Two new benzophenone glycosides from the aerial parts of Hypericum przewalskii

Article abstract of DOI:10.1080/14786419.2020.1865955

Plants of the genus Hypericum contain various types of secondary metabolites that exhibited extensive biological activities. In the ongoing efforts to discover natural neuroinflammatory inhibitors with the potential to develop into therapeutic agents for neurodegenerative diseases, two new benzophenone glycosides, hyperewalones A and B (1 and 2), along with eight known compounds (3–10), were isolated from the aerial parts of Hypericum przewalskii. Their structures were elucidated by comprehensive analysis of IR, HRESIMS, 1D and 2D NMR spectra, and chemical derivatization. The anti-neuroinflammatory activity of compounds 1–10 was evaluated by determining their ability to inhibit the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Compounds 2, 4, 6–8 exhibited significant anti-neuroinflammatory activity with IC₅₀ values of 0.61–4.90 μM. These findings suggest that the benzophenone, ionone, and flavonoid glycosides isolated from H. przewalskii are promising anti-neuroinflammatory compounds worthy of further investigations.

Full text of DOI:10.1080/14786419.2020.1865955

Natural Product Research
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Two new benzophenone glycosides from the aerial
parts of Hypericum przewalskii
Jin-Yan Xie, Qinghao Jin, Jin-Ming Gao, Shi-Chun Zong & Xi-Tao Yan
To cite this article: Jin-Yan Xie, Qinghao Jin, Jin-Ming Gao, Shi-Chun Zong & Xi-Tao Yan (2020):
Two new benzophenone glycosides from the aerial parts of Hypericumꢀprzewalskii, Natural Product
Research, DOI: 10.1080/14786419.2020.1865955
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1865955
Two new benzophenone glycosides from the aerial parts
of Hypericum przewalskii
Jin-Yan Xiea, Qinghao Jinb, Jin-Ming Gaoa, Shi-Chun Zongc and Xi-Tao Yana
aShaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy,
b
Northwest A&F University, Yangling, Shaanxi, China; Natural Medicine Institute of Zhejiang
c
YangShengTang Co., Ltd, Hangzhou, Zhejiang, China; Division of Medical Clinic, Xi’an University of
Posts and Telecommunications, Xi’an, Shaanxi, China
ABSTRACT
ARTICLE HISTORY
Received 26 October 2020
Accepted 15 December 2020
Plants of the genus Hypericum contain various types of secondary
metabolites that exhibited extensive biological activities. In the
ongoing efforts to discover natural neuroinflammatory inhibitors
with the potential to develop into therapeutic agents for neuro-
degenerative diseases, two new benzophenone glycosides, hyper-
ewalones A and B (1 and 2), along with eight known compounds
(3–10), were isolated from the aerial parts of Hypericum przewal-
skii. Their structures were elucidated by comprehensive analysis of
IR, HRESIMS, 1D and 2D NMR spectra, and chemical derivatization.
The anti-neuroinflammatory activity of compounds 1–10 was eval-
uated by determining their ability to inhibit the production of
nitric oxide (NO) in lipopolysaccharide (LPS)-activated BV-2 micro-
glial cells. Compounds 2, 4, 6–8 exhibited significant anti-neuroin-
flammatory activity with IC50 values of 0.61–4.90 lM. These
findings suggest that the benzophenone, ionone, and flavonoid
glycosides isolated from H. przewalskii are promising anti-neuroin-
flammatory compounds worthy of further investigations.
KEYWORDS
Hypericaceae; Hypericum
przewalskii; benzophenone
glycoside; anti-
neuroinflammatory activity;
antimicrobial activity
1. Introduction
The genus Hypericum, belonging to the family Hypericaceae, comprises about 500 spe-
cies all over the world. Among them, about 64 species are distributed in China.
Several Hypericum species are used in folk medicine all over the world, such as H.
CONTACT Shi-Chun Zong
zong@xupt.edu.cn; Xi-Tao Yan
xty@nwsuaf.edu.cn
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1865955.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
J.-Y. XIE ET AL.
Figure 1. Chemical structures of the new compounds 1–2 from Hypericum przewalskii.
perforatum, H. japonicum, H. erectum, H. attenuatum. Previous chemical investigations
on this genus showed the presences of polycyclic polyprenylated acylphloroglucinols
(PPAPs) (Yang et al. 2018), simple acylphloroglucinol derivatives (Zhao et al. 2015),
xanthones (Xu et al. 2016; Yan et al. 2019), benzophenones (Rouis et al. 2013; Zhang
et al. 2020), naphthodianthrones (Farag and Wessjohann 2012), biphenyl ether glyco-
sides (Yan et al. 2018), flavonoids (Porzel et al. 2014), and others. These secondary
metabolites from Hypericum exhibit extensive biological activities, such as antidepres-
sant (Chatterjee et al. 1998; Grundmann et al. 2010), memory-enhancing (Ben-Eliezer
and Yechiam 2016), anti-inflammatory (Huang et al. 2011; Xie et al. 2020), antimicro-
bial (Bridi et al. 2018; Henrique et al. 2018), cytotoxic (Zhao et al. 2015; Keser et al.
2020), antiviral (Schmitt et al. 2001), antioxidant (Athanasas et al. 2004; Zheleva-
Dimitrova et al. 2013), antitumor (Dongre et al. 2007; Quassinti et al. 2013), and neuro-
protective (Gao et al. 2016; Oliveira et al. 2016; Yang et al. 2019) activities. These struc-
tures and biological activities have attracted much attention in the natural products
and synthesis chemistry fields.
In our ongoing search for new secondary metabolites with significant biological
activities from Hypericum species, we conducted a phytochemical investigation of H.
przewalskii, which is an annual herb growing as an endemic plant in northwest China.
Two new benzophenone glycosides, named hyperewalones A and B (1 and 2, Figure
1), along with eight known compounds were isolated. Their structures were deter-
mined by means of NMR spectroscopy, HRESIMS, and chemical derivatization. In this
study, we present the isolation and structural elucidation of compounds 1–10 and
their anti-neuroinflammatory, antibacterial, and antifungal activities.
2. Results and discussion
The MeOH extract of H. przewalskii was partitioned successively with n-hexane, EtOAc,
and n-BuOH. The EtOAc-soluble layer was further separated by using repeated silica
gel, RP-C18, Sephadex LH-20 column chromatography (CC), as well as semipreparative
HPLC, to afford two new compounds (1–2) and eight known compounds (3–10).
Compound 1 was obtained as a yellow amorphous powder. Its molecular formula
was determined to be C26H24O12 by HRESIMS at m/z 529.1343 [M þ H]þ (calcd for
C26H25O12, 529.1341), indicating 15 degrees of unsaturation. The IR spectrum showed
the absorption bands due to hydroxyl (3321 cmꢀ1) and conjugated carbonyl

NATURAL PRODUCT RESEARCH
3
Table 1. Inhibitory effects of compounds 1–10 on LPS-induced NO production in BV-2
microglial cells.
Compounds
IC50 (lM)a
1
2
3
>20
0.61 0.12
>20
4
5
1.28 0.15
>20
6
7
8
9
4.90 0.60
1.05 0.03
1.26 0.04
>20
10
>20
4.00 0.23
Quercetinb
aData are presented as means SD (n ¼ 3).
bPositive control.
(1713 cmꢀ1) groups. The low-field region of 1H NMR spectrum of 1 (Table S1 and
Figure S2, Supplementary material) exhibited aromatic proton signals attributable to a
monosubstituted benzene ring [dH 8.07 (2H, d, J ¼ 7.6 Hz, H-30’, H-70’), 7.63 (1H, t,
J ¼ 7.6 Hz, H-50’), and 7.50 (2H, t, J ¼ 7.6 Hz, H-40’, H-60’)] , a symmetrical 1,3,5-trisubsti-
tuted benzene ring [dH 6.71 (2H, d, J ¼ 2.0 Hz, H-2, H-6), 6.49 (1H, t, J ¼ 2.0 Hz, H-4)],
and a 1,2,3,5-tetrasubstituted benzene ring [dH 6.28 (1H, d, J ¼ 1.7 Hz, H-10), 6.11 (1H,
d, J ¼ 1.7 Hz, H-12)]. The remaining proton signals indicated the presence of a sugar
moiety [dH 5.00 (1H, d, J ¼ 7.7 Hz, H-10), 3.19 (1H, t, J ¼ 8.2 Hz, H-20), 3.76 (1H, m, H-30),
5.06 (1H, t, J ¼ 9.6 Hz, H-40), 3.75 (1H, m, H-50), 3.70 (1H, dd, J ¼ 12.4, 1.7 Hz, H-6’a), 3.61
(1H, dd, J ¼ 12.4, 5.3 Hz, H-6’b)]. The proton sequence within this monosaccharide was
1
further established by H–1H COSY correlations of H-10/H-20, H-20/H-30, H-30/H-40, H-40/
H-50, H-50/H-6’a, H-50/H-6’b, and H-6’a/H-6’b (Figure S1, Supplementary material). The
13C NMR spectrum supported by DEPT and HSQC experiments displayed signals of a
ketone carbon (dC 199.2, C-9), an ester carbonyl carbon (dC 167.3, C-10’), 18 aromatic
carbons (dC 95.7–163.5), and a set of monosaccharide unit (dC 101.6, 76.2, 75.6, 74.8,
72.5, and 62.1). The HMBC correlations from H-2 and H-6 to C-7 and from H-10 to C-7
suggested the presence of a benzophenone skeleton in 1. The attachment of a sugar
moiety at C-9 was evidenced by the HMBC correlation from the anomeric proton (H-
10) to C-9 (dC 159.2). The large coupling constant (J ¼ 7.7 Hz) of H-10 and acid hydroly-
sis result of 1 confirmed the sugar to be a b-D-glucopyranose. In addition, the pres-
ence of a benzoyl group located at C-40 of the glucose unit was determined by HMBC
1
correlations from H-40, H-30’, and H-70’ to C-10’ (dC 167.3). The complete H and 13C
NMR assignments along with the key COSY and HMBC correlations of 1 are summar-
ized in Table S1 and Figure S1 (Supplementary material). Therefore, the structure of 1
was elucidated as 2,4,11,13-tetrahydroxybenzophenone 9-O-(40-benzoyl)-b-D-glucopyra-
noside and was named hyperewalone A.
Compound 2 was isolated as a yellow amorphous powder. Its molecular formula
was established as C26H24O12 by positive HRESIMS (m/z 529.1339 [M þ H]þ, calcd for
C26H25O12, 529.1341). The IR spectrum showed absorption bands at 3335 and
1
1701 cmꢀ1 for hydroxy and carbonyl groups, respectively. The H and 13C NMR data
(Table S2, Supplementary material) were similar to those of 1 except for the chemical
shift differences of their sugar moieties, indicating 2 and 1 shared the same

4
J.-Y. XIE ET AL.
benzophenone skeleton and differed only at the location of the benzoyl group on the
sugar unit. The HMBC spectrum of 2 exhibited key correlations from H-6’a [dH 4.68
(1H, dd, J ¼ 11.7, 2.1 Hz)] and H-6’b [dH 4.34 (1H, dd, J ¼ 11.7, 7.6 Hz)] to C-10’ (dC 168.1,
Figure S1, Supplementary material), suggesting the benzoyl group was connected to
1
the glucosyl unit via the linkage of C-10’–O–C-60. Complete assignment of the H and
13C NMR signals of 4 was accomplished by analysis of 2D NMR spectra (Table S2,
Supplementary material). Thus, the structure of 2 was elucidated to be 2,4,11,13-tetra-
hydroxybenzophenone 9-O-(60-benzoyl)-b-D-glucopyranoside and was named hyper-
ewalone B.
The structures of the known compounds were characterized by comparison of
their NMR and MS data with literature data (1H and 13C NMR data for compounds
3–10, Tables S3–S5, Supplementary material). They were identified as (6S, 9R)-roseo-
side (3) (Yoshikawa et al. 1997), dihydrovomifoliol-O-b-D-glucopyranoside (4)
(Matsunami et al. 2010), quercetin 3-O-b-D-galactopyranoside (5) (Foo et al. 2000),
myricetin 3-O-a-L-rhamnopyranoside (6) (Mahmoud et al. 2001), quercetin 3-O-a-L-
rhamnopyranoside (7) (Pyo et al. 2002), quercetin 3-O-glucopyranoside (8) (Kazuma
et al. 2003), epicatechin (9) (Zhou et al. 2000), and piceatannol 30-O-b-D-glucopyra-
noside (10) (Kashiwada et al. 1984). Compounds 4 and 10 were obtained from the
genus Hypericum for the first time and 3, 6, 7 and 9 were isolated from this plant
for the first time.
Neuroinflammation plays a crucial role in the development of neurodegenerative
diseases such as Alzheimer’s and Parkinson’s diseases. The inhibitory effects of com-
pounds 1–10 on LPS-stimulated NO production in BV-2 microglial cells were investi-
gated to establish their anti-neuroinflammatory activities (Table 1). As a result,
compounds 2, 4 and 6–8 showed significant inhibitory effects with IC50 values of
0.61 0.12, 1.28 0.15, 4.90 0.60, 1.05 0.03, and 1.26 0.04 lM, respectively. In
particular, 2, 4, 7, and 8 exhibited much stronger activities than the positive con-
trol (4.00 0.23 lM). In order to investigate whether the inhibitory activities of the
active compounds were due to their cytotoxicity, the effects of compounds 2, 4
and 6–8 on cell viability were measured by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-
tetrazolium bromide (MTT) method. All the tested compounds (up to 50 lM) did
not show any significant cytotoxicity with LPS treatment for 24 h. Interestingly,
hyperewalone B (2) showed the strongest anti-neuroinflammatory activity, whereas
hyperewalone A (1) had no activity. This suggested that attachment of a benzoyl
group to the O-60 position of the glucoside moiety could be better for this activity
than attachment to the O-40 position. Our study demonstrates that the new sec-
ondary metabolite, hyperewalone B, from H. przewalskii has potent anti-neuroinflam-
matory activity and may be useful in the prevention and treatment of
neurodegenerative diseases.
In addition, recent chemical and pharmacological studies carried out with
Hypericum species led to the isolation of a serial of antimicrobial compounds
(Henrique et al. 2018). Therefore, the antibacterial and antifungal properties of com-
pounds 1–10 were evaluated against Staphylococcus aureus, Bacillus subtilis, Escherichia
coli, Pseudomonas aeruginosa, and Candida albicans strains in the present study, but
these tested compounds showed no significant effects.

NATURAL PRODUCT RESEARCH
5
3. Experimental
3.1. General experimental procedures
Optical rotations were measured with an Auton Paar MCP300 automatic polarimeter
(Anton Paar, Graz, Austria). The UV spectra were obtained on a Thermo Scientific
Evolution-300 UV–visible spectrophotometer (Thermo Fisher Scientific, Waltham, MA,
USA). The IR spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer with KBr
pellets (Bruker, Billerica, MA, USA). The NMR spectra were obtained on a Bruker
Avance III 500 spectrometer (Bruker, Karlsruhe, Germany). HRESIMS data were acquired
on a Thermo Scientific LTQ Orbitrap XL mass spectrometer (Thermo Fisher Scientific,
Waltham, MA, USA). Semi-preparative HPLC was performed on an Agilent 1100 series
instrument equipped with a quaternary pump, a vacuum degasser, an autosampler, a
diode array detector, and YMC Packed C18 columns (5 lm, 250 ꢁ 10.0 mm and
150 ꢁ 4.6 mm, YMC Co., Ltd., Kyoto, Japan). Column chromatography was performed
on silica gel (100–200 and 200–300 mesh, Qingdao Marine Chemical Ltd., Qingdao,
China), reversed phase RP-C18 resins (YMC Gel ODS-A-HG, 50 lm particle size, YMC Co.,
Ltd., Kyoto, Japan), and Sephadex LH-20 (Pharmacia Fine Chemicals, Uppsala, Sweden).
Thin-layer chromatography was performed on silica gel 60 F254 and RP-18 F254S
plates (Merck KGaA, Darmstadt, Germany). The strains used in the experiment were
obtained from National Institutes for Food and Drug Control.
3.2. Plant material
The aerial parts of H. przewalskii were collected in Niubeiliang Mountain, Zhashui
County, Shaanxi Province, China in August 2018. The plant was identified by Professor
Zai-Min Jiang, College of Life Sciences, Northwest A&F University. A voucher specimen
(Zai-Min Jiang 313) was deposited at the herbarium of Northwest A&F University
(WUK), Yangling, China.
3.3. Extraction and isolation
The dried aerial parts of H. przewalskii (1.0 kg) were powdered and extracted with
MeOH (4 ꢁ 3.0 L, each 2 h) at 60 ꢂC to afford a crude MeOH extract (99.7 g). The extract
was suspended in H2O and partitioned successively with n-hexane (3 ꢁ 3.0 L), EtOAc
(3 ꢁ 3.0 L), and n-BuOH (3 ꢁ 3.0 L). The obtained EtOAc-soluble layer (9.72 g) was sepa-
rated by silica gel CC with a gradient of CH2Cl2–MeOH (30:1 to 2:1) to yield ten frac-
tions (Frs. E1–E10). Fr. E5 (1.5 g) was further subjected to RP-C18 CC (MeOH–H2O, 3:1 to
1:1) to yield twelve subfractions (Frs. E5.1–E5.12). Compound 1 (225 mg) and 2
(4.1 mg) were obtained from Fr. E5.6 by silica gel CC (CHCl3–MeOH, 9:1 to 4:1). Frs.
E5.9 and E5.10 were purified by preparative HPLC to afford compounds 8 (15.4 mg)
and 9 (166.9 mg). Fr. E6 (0.91 g) was separated using RP-C18 CC (MeOH ꢀ H2O, 5:2 to
3:2) to provide ten fractions (Fr. E6.1–E6.10). Fr. E6.8 was subjected to Sephadex LH-
20 CC (MeOH) followed by silica gel CC (CHCl3ꢀMeOH ꢀ H2O (3:1:0.1) to afford com-
pound 7 (3.8 mg). Fr. E7 (4.4 g) was subjected to RP-C18 CC (MeOH–H2O, 5:2 to 3:2)
give nine fractions (Frs. E7.1 ꢀ E7.9). Fr. E7.3 was further purified by silica gel CC

6
J.-Y. XIE ET AL.
(CHCl3ꢀMeOH ꢀ H2O, 7:1:0.1 to 5:1:0.1) followed by preparative HPLC to afford com-
pounds 3 (1 mg) and 4 (1 mg). Compound 10 (6.8 mg) was obtained from Fr. E7.5 by
Sephadex LH-20 CC (MeOH) followed by preparative HPLC. Fr. E7.8 (156 mg) was sepa-
rated by Sephadex LH-20 CC (MeOH) to yield compounds 5 (39.4 mg) and 6 (52.7 mg).
3.3.1. Hyperewalone A (1)
25
Yellow amorphous powder; ½aꢃD ꢀ14.0 (c 0.1, MeOH); UV (MeOH) kmax (log e) 209
(4.56), 227(4.53), 282(4.03) nm; IR (KBr) mmax 3321, 1713, 1600, 1455, 1343, 1272, 1163,
1090, 1029, 828, 713 cmꢀ1; H NMR (500 MHz, CD3OD) and 13C NMR data (125 MHz,
1
CD3OD) see Table S1 (Supplementary material); HRESIMS (positive) m/z 529.1343
[M þ H]þ (calcd for C26H25O12, 529.1341).
3.3.2. Hyperewalone B (2)
25
Yellow amorphous powder; ½aꢃD ꢀ33.0 (c 0.05, MeOH); UV (MeOH) kmax (log e) 214
(5.26), 229(5.34), 283(4.94) nm; IR (KBr) mmax 3335, 1701, 1600, 1453, 1342, 1280, 1162,
1074, 1015, 826, 713 cmꢀ1; H NMR (800 MHz, CD3OD) and 13C NMR data (200 MHz,
1
CD3OD) see Table S2 (Supplementary material); HRESIMS (positive) m/z 529.1339
[M þ H]þ (calcd for C26H25O12, 529.1341).
3.4. Anti-neuroinflammatory activity assay
BV-2 cells were purchased from Peking Union Medical College Cell Bank (Beijing,
China) and cultured in DMEM supplemented with 10% FBS, penicillin G (100 U/mL),
and streptomycin (100 lg/mL) at 37 ꢂC in a humidified incubator with 5% CO2. The NO
concentration was detected by the Griess reagent (Beyotime Institute of
Biotechnology, Shanghai, China). BV-2 cells were seeded at the density of 1.5 ꢁ 105
cells/mL in 96-well culture plates and treated individually with six different concentra-
tions (0.625, 1.25, 2.5, 5.0, 10.0 and 20.0 lM) of tested compounds and LPS (1.0 lg/mL)
for 24 h. After that, 50 lL of cell-free supernatant was allowed to react with an equal
volume of Griess reagent for 15 min at room temperature in the dark. Then, the
absorbance was measured at 550 nm using a microplate reader. Quercetin was used
as a positive control. Cell viability of the cultured cells was analyzed using MTT assay.
3.5. Antibacterial and antifungal activity evaluation
The standard fungus was Candida albicans (CMCC-F 98001). For antibacterial activity,
cultures of Gram-positive Staphylococcus aureus (CMCC-B 26003), Bacillus subtilis
(CMCC-B 63501), Escherichia coli (CMCC-B 44102), and Pseudomonas aeruginosa (CMCC-
B 10104) were used. The stock solutions of the tested compounds were prepared in
1% DMSO at final concentrations of 70.5, 35.2, 17.6, 8.8, 4.4, and 2.2 lM. Fluconazole
and chloramphenicol were used as positive controls of fungistatic and bacteriostatic
actions. The microplates were kept at 37 ꢂC for 24 h for bacteria and 30 ꢂC for 24 h for
fungus. Results were analyzed at 265 and 530 nm using a microplate reader.

NATURAL PRODUCT RESEARCH
7
3.6. Statistical analysis
The data were presented as mean standard deviation of three independent experi-
ments. Statistical analysis of the half-maximal inhibitory concentration (IC50) was car-
ried out using the SPSS statistical package program (SPSS Inc., Chicago, IL, USA).
4. Conclusions
Phytochemical study of H. przewalskii led to the isolation of two new benzophenone
glycosides (1 and 2), which were named hyperewalones A and B, together with eight
known compounds (3–10). Dihydrovomifoliol-O-b-D-glucopyranoside (4) and piceatan-
nol 30-O-b-D-glucopyranoside (10) were isolated from the genus Hypericum for the first
time. Compounds 2, 4, and 6–8 exhibited significant anti-neuroinflammatory activity
with IC50 values of 0.61 0.12, 1.28 0.15, 4.90 0.60, 1.05 0.03, and 1.26 0.04 lM,
respectively.
Acknowledgements
The authors thank the Xi’an Institute for Food and Drug Control for kind help in our
experiments.
Disclosure statement
The authors declare no conflict of interest.
Funding
This study was supported by the National Natural Science Foundation of China (No. 31800291),
Natural Science Basic Research plan in Shaanxi Province (No. 2018JQ3032), the Fundamental
Research Funds for the Central Universities (No. 2452017173).
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