Three new flavonoids from Penthorum chinense Pursh and their docking studies

Article abstract of DOI:10.1080/14786419.2019.1613394

Three new flavonoids, pinocembrin-7-O-[3″-O-galloyl]-β-D-glucose (1), pinocembrin-7-O-[2″-O-galloyl-4″,6″-hexahydroxydiphenoyl]-β-D-glucose (2), 2′,6′-dihydroxydihydrochalcone-4′-O-[2″-O-galloyl-4″,6″-hexahydroxydiphenoyl]-β-D-glucopyranoside (3), and 12 known compounds (4–15) were isolated from Penthorum Chinense Pursh. The structures of all compounds were established mainly by NMR and MS experiments as well as the necessary chemical evidence. The anti-hyperlipidemic activities of the three new flavonoids were predicted by molecular docking.

Full text of DOI:10.1080/14786419.2019.1613394

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Three new flavonoids from Penthorum chinense
Pursh and their docking studies
Wen-Wen Zhao, Wei-Wei Guo, Jun-Fang Guo, Xing Wang, Xiao-Qing Chen &
Xia Wu
To cite this article: Wen-Wen Zhao, Wei-Wei Guo, Jun-Fang Guo, Xing Wang, Xiao-Qing Chen &
Xia Wu (2019): Three new flavonoids from Penthorumꢀchinense Pursh and their docking studies,
Natural Product Research, DOI: 10.1080/14786419.2019.1613394
To link to this article: https://doi.org/10.1080/14786419.2019.1613394
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1613394
Three new flavonoids from Penthorum chinense Pursh and
their docking studies
a
b
a
a
ꢀ
ꢀ
Wen-Wen Zhao , Wei-Wei Guo , Jun-Fang Guo , Xing Wang , Xiao-Qing
Chena and Xia Wua
aBeijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine,
b
Capital Medical University, Beijing, China; NHC Key Laboratory of Biotechnology of Antibiotics,
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical
College, Beijing, China
ABSTRACT
ARTICLE HISTORY
Three new flavonoids, pinocembrin-7-O-[300-O-galloyl]-b-D-glucose
(1), pinocembrin-7-O-[200-O-galloyl-400,600-hexahydroxydiphenoyl]-
b-D-glucose (2), 20,60-dihydroxydihydrochalcone-40-O-[200-O-galloyl-
400,600-hexahydroxydiphenoyl]-b-D-glucopyranoside (3), and 12
known compounds (4–15) were isolated from Penthorum
Chinense Pursh. The structures of all compounds were established
mainly by NMR and MS experiments as well as the necessary
chemical evidence. The anti-hyperlipidemic activities of the three
new flavonoids were predicted by molecular docking.
Received 27 January 2019
Accepted 24 April 2019
KEYWORDS
Penthorum chinense;
flavonoid; molecular
docking; anti-
hyperlipidemic activity
1. Introduction
Penthorum chinense Pursh (Saxifragaceae), named ‘GanHuang-Cao’, is a traditional
Chinese medicine with anti-oxidation and anti-hepatitis virus effect. It has been used
as food and Chinese tea in the region of the Miao nationality for thousands of years
(Wang et al. 2015). Gansu granule, prepared from the extracts of P. chinense, has been
used in clinics to treat acute hepatitis (Zhang et al. 2013; Wang et al. 2014). Due to its
CONTACT Xia Wu
These authors contributed equally to this work.
wuxia6710@ccmu.edu.cn
ꢀ
Supplementary material for this article can be accessed at https://doi.org/10.1080/14786419.2019.1613394.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
W.-W. ZHAO ET AL.
wide pharmacological activities and clinical use, lots of bioactive constituents have
been isolated from P. chinense, including flavonoids, triterpenoids, polyphenols, ste-
roids and neolignans (Huang et al. 2014; Huang et al. 2018). Flavonoids are considered
to be the main bioactive constituents of P. chinense. (Zhang et al. 2007; Huang et al.
2014; Huang et al. 2015). In our previous study, three flavonoids isolated from P. chi-
nense have shown the protective effects on hepatic steatosis in HepG2 cells by activat-
ing the SIRT1/AMPK pathway (Guo et al. 2018). To seek for novel potential
hypolipidemic compounds from P. chinense, three new flavonoid glycosides (1–3)
along with 12 known compounds (4–15) have been isolated (Figure 1). In this paper,
we describe the structural elucidation of these new compounds, as well as their anti-
hyperlipidemic property predicted by molecular docking.
2. Results and discussion
2.1. Chemistry
Compound 1 was purified as salmon pink powder and its molecular formula was
determined as C28H28O13 by HR-ESI-MS spectrum (m/z 593.12486 [M þ Na]þ, calcd. for
Figure 1. The structures of compounds 1-15

NATURAL PRODUCT RESEARCH
3
593.12656). The UV spectrum showed absorption maximum at 280 and shoulder peak
at 330 nm. The IR spectrum showed the presence of hydroxyl group (3406 cmꢁ1) and
carbonyl group (1695 cmꢁ1). The flavanone skeleton was inferred by UV spectrum and
1
the signals appearing at dC 197.4 (C-4) in the 13C-NMR. The H-NMR spectrum of 1
showed a mono-substituted aromatic protons at dH 7.44 (2H, d, J ¼ 7.2 Hz, H-20, 60),
7.54 (2H, t, H-30, 50), 7.40 (1H, m, H-40) on B-ring, together with two meta-coupled aro-
matic protons at dH 6.20 and 6.25 on A-ring. The resonance signals at dH 5.67 (1H, dd,
J ¼ 12.8, 2.4 Hz), 3.38 (1H, dd, J ¼ 16.8, 12.8 Hz) and 2.77 (1H, dd, J ¼ 16.8, 2.4 Hz) were
reminiscent of the protons at the H-2 and H-3 positions in flavanone (Leu et al. 2004).
The aglycone of 1 was proved to be pinocembrin (Wang et al. 2014). The 1H-NMR
spectrum of 1 also exhibited a series of sugar signals at d 3.48–5.08. The 13C NMR
showed a sugar moiety at dC 99.7 (C-100), 71.7 (C-200), 77.8 (C-300), 67.9 (C-400), 77.3 (C-500)
and 60.7 (C-600). The sugar was identified as D-glucose by acid hydrolysis. The gluco-
pyranose moiety was determined to have a b-configuration at C-100 with the large cou-
pling constant of H-100, a signal at dH 5.21 (d, J ¼ 7.2 Hz). In HMBC spectrum,
correlation between the anomeric proton H-100 (dH 5.21) and C-7 (dC 165.5) suggested
1
the glucosyl residue was located at the 7-O-position (Figure S1). In the H-NMR spec-
trum, the symmetrical benzene ring at dH 7.00 (H-2000 and H-6000) suggested the pres-
ence of a galloyl group (Wang et al. 2006). In the HMBC spectrum, the galloyl group
was shown to be at C-300-O-position due to a down field shift of the H-300 (dH 5.08)
and the HMBC correlation between H-300 (dH 5.08) and C-7000 (dC 165.8) (Figure S1). The
configuration of C-2 was inferred from the CD spectrum to 2R, which showed a posi-
tive cotton effect around 291.5 nm and a negative one around 337 nm (Pei et al.
1990). Accordingly, compound 1 was established as pinocembrin-7-O-[300-O-galloyl]-
b-D-glucose and has been named Penthorumside A.
Compound 2 was obtained as yellow powder and its molecular formula of elemen-
tal composition was determined to be C42H32O21 by HR-ESI-MS spectrum (m/z
1
911.10153 [M þ K]þ, calcd. for 911.10677). The H and 13C-NMR spectra of 2 (Table S1)
are similar to those of compound 7, Pinocembrin-7-O-[300-O-galloyl-400, 600-hexahydroxy-
diphenoyl]-b-glucose (Wang et al. 2006), except for the connected position of one gal-
loyl group. The sugar in 2 was considered to be linked to the C-7 of the aglycone
based on the HMBC experiments. In the HMBC spectrum, the correlations from the
anomeric proton H-100 (dH 5.50), the H-6 (dH 6.17) and H-8 (dH 6.10) to C-7 (dC 164.6)
were observed. Correlations between H-400 (dH 4.72), H-600 (dH 5.01 and dH 3.79) and
the two carboxyl signals (dC 167.3 and dC 168.2) of HHDP were also observed, indicat-
ing that the HHDP group was connected to the C-400/600 position. This was consistent
with the appearance of two low-field-shift signals at dH 4.72 (1H, m, H-400) and 5.01
(1H, t, J ¼ 6.4 Hz, H-600) of the glucopyranosyl in the 1H-NMR spectrum. The galloyl
group was shown to be at C-200 due to a downfield shift of the H-200 (dH 5.06) and the
HMBC correlation between the H-200 and the C-1’’’’’ (dC 165.0) of the galloyl group
(Figure S1). The CD spectrum of 2 also shows a negative cotton effect at 259.5 nm
and a positive effect at 239 nm, indicating an S-configuration of the HHDP group
(Wang et al. 2006; Huang et al. 2014). Thus, compound 2 was established as pinocem-
brin-7-O-[200-O-galloyl-400, 600-hexahydroxydiphenoyl]-b-D-glucose and has been named
Penthorumside B.

4
W.-W. ZHAO ET AL.
The molecular formula of Compound 3 was determined as C42H34O21 by HR-ESI-MS
spectrum (m/z 897.14995 [M þ Na]þ, calcd. for 897.14848). The presence of a dihydro-
1
chalcone skeleton in the molecule could be easily deduced from the H-NMR spectrum
(Calanasan and Macleod 1998; Tanimoto et al. 2009), in which compound 3 showed
the signals for a mono-substituted aromatic protons at dH [7.26 (H-2 and H-6), 7.23
(H-3 and H-5), 7.17 (H-4)] on A-ring, together with one singlet in the aromatic region
dH 5.99 (s, H-30, 50) (She et al. 2011). The 13C-NMR spectrum showed that compound
1
3 exhibited two methylene at dC 45.7 (C-b) and dC 30.4 (C-a). The H and 13C-NMR
spectra of compound 3 are similar to those of compound 2 except for dihydrochal-
cone skeleton and showed signals attributed to a glucose moiety, a galloyl unit and
an HHDP group. The sugar in 3 was considered to be linked to the C-40 of the agly-
cone based on the HMBC experiments. The HMBC correlations from the anomeric
proton H-100 (dH 5.40), the H-30 (dH 5.99) and H-50 (dH 5.99) to C-40 (dC 162.9) were
observed. The correlations between H-400 (dH 4.72), H-600 (dH 5.03 and dH 3.81) and
the two carboxyl signals (dC 167.4 and dC 168.2) of HHDP were also observed, indi-
cating that the HHDP group was connected to the C-400/600 position. The galloyl
group was linked to C-200 via an ester bond due to the HMBC correlation between
the H-200 and the C-1’’’’’ (dC 165.1) (Figure S1). The CD spectrum showed that the
absolute configurations of HHDP was S. Thus, compound 3 was established as 20,60-
dihydroxydihydro-chalcone-40-O-[200-O-galloyl-400,
600-hexahydroxydiphenoyl]-b-D-
glucopyranoside and has been named Penthorumside C.
The known compounds were identified as daidzein (4) (Diao et al. 2011), 20,60-dihy-
droxydihydrochalcone-40-O-b-D-glucopyranoside (5) (Williams 1979), 20,60-dihydroxydi-
hydro-chalcone-40-O-[300-O-galloyl]-b-D-glucopyranoside (6) (Ohtani et al. 2000),
pinocembrin-7-O-[300-O-galloyl-400,600-hexahydroxydiphenoyl]-b-D-glucose (7) (Wang
et al. 2006), 20,60-dihydroxydihydro-chalcone-40-O-[300-O-galloyl-400,600-hexahydroxydiphe-
noyl]-b-D-glucopyranoside (8) (Ohtani et al. 2000), kaempferol (9) (Sloley et al. 2000),
pinocembrin-7-O-[400,600-hexahydroxydiphenoyl]-b-D-glucose (10) (Hegde et al. 2003),
thonningianin B (11) (Ohtani et al. 2000), brervifolincaboxylic acid (12) (Yan et al.
1996), brevifolin (13) (Guo et al. 1987), methyl brevifolincarboxylate (14) (Yao and Zuo
1993), 2,6-dihydroxyacetophenon-4-O-b-D-glucoside (15) (Chosson et al. 1998). Among
them, compound 4 was isolated from this genus for the first time.
2.2. Molecular modeling
Molecular docking study was performed to investigate the interactions between four
anti-hyperlipidemic targets including FXR, AMPK, PCSK9, ASBT and the three new flavo-
noids (1–3). The docking score and binding mode were evaluated with docking studies
(Table S2, Figure S22). The phenolic hydroxyl (Ph-O-H, H-bond acceptor) groups in gal-
loyl or HHDP showed strong hydrogen bond interactions with amino acid residue (H-
bond donor) in all the three ligands. In compound 1, H-bond interaction was observed
at oxygen atom (200-O-H or 600-O-H) of the glucopyranosyl unit with amino acid residue.
In compound 2, H-bond interactions were also observed at position of oxygen atom (5-
O-H) in the A-ring or the carbonyl (C¼ O) group in the C-ring with amino acid residue.

NATURAL PRODUCT RESEARCH
5
In compound 3, H-bond interactions was observed in the oxygen atom of the 60-OH
and 70 C ¼ O, respectively (Figure S22). Compounds 2 and 3 showed higher docking
scores for binding with FXR (10.5725 and 9.8215) than the co-crystallized ligand 1 (4-
(f(2S)-2-[2-(4-chlorophenyl)-5,6-difluoro-1H-benzimidazol-1-yl]-2-cyclo-hexylacetylgamino)-
3-methylbenzoic acid, C29H26ClF2N3O3), indicating their effects by activating hepatic FXR
to maintain bile acid (BA) homeostasis and thus regulating lipid metabolism. Compound
1 showed better binding action with AMPK, ASBT and PCSK9 (5.2458, 7.0601 and 3.
7019, respectively) than compounds 2 and 3. Further investigations are in progress on
enzyme inhibitory activity and cytotoxicity to validate these results.
3. Experimental
3.1. General experimental procedures
IR and UV spectra were measured on Thermo Nicolet iS5 spectrophotometer
(Tewksbury, MA, US) and Agilent 8453 UV-visible Spectroscopy System (Agilent,
1
Mississauga, Ontario, Canada), respectively. The NMR spectra including H, 13C and 2D-
NMR were recorded on a Bruker Avance II spectrometer (Bruker Co., Karlsruhe,
1
Germany) operating at 800 MHz for H- and 200 MHz for 13C- in DMSO-d6 and the chem-
ical shifts were expressed in d values (ppm). CD spectra were obtained using a JASCO J-
810 Circular Dichroism Chiroptical spectrometer (JASCO, Tokyo, Japan). The HR-ESI-MS
data were measured on FT-ICR-MS (Bruker Co., Karlsruhe, Germany) in m/z. MCI gel
(CHP20/P120, Mitsubishi Chemical Co., Japan) was used for column chromatography.
HPLC was carried on Shimadzu LC-6A (Kyoto, Japan) and the detector was Shimadzu
R
V
SPD-10A. A semi-preparative RP-HPLC column (Hibar Purospher STAR RP-18e Semi-
Prep 5 lm, 10 ꢂ 250 mm, Merck & Co., Inc., NJ, USA) was employed for the isolation.
3.2. Plant materials
P. chinense was provided by Sichuan New Lotus Traditional Chinese Herb Limited
Company, Chengdu, Sichuan, in January 2012 and authenticated by Zhang Li Senior
Engineer of this company. A voucher specimen (No. 111138) was deposited at School
of Traditional Chinese Medicine, Capital Medical University, China.
3.3. Extraction and isolation
The extract (1 kg) was prepared from the dry aerial parts of P. chinense (8 kg) by the
same method as descripted in the previous study (Wang et al. 2014). The extract was
fractionated by MCI column chromatography, eluted with the EtOH-H2O (20:80, 40:60,
60:40, 85:15) gradient to provide four fractions (Frs I-IV), respectively. The residue in Fr.
III were combined (50 g) and subjected to the silica gel column by elution with
CH2Cl2: MeOH (99:1–88:12), which afforded Fr.1-39. The sub-fraction Fr. III-Fr. 33 (1 g)
was dissolved in methanol and isolated by semi-preparative HPLC using ACN (A)-H2O
(B) (0–10 min 20%A, 10–50 min 20%–50%A, 50–60 min 50%A, v/v, 200 lL ꢂ 30 runs) to
afford compound 1 (25.0 mg, tR 45.2 min), compound 5 (29.7 mg, tR 45.9 min), com-
pound 2 (10.3 mg, tR 46.7 min), compound 3 (7.4 mg, tR 51.2 min) and compound 6

6
W.-W. ZHAO ET AL.
(7.4 mg, tR 50.3 min). Fr. III-Fr. 36 (1 g) was isolated by semipreparative HPLC using the
same elution condition as Fr. III-Fr. 33 to afford compound 7 (34.9 mg, tR 50.8 min) and
compound 8 (38.1 mg, tR 55.0 min). Fr. III-Fr. 1 (0.6 g), was separated by semiprepara-
tive HPLC using MeOH-H2O (60:40, v/v) to yield compound 4 (5 mg) and compound 9
(10 mg). Fr. III-Fr.24 (0.6 g) and Fr. III-Fr.29 (0.5 g) were separated by semipreparative
HPLC using MeOH-H2O (60:40, v/v) to yield compound 10 (8 mg) and compound 11
(5 mg), respectively. The residue in Fr. I were combined (50 g) and isolated by C18 col-
umn chromatography (MeOH: H2O, 20:80–100:0), which afforded Fr.1-20. Fr. I-Fr. 5
(1.1 g) was subjected to semipreparative HPLC using ACN-H2O (23:67, v/v) to yield
compound 12 (25.0 mg, tR 7.0 min), compound 13 (10.5 mg, tR 13.0 min) and com-
pound 14 (5.9 mg, tR 15.5 min). Fr. I-Fr.10 ꢃ 16 were combined and subjected to semi-
preparative HPLC using MeOH-H2O (30:70, v/v) to yield compound 15 (20 mg,
tR 16.0 min).
Pinocembrin-7-O-[300-O-galloyl]-b-D-glucose (1): Salmon pink powder; HR-ESI-MS m/z
1
593.12486 [M þ Na]þ (calcd. for C28H26O13Na: 593.12656); H- and 13C-NMR data, see
Table S1.
Pinocembrin-7-O-[200-O-galloyl-400,600-hexahydroxydiphenoyl]-b-D-glucose (2): Yellow
1
powder; HR-ESI-MS m/z 911.10153 [M þ K]þ (calcd. For C42H32O21K: 911.10677); H- and
13C-NMR data, see Table S1.
20,60-dihydroxydihydrochalcone-40-O-[200-O-galloyl-400,600-hexahydroxydiphenoyl]-b-D-
glucopyranoside (3): Yellow solid; HR-ESI-MS, at m/z 897.14995 [M þ Na]þ (calcd. for
1
C42H34O21Na: 897.14848); H- and 13C-NMR data, see Table S1.
3.4. Acid hydrolysis of 1–3 and sugar analysis
The acid hydrolysis tests of compounds 1–3 were performed as described in the sup-
plementary material. The monosaccharide composition was determined by a PMP deri-
vatization method by HPLC. The absolute configuration of the sugar is determined by
comparing the retention time (tR) of the derivative of the sugar with the derivative of
the monosaccharide reference prepared in the same manner. The tR values of D-glu-
cose was 17.4 min.
3.5. Molecular docking
The docking studies of the three compounds were performed with energy-metabol-
ism-related molecular targets, including FXR (Protein Data Bank identifier (PDB ID):
3OLF), AMPK (PDB ID: 4ZHX), ASBT (PDB ID: 3ZUX) PCSK9 (PDB ID: 4OV6). The virtual
screening and ligand-receptor interaction were evaluated using the same method as
previously reported (Guo et al. 2018). The docking studies of the co-crystallized ligands
and the targets were also done.
Acknowledgements
The authors wish to thank Jie Chen (School of Traditional Chinese Medicine, Capital Medical
University) for acid hydrolysis of compounds 1–3 and sugar analysis.

NATURAL PRODUCT RESEARCH
7
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was financially supported by the National Natural Science Foundation of China under
Grant No. 81773999.
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