2016JM8076].
References
[1] M. Anselmi, F. Avanzini, J.M. Moreira, G. Montalvo, D. Armani, R. Prandi, M. Marquez, C.
Caicedo, F. Colombo, and G. Tognoni, Lancet 361, 1186 (2003).
[2] P.M. Kearney, M. Whelton, K. Reynolds, P. Muntner, P.K. Whelton, and J. He, Lancet 365, 217
(2005).
[3] M.M. Ibrahim and A. Damasceno, Lancet. 380, 611 (2012).
[4] M.H. Olsen, K. Wachtell, C. Aalkjaer, H. Dige-Petersen, J. Rokkedal, and H. Ibsen, Am. J.
Hypertens. 15, 398 (2002).
[5] G.S. Stokes, J. Clin. Hypertens. 6, 192 (2004).
[6] C. Lenfant, A.V. Chobanian, D.W. Jones, and E.J. Roccella, Hypertension 41, 1178 (2003).
[7] K. Tsuneyama, K. Ohba, Y. Zen, Y. Sato, H. Niwa, H. Minato, and Y. Nakanuma, Histopathology
43, 55 (2003).
[8] C.R. Tirapelli, S.R. Ambrosio, A.M. de Oliveira, and R.C. Tostes, Fitoterapia 81, 690 (2010).
[9] P. Jansa, M. Aschermann, D. Ambroz, and A. Linhart, Curr. Med. Res. Opin. 23, S3 (2007).
[10] O. Ceska, S.K. Chaudhary, P.J. Warrington, and M.J. Ashwood-Smith, Phytochemistry 26, 165
(1986).

8
Y.-J. HOU ET AL.
[11] A.C. Adebajo, E.O. Iwalewa, E.M. Obuotor, G.F. Ibikunle, N.O. Omisore, C.O. Adewunmi,
O.O. Obaparusi, M. Klaes, G.E. Adetogun, T.J. Schmidt, and E.J. Verspohl, J. Ethnopharmacol.
122, 10 (2009).
[12] J.J. Luszczki, E. Wojda, M. Andres-Mach, W. Cisowski, M. Glensk, K. Glowniak, and S.J.
Czuczwar, Epilepsy Res. 85, 293 (2009).
[13] S.J. Wang, T.Y. Lin, C.W. Lu, and W.J. Huang, Neurochem. Int. 53, 416 (2008).
[14] R. Sancho, N. Márquez, M. Gómez-Gonzalo, M.A. Calzado, G. Bettoni, M.T. Coiras, J. Alcamí,
M. López-Cabrera, G. Appendino, and E. Muñoz, J. Biol. Chem. 279, 37349 (2004).
[15] J.Y. He, W. Zhang, L.C. He, and Y.X. Cao, Eur. J. Pharmacol. 573, 170 (2007).
[16] X. Hou, M. Zhou, Q. Jiang, S. Wang, and L. He, J. Chromatogr. A. 1216, 7081 (2009).
[17] G.D. Yang, C. Li, A.G. Zeng, Y.L. Guo, X. Yang, and J.F. Xing, J. Mol. Liq. 167, 86 (2012).
[18] J. Pan, W. Lu, C. Li, S. Wang, and L. He, Arch. Pharm. Res. 33, 1209 (2010).
[19] C. Marzano, F. Baccichetti, F. Carlassare, A. Chilin, S. Lora, and F. Bordin, Photochem. Photobiol.
71, 263 (2000).
[20] C. Wang, T. Wang, N. Zhou, X.Y. Pan, and H.Z. He, J. Asian Nat. Prod. Res. 16, 304 (2014).
[21] T. Wang, C. Wang, J. Zhang, and H.Z. He, J. Heterocycl. Chem. 52, 1406 (2014).
[22] R. Bansal, D. Kumar, R. Carron, and C. de la Calle, Eur. J. Med. Chem. 44, 4441 (2009).
[23] E. Doğan, Turk. Gogus. Kalp. Dama. 23, 330 (2015).