Angustifolinoid B, a flavonoid glycoside dimer with cyclobutane from Elaeagnus angustifolia flowers

Article abstract of DOI:10.1016/j.tetlet.2020.151946

A novel flavonoid glycoside dimer with an unprecedented cyclobutane moiety, named angustifolinoid B (1), was isolated from Elaeagnus angustifolia flowers. Its structure was determined by extensive spectroscopic analysis (HRMS, NMR) and chemical hydrolysis. The new dimer was formed via a [2 + 2] cycloaddition between two symmetric tiliroside. Bioassay revealed that compound 1 showed significant α-glucosidase inhibitory activity with IC₅₀ value at 4.40 μM.

Full text of DOI:10.1016/j.tetlet.2020.151946

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Angustifolinoid B, a flavonoid glycoside dimer with cyclobutane from
Elaeagnus angustifolia flowers
a,b,
Huijun Xie a,c,1, Xiaoyu Chen a,d,1, Miaomiao Li b, Haji Akber Aisa a, , Tao Yuan
⇑
⇑
a The Key Laboratory of Plant Resources and Chemistry of Arid Zone, State Key Laboratory of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute
of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China
b The Laboratory of Effective Substances of Jiangxi Genuine Medicinal Materials, College of Life Sciences, Jiangxi Normal University, Nanchang 330022, China
c University of Chinese Academy of Sciences, Beijing 100049, China
d Xinjiang Fukang Center for Disease Control and Prevention, Fukang 831500, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel flavonoid glycoside dimer with an unprecedented cyclobutane moiety, named angustifolinoid B
(1), was isolated from Elaeagnus angustifolia flowers. Its structure was determined by extensive
spectroscopic analysis (HRMS, NMR) and chemical hydrolysis. The new dimer was formed via a [2 + 2]
cycloaddition between two symmetric tiliroside. Bioassay revealed that compound 1 showed significant
Received 17 February 2020
Revised 7 April 2020
Accepted 13 April 2020
Available online xxxx
a-glucosidase inhibitory activity with IC50 value at 4.40 lM.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Elaeagnus angustifolia
Flavonoid glycoside
Cyclobutane
a-Glucosidease
Compounds with cyclobutane moiety are not common, whether
while most of researches focused on the determination of essential
oil and the total flavonoids content [9,10]. Our group previously
reported the identification of a novel macrocyclic flavonoid gly-
coside, angustifolinoid A, and a predominant compound, tiliroside,
from the E. angustifolia flowers [11,12]. In order to obtain more
quantity of angustifolinoid A for bioassay, increased raw materials
were used, which led to isolate a flavonoid glycoside dimer with an
unprecedented cyclobutane, named angustifolinoid B (1) (Fig. 1),
except angustifolinoid A. Herein, the isolation, structural elucida-
from natural products or chemical synthesis, due to its highly
strained ring systems [1]. However, in some case, the ring strains
can be reduced by some functional group such as carbonyl group,
heteroatom, and so on [2]. Natural products bearing cyclobutane
motif have been found in difference classes of compounds, includ-
ing flavonoids, terpenoids, alkaloids and steroids [3–6]. They not
only showed fascinating structure characteristic, but also exhibited
broad biologic activities. Therefore, more and more scientists pay
attention to this class of compounds.
tion, and
a-glucosidase inhibitory activity of this flavonoid gly-
Elaeagnus angustifolia L. (Elaeagnaceae), commonly called Rus-
sian or oleaster olive, is widely distributed from the northern
regions of Asia to the Himalayas and Europe [7]. For wind breaks
and sand fixation, E. angustifolia is mainly planted in the Northwest
of China [8]. However, it is also a important traditional medicine
used by Xinjiang local doctor. For example, the flowers of
E. angustifolia were used to treat brain disease, thoracalgia and
asthma in Chinese Uygur medicine. Few studies had been worked
on the isolation and identification of compounds from the flowers,
coside dimer, were presented.
Compound 1 was obtained as a yellow amorphous powder with
the molecular formula of C60H52O26, as determined by its (-)-HRE-
SIMS data (m/z 1187.2654 [M
ꢀ
H]ꢀ, calcd for C60H51O26
,
1187.2669). The IR spectrum showed absorption for hydroxyl
(3431 cmꢀ1), carbonyl (1724, 1655 cmꢀ1) and aromatic ring
(1606, 1515 cmꢀ1). In the 1H NMR spectrum (Table 1), two sets
of meta aromatic proton signals at dH 6.25/6.13 (each 1H, d,
J = 2.0 Hz), 6.20/6.10 (each 1H, d, J = 2.0 Hz), two sets of p-hydroxy
benzene ring protons at dH 7.94/6.73 (each 2H, d, J = 8.9 Hz) and
8.04/6.77 (each 2H, d, J = 8.9 Hz), were typical of two sets of
kaempferol moieties, which were confirmed by the 13C NMR and
HMBC spectrum. Except the above signals for kaempferol moieties,
there are two sets of glucopyranose signals showed in the NMR
spectrum, whose anomeric protons signals were observed at dH
5.17 (d, J = 7.7 Hz, H-100) and 5.05 (d, J = 7.8 Hz, H-1100). In addition,
⇑
Corresponding authors at: The Laboratory of Effective Substances of Jiangxi
Genuine Medicinal Materials, College of Life Sciences, Jiangxi Normal University,
Nanchang 330022, China and Xinjiang Technical Institute of Physics and Chemistry,
Chinese Academy of Sciences, Urumqi 830011, China (T. Yuan).
E-mail addresses: haji@ms.xjb.ac.cn (H.A. Aisa), tyuan@jxnu.edu.cn (T. Yuan).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.tetlet.2020.151946
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: H. Xie, X. Chen, M. Li et al., Angustifolinoid B, a flavonoid glycoside dimer with cyclobutane from Elaeagnus angustifolia flowers,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151946

2
H. Xie et al. / Tetrahedron Letters xxx (xxxx) xxx
were mutually correlated to each other in the sequence of dH 4.02,
3.41, 3.72, 3.46, the last one was found in turn to correlate with the
first one, which indicated the presence of a cyclobutane moiety in
compound 1. The HMBC correlations from H-2000 and H-6000 to C-7000,
and from H-12000 and H-16000 to C-17000, revealed that the two
p-hydroxyphenyl groups were attached to the C-7000 and C-17000 of
cyclobutane, respectively. The HMBC correlations from H-7000 and
H-17000 to C-9000 (dC 173.66) and C-19000 (dC 173.10), from H-8000 to
C-9000, and from H-18000 to C-19000, indicated two ester carbonyls were
connected to the C-8000 and C-18000 of cyclobutane. The above assign-
ments indicated the p-hydroxyphenyls and carbonyls were
arranged in the truxillic type (head-to-tail) rather than the truxinic
type (head-to-head), indicative of the presence of truxillate [13].
The HMBC correlations from H-600 to C-9000, and from H-1600 to
C-19000, indicated the position-6 of glucoses were connected to the
cyclobutane via ester bonds, which was supported by the observa-
tion of downfield shift of the chemical shift of CH2-600 and
1600. Therefore, compound 1 was formed via [2 + 2]-cycloaddition
Fig. 1. Chemical structures of compounds 1.
another two sets of p-hydroxyphenyl signals at dH 6.80/6.61 (each
2H, d, J = 8.5 Hz), 6.63/6.56 (each 2H, d, J = 8.5 Hz), as well as four
methine proton signals at dH 4.02 (dd, J = 10.8, 7.9 Hz, H-17000), 3.72
(dd, J = 10.9, 6.3 Hz, H-7000), 3.46 (m, H-18000) and 3.41 (m, H-8000),
were also observed in the 1H NMR spectrum. Analysis of 13C
NMR (Table 1) and HSQC spectra revealed the presence of 60 car-
bon resonances attributable to two kaempferol moieties, two glu-
copyranoses, two p-hydroxyphenyl groups, four unassigned
methines and two carbonyls (dC 173.66 and 173.10). The afore-
mentioned NMR data implied that compound 1 is likely a flavonoid
glycoside dimer.
between two symmetric tiliroside,
a predominant flavonoid
glycoside previously isolated from this species [12].
The glucoses were assigned as b-configuration by coupling con-
stant (J = 7.7 Hz, H-100; J = 7.8 Hz, H-1100) of their anomeric protons,
and determined as D-glucose by comparison the TLC and optical
rotation with an authentic sample after acid hydrolysis of com-
pound 1. The relative configuration of cyclobutane was determined
according to its NOESY (Fig. 3) spectrum. The NOESY correlations
from H-2000 (dH 6.80) to H-17000 (dH 4.02) and H-18000 (dH 3.46), from
H-12000 (dH 6.63) to H-7000 (dH 3.72) and H-8000 (dH 3.41), indicated
the two p-hydroxyphenyl groups and two ester carbonyls were
Further analysis 2D NMR data (1H-1H COSY, HSQC, and HMBC)
allowed elucidating the structure of 1. The two glucoses were
linked to position-3 of kaempferol by the HMBC correlations from
H-100 to C-3 (dC 135.58), and from H-1100 to C-13 (dC 135.53). The
HSQC data indicated that the four unassigned methine protons
were connected to corresponding carbons at dC 41.37 (C-17000),
42.23 (C-7000), 49.00 (C-18000), and 47.76 (C-8000), respectively. The
1H-1H COSY (Fig. 2) correlations showed the four methine protons
in the trans-configuration, which is consistent with
arrangement. The central core of 1 was thus determined as 4,40-
dihydroxy- -truxillate. To determine the absolute configurations
of central core, the 4,40-dihydroxy-
-truxillic acid was isolated
and identified by the 1H NMR and HRMS (see SI) after hydrolysis.
a-truxillate
a
a
Table 1
1H and 13C NMR spectroscopic data of 1.a
Position
dH (mult; J, Hz)
dC
Position
dH (mult; J, Hz)
dC
2
3
4
4a
5
6
7
8
158.77
135.58
179.46
105.73
163.04
100.15
165.96
95.13
12
158.96
135.53
179.43
105.88
162.93
100.15
165.90
95.47
13
14
14a
15
6.13 (d, 2.0)
6.25 (d, 2.0)
16
6.10 (d, 2.0)
6.20 (d, 2.0)
17
18
8a
10
20
30
40
50
60
100
200
300
400
500
600
158.33
122.66
132.31
116.11
161.67
116.11
132.31
104.12
75.77
78.01
71.95
76.42
65.65
18a
110
120
130
140
150
160
1100
1200
1300
1400
1500
1600
158.23
122.69
132.57
116.18
161.67
116.18
132.57
103.88
75.84
77.97
71.69
76.10
64.90
7.94 (d, 8.9)
6.73 (d, 8.9)
8.04 (d, 8.9)
6.77 (d, 8.9)
6.73 (d, 8.9)
7.94 (d, 8.9)
5.17 (d, 7.7)
3.47 (m)
6.77 (d, 8.9)
8.04 (d, 8.9)
5.05 (d, 7.8)
3.43 (m)
3.33 (m)
3.00 (t, 9.3)
2.78 (m)
3.39 (m)
3.08 (d, 2.2)
3.08 (dd, 5.1, 2.2)
3.94 (brd, 11.8)
3.69 (m)
4.35 (dd, 11.8, 1.5)
3.32 (m)
1000
2000
3000
4000
5000
6000
7000
8000
9000
131.14
129.81
116.37
157.56
116.37
129.81
42.23
11000
12000
13000
14000
15000
16000
17000
18000
19000
131.14
129.31
116.28
157.28
116.37
129.31
41.37
6.80 (d, 8.5)
6.61 (d, 8.5)
6.63 (d, 8.5)
6.56 (d, 8.5)
6.61 (d, 8.5)
6.80 (d, 8.5)
3.72 (dd, 10.9, 6.3)
3.41 (m)
6.63 (d, 8.5)
6.56 (d, 8.5)
4.02 (dd, 10.8, 7.9)
3.46 (m)
47.76
173.66
49.00
173.10
a
Data were recorded in CDCl3 at 400 MHz (1H) and 100 MHz (13C).
Please cite this article as: H. Xie, X. Chen, M. Li et al., Angustifolinoid B, a flavonoid glycoside dimer with cyclobutane from Elaeagnus angustifolia flowers,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151946

H. Xie et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Fig. 2. Key 1H-1H COSY and HMBC correlations of 1.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China (U1703331, 21502222), and Jiangxi ‘‘Shuangqian”
Program (JXSQ2018101008).
Fig. 3. Key NOESY correlations of core moiety of 1.
Appendix A. Supplementary data
However, the 4,40-dihydroxy-
the absolute configurations of central core were unassignment.
Therefore, the structure of 1 was determined as shown in Fig. 1,
given the trivial name angustifolinoid B.
a
-truxillic acid is a meso compound,
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151946.
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dimerization is important for the bioactivity.
In summary, this work presents the isolation and identification
of an unusual flavonoid glycoside dimer from the flowers. Its struc-
ture is characterized by a rare cyclobutane. Biosynthetic analysis
suggested that the unusual flavonoid glycoside dimer was formed
via [2 + 2] cycloaddition reaction between two symmetric tiliro-
side, which was isolated from this species as major compound.
As the [2 + 2] cycloaddition is usually a photocatalytic reaction,
while the species is from Xinjiang with a long time of sunshine,
which may explain the production of this compound. Bioassay
indicated that compound 1 showed stronger a-glucosidase inhibi-
tory activity than that of positive control acarbose. The structure
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Please cite this article as: H. Xie, X. Chen, M. Li et al., Angustifolinoid B, a flavonoid glycoside dimer with cyclobutane from Elaeagnus angustifolia flowers,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151946