Antihyperlipidemic glycosides from the root bark of Lycium chinense

Article abstract of DOI:10.1080/14786419.2018.1466125

Three new glycosides (1–3), together with six known ones (4–9), were isolated from the root bark of Lycium chinense. Their structures were elucidated on the basis of MS and NMR spectroscopic data. Five compounds (3, 5, 6, 8, and 9) exhibited potent antihyperlipidemic activities in HepG2 cells as assessed by Oil Red O staining and significant inhibition of intracellular triglyceride (TG) levels, whereas two compounds (5 and 9) significantly reduced total cholesterol (TC) levels.

Full text of DOI:10.1080/14786419.2018.1466125

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Antihyperlipidemic glycosides from the root bark
of Lycium chinense
Hui Chen, Yu-Jie Li, Yan-Jun Sun, Xiao-Kun Li, Gong Jian-Hong, Ya Wu, Fang-Yi
Su, Kun Du, Yan-Li Zhang & Wei-Sheng Feng
To cite this article: Hui Chen, Yu-Jie Li, Yan-Jun Sun, Xiao-Kun Li, Gong Jian-Hong, Ya Wu,
Fang-Yi Su, Kun Du, Yan-Li Zhang & Wei-Sheng Feng (2018): Antihyperlipidemic glycosides from
the root bark of Lycium chinense, Natural Product Research
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Natural Product research, 2018
ꢁꢁpꢂ://ꢃꢄi.ꢄꢅg/10.1080/14786419.2018.1466125
ꢀ
Antihyperlipidemic glycosides from the root bark of Lycium
chinense
a,b
c
a,b
a,b
a,b
a,b
Hui Chen , Yu-Jie Li , Yan-Jun Sun , Xiao-Kun Li , Gong Jian-Hong , Ya Wu ,
a,b
a,b
a,b
a,b
Fang-Yi Su , Kun Du , Yan-Li Zhang and Wei-Sheng Feng
ꢆ
cꢄꢇꢇꢆbꢄꢅꢆꢁivꢈ Innꢄvꢆꢁiꢄn cꢈnꢁꢈꢅ fꢄꢅ rꢈꢂpiꢅꢆꢁꢄꢅy diꢂꢈꢆꢂꢈ diꢆgnꢄꢂiꢂ, tꢅꢈꢆꢁmꢈnꢁ & cꢀinꢈꢂꢈ Mꢈꢃiꢉinꢈ
b
dꢈvꢈꢇꢄpmꢈnꢁ ꢄf hꢈnꢆn Pꢅꢄvinꢉꢈ, hꢈnꢆn univꢈꢅꢂiꢁy ꢄf cꢀinꢈꢂꢈ Mꢈꢃiꢉinꢈ, Zꢀꢈngzꢀꢄꢊ, cꢀinꢆ; sꢉꢀꢄꢄꢇ ꢄf
Pꢀꢆꢅmꢆꢉy, hꢈnꢆn univꢈꢅꢂiꢁy ꢄf cꢀinꢈꢂꢈ Mꢈꢃiꢉinꢈ, Zꢀꢈngzꢀꢄꢊ, cꢀinꢆ; sꢉꢀꢄꢄꢇ ꢄf Bꢆꢂiꢉ Mꢈꢃiꢉꢆꢇ sꢉiꢈnꢉꢈꢂ,
ꢉ
hꢈnꢆn univꢈꢅꢂiꢁy ꢄf cꢀinꢈꢂꢈ Mꢈꢃiꢉinꢈ, Zꢀꢈngzꢀꢄꢊ, cꢀinꢆ
ABSTRACT
ARTICLE HISTORY
Three new glycosides (1–3), together with six known ones (4–9),
were isolated from the root bark of Lycium chinense. Their structures
were elucidated on the basis of MS and NMR spectroscopic data. Five
compounds (3, 5, 6, 8, and 9) exhibited potent antihyperlipidemic
activities in HepG2 cells as assessed by Oil Red O staining and
significant inhibition of intracellular triglyceride (TG) levels, whereas
two compounds (5 and 9) significantly reduced total cholesterol (TC)
levels.
rꢈꢉꢈivꢈꢃ 22 Jꢆnꢊꢆꢅy 2018
aꢉꢉꢈpꢁꢈꢃ 13 apꢅiꢇ 2018
KEYWORDS
Lycium chinense; gꢇyꢉꢄꢂiꢃꢈꢂ;
ꢆnꢁiꢀypꢈꢅꢇipiꢃꢈmiꢉ ꢆꢉꢁiviꢁy
1
. Introduction
The genus Lycium (Solanaceae) consists of about 80 species worldwide, with seven occurring
in China. Two species in particular, Lycium chinense and Lycium barbarum, have been used
as traditional Chinese medicine (TCM) and nutrient supplements for thousands of years in
Southeast Asia, especially in China (Qian et al. 2017). Lycii Radicis Cortex, the root bark of
L. chinense or L. barbarum., has been widely used in TCM as a ‘heat cleansing’ drug for the
treatment of hectic fever, night-sweats, pneumonia, cough, hematemesis, and diabetes mel-
litus (Xie et al. 2014). Modern pharmacological studies showed that Lycii Radicis Cortex
exhibited extensive biological activities, such as lowering blood pressure, serum glucose,
and lipid levels. Previous phytochemical investigations have resulted in the isolation of
CONTACT hꢊi cꢀꢈn
ꢉꢀꢀ701@163.ꢉꢄm; Xiꢆꢄ-Kꢊn li
ꢇi96052122@126.ꢉꢄm
sꢊppꢇꢈmꢈnꢁꢆꢇ ꢃꢆꢁꢆ fꢄꢅ ꢁꢀiꢂ ꢆꢅꢁiꢉꢇꢈ ꢉꢆn bꢈ ꢆꢉꢉꢈꢂꢂꢈꢃ ꢆꢁ ꢀꢁꢁpꢂ://ꢃꢄi.ꢄꢅg/10.1080/14786419.2018.1466125.
©
2018 Infꢄꢅmꢆ uK limiꢁꢈꢃ, ꢁꢅꢆꢃing ꢆꢂ tꢆyꢇꢄꢅ & Fꢅꢆnꢉiꢂ Gꢅꢄꢊp

2
H. CHEN ET AL.
phenolic amides (Zhang et al. 2013; Chen et al. 2017), flavonoids, lignans, phenolic glucosides
Yang et al. 2017), steroids (An et al. 2016) and some cyclopeptides (Yahara et al. 1993). In
(
an ongoing program to search for antihyperlipidemic agents from natural sources, a sys-
tematic chemical study was carried out on the n-butanol fractions of ethanol extract of the
root bark of L.chinense. As a result, three new glycosides (1–3), together with six known ones
(
4–9), were isolated. Details of the isolation, structure elucidation, and antihyperlipidemic
activities of these metabolites are reported herein.
2
. Results and discussion
Compound 1 was obtained as a white amorphous powder. The molecular formula was estab-
+
lished to be C H O by the HRESIMS ion peak at m/z [M + Na] 573.2305 (C H O Na, calcd
28
38 11
1
28 38 11
for 573.2306). The H NMR spectrum of 1 exhibited an ABX-like system aromatic ring at
δH 6.57 (1H, overlap), 6.55 (1H, d, J = 8.0 Hz), and 6.48 (1H, dd, J = 8.0, 2.0 Hz), a 1,3,4,5-tetra-
substituted benzene ring at δ 6.94 (1H, d, J = 1.5 Hz) and 6.91 (1H, d, J = 1.5 Hz), and two
H
trans-olefinic protons at δ 6.59 (1H, d, J = 16.0 Hz) and 6.25 (1H, dt, J = 16.0, 6.0 Hz). Three
H
oxygenated methylene groups at δ 4.12 (2H, dd, J = 6.0, 1,5 Hz), 3.78 (1H, m), 3.68 (1H, m)
H
and 3.56 (2H, m), a methylene group at δ 2.95 (1H, dd, J = 14.0, 5.5 Hz) and 2.72 (1H, dd,
H
J = 14.0, 5.5 Hz), two methoxy groups at δ 3.82 (3H, s) and 3.69 (3H, s), and a methyl signal
H
13
at δ 1.22 (3H, t, J = 7.0 Hz) were observed in the upfield region. The C NMR and HSQC
H
spectra displayed a total of 28 carbon signals. Apart from one glucopyranose moiety and
two methoxy groups, the remaining 20 carbon signals were assigned to two C –C units and
6
3
an oxygenated ethyl group [δ 3.56 (2H, m) and 1.22 (3H, t, J = 7.0 Hz)]. On the basis of the
H
above analysis, the planner structure of 1 was similar to that of Icariside E (4) (Iorizzi et al.
5
2
001), except that the hydroxyl group at C-9′ of 4 was replaced by an oxygenated ethyl group.
This structural variation was confirmed by the HMBC correlations from the methyl protons
δH 1.22) and H-9′ to C-10′ (Figure S4). Acid hydrolysis of 1 gave a glucose molecule. The large
(
coupling constant (7.5 Hz) of the anomeric proton at δ 4.67 reavealed that the glucose was
H
in the β-configuration, and the D-configuration of the moiety was established by hydrolysis
and GC analysis. The absolute configuration at C-8 was suggested to be R on the basis of the
2
0
25
optical rotation ([ꢀ]D − 82.7) with those of R-isomer of 4 ([ꢀ]D − 116.3) (Iorizzi et al. 2001) and
2
3
of S-isomer of saikolignanoside A ([ꢀ] + 32.8) (Tan et al. 2004). Therefore, the structure of 1
D
was established as shown, and was accorded the trivial name lyciumoside B.
To rule out the possibility of 1 being artifact formed as a result of the extraction and
purification process, a careful LC-ESIMS analysis of a methanolic extract was carried out,
+
which clearly revealed an ion peak at m/z 573.2303 ([M + H] , t 10.5 min) (Figure S6) in accord
R
with that of 1 and confirmed the natural occurrence of 1.
Compound 2 exhibited a molecular formula of C H O according to the positive
2
2
34 13
+
1
HRESIMS ion observed at m/z 529.1877 [M + Na] . The H NMR spectrum of 2 revealed a
symmetrical 1,3,4,5-tetrasubstituted aromatic ring at δ 6.49 (2H, s), an oxymethylene pro-
H
tons at δ 3.90 (2H, m), two methylene protons at δ 2.65 (2H, dd, J = 10.0, 5.0 Hz) and 1.88
H
H
(
2H, m), two methoxyl groups at δ 3.84 (6H, s). Moreover, two anomeric protons at δ 4.32
H
H
(
1H, d, J = 7.5 Hz) and 4.24 (1H, d, J = 8.0 Hz) observed in the upfield region confirmed the
13
presence of two sugar moieties with a β-linkage. The C NMR spectra of 2 showed 22 carbon
signals that could be assigned to a glucopyranose unit, a xylopyranose unit and two methoxy
groups. Analysis of the HMBC correlations from the methylene protons at δ 1.88 (H-8) to
H

NATURAL PRODUCT RESEARCH
3
C-1 (δ 134.2), C-7 (δ 33.2) and C-9 (δ 70.1) and from H-7 to C-2, C-6, C-8 and C-9 permitted
C
C
C
assignment of a phenylpropanol moiety (Figure S10). The sequence of two sugar units was
determined to be β-xylopyranosy-(1→6)-O-β-glucopyranosyl based on correlations from H-1″
(
7
δ 4.32) to C-6′ in the HMBC spectrum. The presence of a downfield methylene signal at δ
0.1 (C-9) in the C NMR spectrum indicated the attachment of the sugar moiety. This was
H
C
13
further confirmed by the HMBC correlation from H-1′ to C-9. The d-configuration of these
two sugars was determined by hydrolysis and GC analysis. Accordingly, the structure of 2
was elucidated as 4′-hydroxy-3′, 5′-dimethoxy-phenylpropanol-1-O-β-d-xylopyranosyl-(1→6)-
O-β-d-glucopyranoside, and named lyciumoside C.
Compound 3 was obtained as a white powder. The molecular formula, C H O , was
1
4
22
7
+
established by positive HRESIMS (m/z 325.1254 [M + Na] , calcd for 325.1258). The IR absorp-
tion bands at 3330, 1670, 1075 and 1030 cm indicated the presence of hydroxyl, carbonyl
and olefinic groups. The H NMR data of 3 indicated the presence of two trans-olefinic protons
−1
1
at δ 6.34 (1H, d, J = 13.0 Hz) and 5.97 (1H, d, J = 13.0 Hz) (Lubineau et al. 1995; Mari et al.
H
2
017), an anomeric protons at δ 4.55 (1H, d, J = 7.5 Hz) and three methyls signals at δ 2.29
H
H
1
3
(
3H, s), 1.76 (3H, s) and 1.72 (3H, s). The C NMR spectra of 3 showed 14 carbon signals,
including a carbonyl carbon (δ 208.9), a pair of disustituted olefinic carbons (δ 147.6 and
C
C
1
06.2), a tetrasubstituted olefinic carbons (δ 134.8 and 132.1), three methyl carbons
C
(
δ 30.8, 21.7 and 19.9) and a glucopyranose unit (δ 103.6→62.2). The HMBC correlations
C
C
(
Figure S15) from the methyl signal at δ 2.29 to C-2 and C-3, from H-5 to C-2, C-4 and C-6,
H
from H-6 to C-3 and C-5, and from the two methyl signals at δ 1.72 and δ 1.76 to C-3 and
H
H
C-4 provided the lingkage from C-1 to C-8, which was assigned as (E)-3-(2-hydroxyviny)-4-
methylpent-3-en-2-one. Acid hydrolysis of 3 gave a glucose. The large coupling constant
(
7.5 Hz) of the anomeric proton at δ 4.55 revealed that the glucose was in the β-configura-
H
tion, and the d-confirguration of the moiety was established by GC analysis. The presence
1
3
of a downfield olefinic carbon (δ 147.6) in the C NMR spectrum indicated the attachment
C
of the β-d-glucopyranosyl moiety, and this was further confirmed by the HMBC correlation
from H-1′ to C-6. Thus, the structure of 3 was elucidated as (E)-3-(2-hydroxyviny)-4-
methylpent-3-en-2-one-6-O-β-d-glucopyranoside, and named lyciumoside D.
Six known compounds (Figure 1), including Icariside E (4) (Iorizzi et al. 2001), pheneth-
5
anol-β-vicianoside (5) (Wang et al. 2012), kelampyoside A (6) (Sunghwa and Koketsu 2009),
3′,4′-dimethoxy-benzylalcohol-1-O-β-d-xylopyranosyl-(1→6)-O-β-d-glucopyranoside
(7)
(
Yang et al. 2017), 3′, 4′, 5′-trimethoxy-benzylalcohol-1-O-β- -xylopyranosyl-(1→6)-O-β-
d
d-glu-
copyranoside (8) (Yang et al. 2017), (2E,4E,1′R,3′S,5′R,8′S)-dihydrophaseic acid 3′-O-β-d-
glucopyranoside (9) (Ngan et al. 2012) were also isolated from the root bark of L. chinense
and were identified by comparison of their spectroscopic data with those reported in the
literature.
Hyperlipidemia is known as abnormal elevation of the serum lipid levels, and is caused
by lipid metabolic changes and can be manifested in the elevation of serum total cholesterol
(
TC)/triglycerides (TG) and/or lipoproteins (Chen et al. 2017). All isolated compounds were
screened for antihyperlipidemic activity in the HepG2 hepatocarcinoma cells, which is a
widely-used cell model for the investigation of lipid metabolic regulation (Li et al. 2014). A
cytotoxic test against HepG2 cells was firstly performed and no compounds showed toxicity
up to 100 μM. In the screening with Oil Red O staining, five compounds (3, 5, 6, 8, and 9)
exhibited potent lipid-lowering effects at a dose of 10 μM in HepG2 cells (Figure S29). Further
investigation was carried out in the same cell model. All the five compounds (3, 5, 6, 8, and

4
H. CHEN ET AL.
Figure 1. tꢀꢈ ꢂꢁꢅꢊꢉꢁꢊꢅꢈꢂ ꢄf ꢉꢄmpꢄꢊnꢃꢂ 1–9.
9
) significantly suppressed intracellular total triglyceride (TG) levels and two (5 and 9) sig-
nificantly reduced intracelluar total cholesterol (TC) levels (Figure S30). In addition, the
anti-inflammatory and PPAR transactivational effects of compound 9 in HepG2 cells has
been reported by Ngan et al. (2012). Currently, PPARs are therapeutic targets in the design
and development of agonists for the treatment of hyperlipidemia, type 2 diabetes and other
metabolic syndrome. These results suggested that compound 9 may be a useful agent in
the prevention and treatment of broad metabolic diseases.
3
. Experimental section
3
.1. General experimental procedures
Optical rotations were obtained on a Rudolph AP-IV polarimeter. UV spectra were measured
on a Thermo EVO 300 spectrophotometer. IR spectra were recorded on a Thermo Nicolet IS
10 spectrometer. NMR spectra were recorded on a Bruker Avance Ⅲ 500 spectrometer.
HRESIMS data were recorded on a Bruker maxis HD Mass Q-TOF LC/MS spectrometer.
Preparative HPLC was performed on a Sepuruisi LC-52 instrument with an UV200 detector
(
5
Beijing Sepurusi scientific Co., Ltd, China), using a YMC-Pack ODS-A column (250 × 20 mm,
μm). Sephadex LH-20 (Amersham Pharmacia Biotech AB, Sweden), ODS (45–70 μm, Merck),
and silica gel (200–300 mesh, Qingdao Marine Chemical Inc. China) were used for column
chromatography. TLC was carried out with glass precoated with silica gel GF254 (Qingdao
Marine Chemical Inc. China). The human heptocelluar (HepG2) cell line was purchased from
the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union
Medical College, China.

NATURAL PRODUCT RESEARCH
5
3
.2. Plant material
The root bark of L. chinense was collected from Henan Province, China, in September of 2013,
which was identified by Prof.. Sui-Qing Chen of Henan University of Chinese Medicine. The
voucher specimen (No. 20130916B) has been deposited at Henan University of Chinese
Medicine.
3
.3. Extraction and isolation
The root bark of L. chinense (25 kg) was macerated for 3 h with 75 L of 95% EtOH(aq) and
refluxed for 9 h (75 L × 3). The filtrate was concentrated under reduced pressure. The residue
(
1070 g) was suspended in H O, followed by successive partition with petroleum ether, EtOAc,
2
and n-BuOH. The n-BuOH fraction (302 g) was applied to an HP-20 macroporous adsorbent
resin column and eluted with H O, 10, 30, and 50% EtOH to yield four corresponding fractions.
2
The 30% EtOH part (15.4 g) was subjected to an ODS column eluting with a step-gradient
of MeOH/H O (from 10:90 to 80:20), to give seven subfractions, S1–S7. Fraction S2 (1.9 g)
2
was chromatographed over a Sephadex LH-20 with MeOH and was further purified with
preparative HPLC [solvent system: MeOH/H O (25:75)] to yield 2 (9.6 mg, t = 27.3 min), 6
2
R
(
23.6 mg, t = 36.2 min), 7 (22.0 mg, t = 42.8 min) and 8 (16.3 mg, t = 53.2 min). Fraction S3
R
R
R
(
3.5 g) was subjected to preparative reversed-phase MPLC, eluted with a gradient of MeOH/
H O (from 10:90 to 90:10) to afford five subfractions S3-1-S3-5. Fraction S3-2 (220 mg) was
2
chromatographed over a Sephadex LH-20 with MeOH and was further purified with pre-
parative HPLC [solvent system: MeOH/H O (30:70)] to yield 9 (29.6 mg, t = 10.3 min) and 5
2
R
(
43.2 mg, t = 26.2 min). Fraction S3-3 was purified by preparative HPLC [solvent system:
R
MeOH/H O (35:65)] to yield 4 (18.3 mg, t = 42.8 min). Purification of fraction S4 with pre-
2
R
parative HPLC [solvent system: MeOH/H O (40:60)] yielded 1 (3.5 mg, t = 30.3 min) and 3
2
R
(
2.2 mg, t = 43.5 min).
R
3
.3.1. Lyciumoside B (1)
2
5
White amorphous powder;[ꢀ] − 82.7 (c 0.09, MeOH); UVλ (MeOH) nm (log ε): 203 (4.29),
D
max
2
1
59 (3.80) nm; IR (KBr) v 3369, 2940, 2851, 1676, 1599, 1515, 1450, 1423, 1203, 1069,
max
−
1
+
1
13
018 cm ; HRESIMS m/z 573.2305 [M + Na] (calcd for C H O Na, 573.2306). H and C
28 38 11
NMR data of 1 see Table S1.
3
.3.2. Lyciumoside C (2)
2
5
White amorphous powder;[ꢀ] − 26.5 (c 0.1, MeOH); UVλ (MeOH) nm (log ε): 206 (4.37),
D
max
−
1
2
72 (3.20) nm; IR (KBr) vmax 3366, 2943, 2922, 1646, 1610, 1518, 1462, 1221, 1108, 1009 cm ;
+
1
13
HRESIMS m/z 529.1877 [M + Na] (calcd for C H O Na, 529.1897). H and C NMR data of
2
2
34 13
2
see Table S2.
3
.3.3. Lyciumoside D (3)
2
5
White amorphous powder;[ꢀ] − 4.7 (c 0.05, MeOH); UVλ (MeOH) nm (log ε): 201 (3.94),
D
max
−
1
2
35 (3.91) nm; IR (KBr) vmax 3330, 2926, 2869, 1670, 1604, 1447, 1405, 1185, 1075, 1030 cm ;
+
1
13
HRESIMS m/z 325.1254 [M + Na] (calcd for C H O Na, 325.1258). H and C NMR data of
1
4
22
7
3
see Table S3.

6
H. CHEN ET AL.
3
.4. Acid hydrolysis of new compounds (1–3)
Each compound (2 mg) was dissolved in 0.5 M HCl (5 mL) and heated at 90 °C for 2 h under
constant stirring. After extraction with EtOAc (3 × 5 mL), the aqueous layer was evaporated
and cryodesiccated. Each residue was dissolved in dry pyridine (1 mL), and then L-cysteine
methyl ester hydrochloride (2 mg) was added. Each mixture was stirred at 60 °C for 2 h, and
then 0.2 mL of N-trimethylsilylimidazole was added, followed by heating to dryness at 60 °C
for 2 h. Each dried reactant was partitioned between n-hexane and H O (0.2 mL), and the
2
n-hexane fraction was subjected to gas chromatography (GC) (column: DM-5,
0.25 mm × 30 m × 25 μM; detector: FID; temperature: 280 °C; injector temperature: 250 °C;
carrier: N gas). D-glucose and D-xylose were identified by comparison of their retention
2
time of their derivatives to the standard sugar derivatized in a similar manner, which exhib-
ited retention times of 20.5 and 14.9 min, respectively.
3
.5. Cell-based lipid accumulation assay
The assay procedure was performed as previously reported (Li et al. 2014). Simvastatin was
used as the positive control at a concentration of 10 μM.
4
. Conclusion
In summary, three new glycosides, lyciumosides B–D (1–3) and six known compounds (4–9),
were isolated from the n-butanol fractions of ethanol extract of the root bark of L.chinense.
The bioassay results revealed that five compounds (3, 5, 6, 8, and 9) exhibited potent anti-
hyperlipidemic activities in HepG2 cells as assessed by Oil Red O staining and significant
inhibition of intracellular triglyceride (TG) levels, whereas two compounds (5 and 9) signifi-
cantly reduced total cholesterol (TC) levels.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the National Natural Science Foundation of China [grant number 21602047];
the Foundation of Henan Province for Excellent Young Teachers of Colleges and Universities [grant
number 2017GGJS-081]; the Basic Science Foundation of Henan University of Chinese Medicine [ grant
number 2014KYYWF-QN09].
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