Acta Pharmaceutica Sinica B 2015;5(3):210–214

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ORIGINAL ARTICLE

Glucosylated caffeoylquinic acid derivatives

from the flower buds of Lonicera japonica
Yang Yua, Zhibo Jianga, Weixia Songa, Yongchun Yanga,
Yuhuan Lib, Jiandong Jianga,b, Jiangong Shia,n

a
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
b
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing 100050, China

Received 21 September 2014; received in revised form 4 December 2014; accepted 30 December 2014

KEY WORDS Abstract Three new glucosylated caffeoylquinic acid isomers (1–3), along with six known compounds,
Flower buds;
have been isolated from an aqueous extract of the flower buds of Lonicera japonica. Structures of the new
Lonicera japonica; compounds were determined by spectroscopic and chemical methods as (
)-4-O-(4-O-β-D-glucopyr-
Caprifoliaceae; anosylcaffeoyl)quinic acid (1), (
)-3-O-(4-O-β-D-glucopyranosylcaffeoyl)quinic acid (2), and (
)-5-O-
Glucosylated (4-O-β-D-glucopyranosylcaffeoyl)quinic acid (3), respectively. In the preliminary in vitro assays, two
caffeoylquinic acid; known compounds methyl caffeate and 2ʹ-O-methyladenosine showed inhibitory activity against
Coxsackie virus B3 Coxsackie virus B3 with IC50 values of 3.70 μmol/L and 6.41 μmol/L and SI values of 7.8 and 12.1,
respectively.

& 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical
Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license ([Link]

n
Corresponding author. Tel.: þ86 10 83154789; fax: þ86 10 63037757.
E-mail address: shijg@[Link] (Jiangong Shi).
Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.

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2211-3835 & 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by
Elsevier B.V. This is an open access article under the CC BY-NC-ND license ([Link]
Glucosylated caffeoylquinic acid derivatives from Lonicera japonica 211

1. Introduction data analysis. Particularly, in the 1H-1H gCOSY spectrum, cross

peaks H2-2/H-3/H-4/H-5/H2-6, H-50 /H-60 , H-70 /H-80 , and H-1″/H-2″/
The flower buds of Lonicera japonica Thunb. (Caprifoliaceae), H-3″/H-4″/H-5″/H2-6″ (Fig. 2) proved the presence of vicinal
known as Jin Yin Hua in Chinese, are used for treating influenza, coupling extensions of the quinic acid, caffeoyl, and β-glucopyranosyl
cold fever, and infections in traditional Chinese medicine1. units in 1. In the HMBC spectrum, correlations from H-4 to C-90 and
Caffeoyl quinic acids, secoiridoids, flavonoids, saponins, cerebro- from H-1″ to C-40 , together with the chemical shifts of these proton
sides, polyphenols and nitrogen containing iridoids2–9 were mainly and carbon resonances, revealed that the caffeoyl unit was located at
isolated from alcoholic extracts of this medicine. As part of a C-4 of the quinic acid moiety and the β-glucopyranosyloxy group at
program to assess the chemical and biological diversity of C-40 of the caffeoyl unit. Therefore, the structure of compound 1 was
traditional Chinese medicines, we conducted detailed chemical determined as (
)-4-O-(4-O-β-D-glucopyranosylcaffeoyl)quinic acid.
analysis of an aqueous extract of the flower buds of L. japonica, Compound 2, a white amorphous powder with ½α20 D of 71.7
since the flower bud decoction is practically used. Our previous (c 0.15, H2O), showed spectral data similar with those of 1 (see
studies on the aqueous extract led to the isolation of 27 homo- Table 1 and Section 3), indicating that it was an isomer of 1.
secoiridoids containing N-substituted pyridinium units (lonijapo- Comparison of the NMR spectral data of 2 with those of 1
sides A–W) and phenylpyruvic acid derived moieties (lonipheny- suggested that the 4-O-β-D-glucopyranosylcaffeoyloxy moiety was
ruviridosides A–D)10–12, two β-amino-acid-coupled secoiridoids at C-3 of the quinic acid unit in 2 instead of at C-4 in 1. This was
(serinosecologanin and threonosecologanin)13, and two 1-(60 -O- confirmed by 2D NMR data analysis and alkali hydrolysis of 2.
acyl-β-D-glucopyranosyl)pyridinium-3-carboxylates (lonijaponini- Especially, the COSY cross peaks H2-2/H-3/H-4/H-5/H2-6 and the
cotinosides A and B)14, as well as 19 known compounds. In HMBC correlations from H-3 to C-90 and from H-1″ to C-40 ,
addition, the decocted flower bud residue was further extracted together with their shifts, proved that the caffeoyl was located at
with EtOH (95%), and six new aromatic glycosides and 48 known C-3 of the quinic acid unit and the glucopyranosyloxy group at
compounds were characterized from the EtOH extract15,16. The C-40 of the caffeoyl unit. Alkali hydrolysis of 2 produced the same
study continues on the aqueous extract, leading to the isolation products as those from 1. Thus, the structure of compound 2
of three glucosylated caffeoylquinic acid isomers (1–3) (Fig. 1), was determined as (
)-3-O-(4-O-β-D-glucopyranosylcaffeoyl)
together with six known compounds. We report herein the quinic acid.
isolation, structure determination and biological activity of the Compound 3, a white amorphous powder with ½α20 D of
74.2
new isolates. (c 0.10, H2O), was another isomer of glucosylated caffeoylquinic
acid, as indicated by the spectral data (see Table 1 and Section 3).
Comparison of the NMR data between 3 and 2 indicated that H-3
2. Results and discussion and C-3, C-4, and C-6 were shielded by ΔδH
1.15 and ΔδC

3.0,
1.7, and
3.1 ppm, respectively, whereas H-5 and C-2
Compound 1 was obtained as a white amorphous powder with ½α20 D
and C-5 were deshielded by ΔδH þ1.1, ΔδC þ1.4 and þ4.4 ppm,
of
78.6 (c 0.10, H2O). The IR spectrum of 1 displayed absorption respectively. This demonstrated that the caffeoyl unit was located
bands for hydroxyl (3335 cm
1), carbonyl (1693 cm
1), double at C-5 in 3. Thus, the structure of compound 3 was assigned as
bond (1631 cm
1), and aromatic ring (1609 cm
1 and 1508 cm
1) (
)-5-O-(4-O-β-D-glucopyranosylcaffeoyl)quinic acid, which was
functional groups. The molecular formula C22H28O14 was indicated also confirmed by the COSY cross peaks H2-2/H-3/H-4/H-5/H2-6
by HR-ESI-MS at m/z 515.1392 [M
H]
and the NMR spectral and the HMBC correlations from H-1″ to C-40 , as well as by alkali
data (Table 1). The NMR spectra of 1 displayed characteristic hydrolysis that generated (
)-quinic acid and (
)-4-O-β-D-
resonances for the caffeoylquinic acid analogues17 except for the glucopyranosylcaffeic acid. A literature survey indicated that the
presence of additional signals assignable to a β-glucopyranosyl structure of 3 was reported in several literatures.21–24. However,
moiety. This suggested that 1 was a caffeoylquinic acid β-glucopy- detailed structural elucidation and physical-chemical properties of
ranoside. The suggestion was confirmed by alkali hydrolysis of 1 with the compound were not documented in the literatures.
2 mol/L NaOH. From the hydrolysate, two products were isolated and Although the 1H NMR spectra of compounds 1–3 in D2O were
identified by comparison of their specific rotation ½α20
D and spectral
acquired at 500 or 600 MHz, the partially overlapping resonances
data with the reported data to be (
)-quinic acid18 and (
)-4-O-β-D- were broadened with a low resolution (see Supporting infor-
glucopyranosylcaffeic acid19,20, respectively. The linkage of the mation). Especially, in the 13C NMR spectra, the carbon reso-
structure moieties was further deduced by 2D NMR spectroscopic nances of the quinic acid moieties were broadened with intensities
lower than those of the other units. This demonstrates that the
conformation of the quinic acid moieties in these compounds is
unstable and that a dynamic conformational fluctuation of the
quinic acid moieties should have occurred in the D2O solutions of
1–3. In addition, two α-D-glucopyranosylated caffeoylquinic acid
isomers were recently reported from the leaves of Moringa
oleifera25, which are only different from compound 1 in the
α-configuration of the D-glucopyranosyl unit. Interestingly, the
reported isomers had the specific rotation data with the signs
opposite to and the magnitudes similar to those of 1–3.
The known compounds were identified by comparing the
spectroscopic data with those reported in the corresponding
literatures as methyl caffeate20, 4-O-caffeoylquinic acid methyl
ester (cryptochlorogenic acid methyl ester)26,27, methyl 4-O-β-D-
Figure 1 The structures of compounds 1–3. glucopyranosylcaffeate28,29, guanosine30, 20 -O-methyladenosine
212 Yang Yu et al.

1 13
Table 1 H and C NMR spectral data (δ) for compounds 1–3.a

No. Compound 1 Compound 2 Compound 3

δH δC δH δC δH δC

1 76.0 75.7 76.0

2a 2.23 m 37.6 2.28 brd (15.0) 35.9 2.21 m 37.3
2b 2.10 m 2.19 brd (15.0) 2.07 m
3 4.37 m 68.5 5.42 brd (1.8) 73.3 4.27 m 70.3
4 4.94 brd (8.0) 78.1 3.79 m 74.1 3.90 m 72.4
5 4.35 m 65.1 4.21 m 67.2 5.31 m 71.6
6a 2.25 m 40.9 2.21 brd (15.0) 40.8 2.25 m 37.7
6b 2.12 m 1.98 dd (15.0, 12.0) 2.10 m
7 179.3 179.7 178.7
10 130.2 130.3 130.1
20 7.21 s 116.0 7.21 s 116.0 7.17 s 115.9
30 146.2 146.2 146.2
40 147.4 147.3 147.5
50 7.17 s 116.7 7.18 s 116.8 7.16 s 116.7
60 7.17 s 122.9 7.18 s 122.8 7.16 s 122.9
70 7.68 d (16.0) 146.5 7.64 d (15.6) 146.2 7.58 d (14.5) 146.2
80 6.49 d (16.0) 116.6 6.47 d (15.6) 117.1 6.38 d (14.5) 116.7
90 169.2 169.4 169.0
1″ 5.13 d (5.0) 101.1 5.13 d (6.6) 101.1 5.11 d (6.0)b 101.2
2″ 3.65 m 73.4 3.64 m 73.4 3.64 m 73.4
3″ 3.66 m 76.0 3.66 m 76.0 3.65 m 76.0
4″ 3.54 dd (8.5, 9.0) 69.9 3.54 dd (8.0, 8.0) 69.9 3.55 m 70.0
5″ 3.64 m 76.8 3.64 m 76.8 3.64 m 76.8
6″a 3.94 d (12.5) 61.1 3.94 brd (12.0) 61.1 3.94 d (12.0) 61.1
6″b 3.78 dd (12.5, 5.0) 3.79 dd (12.0, 5.4) 3.79 dd (12.0, 5.0)
a
Data (δ) were measured in D2O at 500 MHz (1 and 3) and 600 Mz (2) for 1H and 125 MHz for 13C (1–3). Proton coupling constants (J) in Hz are
given in parentheses. The assignments were based on 1H-1H COSY, HSQC, and HMBC experiments; the data for proton resonances were presented
as calculated using the solvent peak (δ 4.80 ppm) as the reference, and for carbon resonances as calculated using the methanol peak (δ 49.50 ppm) as
the reference.
b
The signal split was not resolved in the 1H NMR spectrum and the coupling constant was presented as the half width of the peak.

3. Experimental

3.1. General experimental procedures

Optical rotations were measured on P-2000 polarimeter (JASCO,

Tokyo, Japan). UV spectra were measured on a JASCOP-650
spectrometer (JASCO). CD spectra were recorded on a J-815 CD
spectrometer (JASCO). IR spectra were recorded on a Nicolet
5700 FT-IR microscope transmission (Thermo Electron Corpora-
Figure 2 The 1H-1H COSY (thick lines) and key HMBC correlations tion, Madison, USA). NMR spectra were obtained at 500 MHz or
(arrows, from 1H to 13C) of compound 1. 600 MHz for 1H, and 125 MHz for 13C, respectively, on an Inova
500 or SYS 600 MHz spectrometers (Varian Associates Inc., Palo
Alto, USA) in D2O with solvent peaks used as references (unless
(cordysinin B)31, and (
)-dihydrophaseic acid 40 -O-β-D-gluco- otherwise noted). ESI-MS and HR-ESI-MS data were measured
pyranoside32. using an AccuToFCS JMS-T100CS spectrometer (Agilent Tech-
In the preliminary in vitro assays, methyl caffeate and 20 -O- nologies, Ltd., Santa Clara, USA). Column chromatography (CC)
methyladenosine showed inhibitory activity against Coxsackie was performed with silica gel (200–300 mesh, Qingdao Marine
virus B3 with IC50 values of 3.70 μmol/L and 6.41 μmol/L and Chemical Inc., Qingdao, China) and Sephadex LH-20 (Pharmacia
SI values of 7.8 and 12.1, respectively, and the positive control Biotech AB, Uppsala, Sweden). HPLC separation was performed
Pleconaril gave an IC50 of 0.000370 μmol/L and an SI value of on an instrument consisting of a Waters 600 controller, a Waters
41648.7; while other isolates were inactive in the concentration of 600 pump, and a Waters 2487 dual λ absorbance detector (Waters
10 μmol/L. These results, together with our previous studies10–16, Corporation, Milford, USA), with an Prevail (250 mm  10 mm i.d.)
reveal that the diverse constituents have pharmacological con- column packed with C18 (5 μm) (Alltech Associates Inc., Deer-
tributions to the traditional uses of the flower buds of L. japonica. field, USA). TLC was carried out with glass precoated silica gel
Glucosylated caffeoylquinic acid derivatives from Lonicera japonica 213

GF254 plates (Qingdao Marine Chemical Inc.). Spots were 857, 808, 620 cm
1; 1H NMR (D2O, 500 MHz) and 13C NMR
visualized under UV light or by spraying with 7% H2SO4 in (D2O, 125 MHz) spectral data, see Table 1; ESI-MS: m/z 539
95% EtOH followed by heating. Unless otherwise noted, all [MþNa]þ, 555 [MþK]þ, 515 [M
H]–; (þ)-HR-ESI-MS: m/z
chemicals were obtained from commercially available sources 515.1386 [M
H]
(Calcd. for C22H27O14, 515.1406).
and were used without further purification.
3.4. Alkali hydrolysis of 1–3
3.2. Plant material
A solution of each compound (1–3, 8–12 mg) was hydrolyzed
The flower buds of L. japonica were collected in May 2005 from with 2 mol/L NaOH (2.0 mL) at room temperature for 2 h.
Shangqiu, Henan Province, China. Plant identity was verified by The reaction mixture was neutralized with 2 mol/L HCl, then
Mr. Lin Ma (Institute of Materia Medica, Beijing 100050, China). extracted with EtOAc (5 mL for 3 times). The EtOAc phases were
A voucher specimen (No. ZH02273) was deposited at the separately concentrated to dryness, and isolated by RP-HPLC
herbarium of the Department of Chemistry of Natural Products, using CH3CN-H2O (8:92, v/v) containing 0.1% HOAc as the
Institute of Materia Medica. mobile phase to yield the products (
)-quinic acid and (
)-4-O-
β-glucopyranosylcaffeic acid with ½α20
D values of
43.8 to
44.3
3.3. Extraction and isolation (c 0.04–0.06, H2O) and
86.1 to
87.6 (c 0.53–0.90, MeOH),
respectively, of which the NMR spectral data were in agreement
For the extraction and preliminary fractionation of the extract, see with those reported in the literatures18,20.
Ref. 10. Fraction B3-10 (22.1 g) was separated by MPLC over RP
silica gel and eluted with a gradient of EtOH (0–50%) in H2O to 3.5. Anti-influenza virus and Coxsackie virus assay
give subfractions (B3-10-1–B3-10-13). Fraction B4-5 (3.7 g) was
further separated by flash chromatography over RP silica gel See Ref. 33.
and eluted with a gradient of MeOH (0–50%) in H2O to give
subfractions (B4-5-1–B4-5-4). B4-5-2 (765 mg) and B4-5-3 Acknowledgments
(940 mg) were separately subjected to RP-HPLC using CH3CN/
H2O (7:93, v/v) containing 0.1% HOAc as the mobile phase Financial support from the National Natural Science Foundation
(1.5 mL/min) to afford 2 (20 mg, tR ¼ 27.6 min) from B4-5-2 and 1 of China (NNSFC, Nos. 20772156 and 30825044), the Program
(23 mg, tR ¼ 26.3 min) and 3 (37 mg, tR ¼28.9 min) from B4-5-3. for Changjiang Scholars and Innovative Research Team in
University (PCSIRT, No. IRT1007), and the National Science
3.3.1. (–)-4-O-(4-O-β-D-glucopyranosylcaffeoyl)-quinic acid (1) and Technology Project of China (No. 2012ZX09301002-002) is
White amorphous powder; ½α20 D
78.6 (c 0.10, H2O); UV (H2O) acknowledged.
λmax (logε): 195 (4.48), 212 (4.34, sh), 228 (4.15, sh), 236 (4.12,
sh), 291 (4.28), 317 (4.23, sh); CD (H2O): Δε204 nm (
1.87),
Δε231 nm (
1.01), Δε278 nm (-0.35), Δε294 nm (
0.56), Δε311 nm Appendix A. Supporting information
(
0.63), Δε325 nm (
0.59); IR νmax: 3335, 2927, 1693, 1631,
1609, 1508, 1440, 1354, 1266, 1166, 1127, 1073, 1045, 982, 895, Supplementary data associated with this article can be found in the
856, 812, 627 cm
1; 1H NMR (D2O, 500 MHz) and 13C NMR online version at [Link]
(D2O, 125 MHz) spectral data, see Table 1; ESI-MS: m/z 515
[M
H]
; (
)-HR-ESI-MS: m/z 515.1392 [M
H]
(Calcd. for
C22H27O14, 515.1406). References

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