Antioxidative flavonoids from Cleistocalyx operculatus buds

Article abstract of DOI:10.1248/cpb.56.1725

Four new flavonoids, 3′-formyl-4′,6′,4-trihydroxy- 2′-methoxy-5′-methylchalcone (1), 3′-formyl-6′,4- dihydroxy-2′-methoxy-5′-methylchalcone 4′-O-β-D- glucopyranoside (2), (2S)-8-formyl-6-methylnaringenin (3), and (2S)-8-formyl-6-methylnaringenin 7-O-β-D-g

Full text of DOI:10.1248/cpb.56.1725

December 2008
Notes
Chem. Pharm. Bull. 56(12) 1725—1728 (2008)
1725
Antioxidative Flavonoids from Cleistocalyx operculatus Buds
Byung-Sun MIN, ,a Cao Van THU,b Nguyen Tien DAT,c Nguyen Hai DANG,c Han-Su JANG,d and
*
a
Tran Manh HUNG
a College of Pharmacy, Catholic University of Daegu; Gyeongsan 712–702, Korea: b Hanoi University of Pharmacy;
13–15 Le Thanh Tong, Hanoi, Vietnam: c Institute of Natural Product Chemistry, Vietnamese Academy of Science and
Technology; 18A Hoang Quoc Viet, Caugiay, Hanoi, Vietnam: and d Gyeongbuk Institute for Bio Industry; Gyeongbuk
760–380, Korea. Received July 11, 2008; accepted September 23, 2008; published online October 6, 2008
Four new flavonoids, 3ꢀ-formyl-4ꢀ,6ꢀ,4-trihydroxy-2ꢀ-methoxy-5ꢀ-methylchalcone (1), 3ꢀ-formyl-6ꢀ,4-dihy-
droxy-2ꢀ-methoxy-5ꢀ-methylchalcone 4ꢀ-O-b-D-glucopyranoside (2), (2S)-8-formyl-6-methylnaringenin (3), and
(2S)-8-formyl-6-methylnaringenin 7-O-b-D-glucopyranoside (4) were isolated from the buds of Cleistocalyx oper-
culatus (Myrtaceae). The structures of the new metabolites (1—4) were determined on the basic of spectroscopic
analyses including 2 dimensional NMR. Compounds 1 and 3 exhibited 1,1-diphenyl-2-picrylhydrazyl radical
scavenging activity with IC50 values of 22.8 and 27.1 mM, respectively.
Key words Cleistocalyx operculatus; Myrtaceae; anti oxidant; flavonoid
Cleistocalyx operculatus (ROXB.) MERR. et PERRY (Myr- 2.0 Hz, H-2, 6) and d 6.94 (2H, dd, Jꢂ8.5, 1.8 Hz, H-3, 5)
taceae) is a large green tree that grows in rural areas of North and assigned to 4-substituted phenyl in the B ring of chal-
Vietnam where it is commonly called Voi. The flower buds cone.12) An AB spin system with Jꢂ15.8 Hz at d 7.73 and
(name as Nu Voi) and leaves (La Voi) have been used to 7.78 indicated the presence of protons of an a,b-unsaturated
make a beverage since ancient times.1) It is also a well- ketone moiety.2) The 13C-NMR and distortionless enhance-
known medicinal plant whose buds are commonly used as an ment by polarization transfer (DEPT) spectrum of 1 showed
ingredient for tonic drinks in Southern China.2) The water ex- 18 signals, including three oxygenated aromatic carbons at d
tract of C. operculatus buds has been shown to increase the 165.7 (C-2ꢃ), 169.8 (C-6ꢃ) and 160.7 (C-4), one carbonyl car-
contractility and decrease the frequency of contraction in an bon at d 193.8 (CꢂO), one aldehyde carbon at d 191.7 (3ꢃ-
isolated rat heart perfusion system.3) It showed strong protec- CHO), one methyl carbon at d 10.6 (5ꢃ-CH3), and four aro-
tive effects on lipid peroxidation in rat liver microsomes, and matic carbons at d 130.2 (C-2, 6) and 118.3 (C-3, 5). The
the H2O2-induced trauma of rat pheochromocytima (PC12) 1H- and 13C-NMR spectra (Table 1) were very similar to
cells.4) C. operculatus extract showed inhibitory activity those of 3ꢃ-formyl-4ꢃ,6ꢃ-dihydroxy-2ꢃ-methoxy-5ꢃ-methylchal-
against the a-glucosidase, rat-intestinal maltase, and sucrase cone,2,10) except for the hydroxy group at the position C-4 of
activities. It is also considered a promising material for pre- the B ring. The full NMR assignments and connectivities of
venting and treating diabetes.5) Previous phytochemical at- 1 were determined by heteronuclear multiple-quantum corre-
tention characterized the oleanane-type triterpenes,6,7) and lation (HMQC) and heteronuclear multiple-bond correlation
flavonoids.2) Analysis of its leaf oil by gas chromatography (HMBC) spectroscopic data analyses. The HMBC spectrum
(GC) and chromatography/mass spectrometry (GC/MS) has confirmed the correlations between aldehyde proton (d
also been reported.8) Chalcone compounds from this plant 10.41, s) and C-3ꢃ (d 108.7), between methoxy protons (d
possess antioxidant and anticancer activities.9—11) In this re- 3.82, s) and C-2ꢃ (d 165.7), and between methyl protons (d
port, we describe the isolation and structural determination 2.04, s) and C-5ꢃ (d 110.2) (Fig. 2). Based on the above
of four new flavonoids (1—4), and evaluate their DPPH radi- analyses, the structure of compound 1 was elucidated as 3ꢃ-
cal scavenging activity.
formyl-4ꢃ,6ꢃ,4-trihydroxy-2ꢃ-methoxy-5ꢃ-methylchalcone.
Results and Discussion
The MeOH extract of the buds of C. operculatus was par-
titioned into hexane-, EtOAc-, and BuOH-soluble fractions.
Chromatographic purification of the EtOAc-soluble fraction
led to the isolation of four compounds (1—4) (Fig. 1).
Compound 1 was isolated as a yellow amorphous powder.
In the positive ion mode, electrospray ionization mass spec-
trometry (ESI-MS), a quasimolecular ion peak at m/z 329
[MꢀH]ꢀ was observed, and high-resolution ESI-MS (HR-
ESI-MS) analysis indicated an ion peak at 329.1813 which
corresponded to the molecular formula, C18H16O6. The in-
frared (IR) absorptions at 3452, 2873 and 2758 cmꢁ1 showed
1
the presence of hydroxy and aldehyde groups. The H nu-
clear magnetic resonance (NMR) spectrum of 1 indicated the
presence of methoxy group at d 3.82 (3H, s), aldehyde group
at d 10.41 (1H, s), and methyl group at d 2.04 (3H, s). Pro-
ton signals were also observed at d 7.54 (2H, dd, Jꢂ8.5,
Fig. 1. Chemical Structures of Isolated Compounds
© 2008 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: bsmin@cu.ac.kr

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Vol. 56, No. 12
Table 1. 1H- (400 MHz) and 13C-NMR (100 MHz) Spectral Data of Com-
Table 2. 1H- (400 MHz) and 13C-NMR (100 MHz) Spectral Data of Com-
pounds 1 and 2 in MeOH-d4 (d ppm)
pounds 3 and 4 in MeOH-d4 (d ppm)
1
2
3
4
Position
Position
1H (mult., J in Hz)
13C
1H (mult., J in Hz)
13C
1H (mult., J in Hz)
13C
1H (mult., J in Hz)
13C
1
2
3
128.3
127.5
2
3
5.41 (1H, dd, 12.5, 2.4) 79.8 5.45 (1H, dd, 12.4, 2.2) 80.3
2.91 (1H, dd, 16.5, 12.5) 44.7 2.87 (1H, dd, 16.5, 12.4) 45.6
7.54 (1H, dd, 8.5, 2.0) 130.2 7.57 (1H, dd, 8.5, 2.2) 130.3
6.94 (1H, dd, 8.5, 1.8) 118.3 6.95 (1H, dd, 8.5, 2.0) 117.9
2.58 (1H, dd, 16.5, 2.4)
2.58 (1H, dd, 16.5, 2.2)
4
5
6
a
b
1ꢃ
2ꢃ
3ꢃ
4ꢃ
5ꢃ
6ꢃ
CꢂO
160.7
158.4
4
4a
5
6
7
188.3
108.1
167.4
110.5
166.5
110.8
160.4
128.1
185.2
109.6
167.2
111.4
165.2
110.5
159.7
128.0
6.94 (1H, dd, 8.5, 1.8) 118.3 6.95 (1H, dd, 8.5, 2.0) 117.9
7.54 (1H, dd, 8.5, 2.0) 130.2 7.57 (1H, dd, 8.5, 2.2) 130.3
7.73 (1H, d, 15.8)
7.78 (1H, d, 15.8)
125.8 7.72 (1H, d, 15.8)
145.3 7.79 (1H, d, 15.8)
108.5
165.7
108.7
166.9
110.2
169.8
125.9
145.6
108.8
166.2
107.4
166.8
110.6
169.9
193.5
67.7
8
8a
1ꢃ
2ꢃ
3ꢃ
4ꢃ
5ꢃ
6ꢃ
7.50 (1H, dd, 8.5, 2.2) 127.0 7.55 (1H, dd, 8.5, 2.0) 126.8
6.88 (1H, dd, 8.5, 2.0) 114.8 6.89 (1H, dd, 8.5, 1.8) 115.2
159.2
158.4
193.8
6.88 (1H, dd, 8.5, 2.0) 114.8 6.89 (1H, dd, 8.5, 1.8) 115.2
7.50 (1H, dd, 8.5, 2.2) 127.0 7.55 (1H, dd, 8.5, 2.0) 126.8
2ꢃ-OCH3 3.82 (3H, s)
3ꢃ-CHO 10.41 (1H, s)
5ꢃ-CH3
Glc
1ꢄ
2ꢄ
3ꢄ
4ꢄ
5ꢄ
68.5 3.85 (3H, s)
191.7 10.58 (1H, s)
10.6 2.05 (3H, s)
190.8
10.5
8-CHO 10.28 (1H, s)
192.0 10.25 (1H, s)
10.1 2.12 (3H, s)
192.2
10.4
2.04 (3H, s)
6-CH3
Glc
1ꢄ
2ꢄ
3ꢄ
2.05 (3H, s)
5.08 (1H, d, 7.8)
3.55 (1H, m)
3.47 (1H, m)
3.38 (1H, m)
3.52 (1H, m)
101.7
74.5
78.6
70.8
78.9
4.96 (1H, d, 7.5)
3.35 (1H, m)
3.38 (1H, m)
3.27 (1H, m)
3.51 (1H, m)
101.6
72.7
78.7
70.2
77.4
4ꢄ
5ꢄ
6ꢄ
3.92 (1H, dd, 12.2, 2.0) 62.9
3.57 (1H, m)
6ꢄ
3.74 (1H, dd, 12.2, 2.0) 62.5
3.50 (1H, m)
a b-linkage. In addition, the aromatic signal was shifted
downfield at d 166.8 (C-4ꢃ), which suggested that the OH
group at C-4ꢃ of 1 was glucosylated in 2. This finding was
confirmed by the HMBC correlation between H-1ꢄ and C-4ꢃ
(Fig. 2). The NMR data were unambiguously assigned for
both the aglycone and the sugar moiety by HMQC experi-
ments. The structure of 2 was therefore established as 3ꢃ-
formyl-6ꢃ,4-dihydroxy-2ꢃ-methoxy-5ꢃ-methylchalcone 4ꢃ-O-
b-D-glucopyranoside.
Compound 3 was obtained as a yellow amorphous powder.
Its molecular formula was found to be C17H14O6 by the HR-
ESI-MS (m/z 315.2788 [MꢀH]ꢀ). The UV spectrum exhib-
ited an absorption maxima at 270 and 335 nm, which sug-
gested a flavanone nature for 3.13) Compound 3 displayed
aromatic signals downfield at d 7.50 (2H, dd, Jꢂ8.5, 2.2 Hz,
H-2ꢃ, 6ꢃ), 6.88 (2H, dd, Jꢂ8.5, 2.0 Hz, H-3ꢃ, 5ꢃ), d 127.0 (C-
Fig. 2. Selected HMBC Correlations of 2 and 4
1
2ꢃ, 6ꢃ), 114.8 (C-3ꢃ, 5ꢃ) and 159.2 (C-4ꢃ) in the H- and 13C-
Compound 2 was isolated as a yellow amorphous powder NMR spectra, suggesting the hydroxygenated position to be
with a specific rotation [a]D22 of ꢁ125.5 (cꢂ0.2, MeOH). at C-4ꢃ. Remarkable differences were observed between the
The HR-ESI-MS of 2 showed an [MꢀH]ꢀ peak at m/z 1H- and 13C-NMR spectra of compound 3 (Table 2) and those
491.1585, which established a molecular formula of of compounds 1 and 2 (Table 1). The three one-proton cou-
C24H26O11, indicating that it was a glycosylated derivative of pled double doublets at d 5.41 (1H, dd, Jꢂ12.5, 2.4 Hz, H-2),
1
1. Its H-NMR spectrum showed seven new characteristic d 2.91 (1H, dd, Jꢂ16.5, 12.5 Hz, H-3ax), and d 2.58 (1H, dd,
signals typical of a sugar moiety, including a peak at d 5.08 Jꢂ16.5, 2.4 Hz, H-3eq) suggested that the C ring was satu-
for an anomeric proton (H-1ꢄ). The 13C-NMR spectrum also rated. This splitting pattern was due to the coupling between
exhibited six carbon signals between d 62.9 and 101.7, in ad- the H-2 axial proton and the H-3 geminal protons. The ab-
dition to the signals assignable to 1. The sugar was assigned solute configuration at the C-2 stereocenter was established
as glucopyranose on the basis of NMR data and the Rf value to be S on the basic of the high-amplitude, negative Cotton
compared with authentic glucose after enzymatic (naringi- effect in the 270—300 nm region and the weak positive
nase) hydrolysis of 2. The absolute configuration was deter- Cotton effect in the 325—350 nm region,13) which indicated
mined to be D-glucose by GC. The JH,H value (7.8 Hz) of the that stereospecificity was achieved in the process of C-ring
anomeric proton (H-1ꢄ) indicated that glucose was linked via cyclization.14) The structure of 3 was also established by

December 2008
1727
Table 3. DPPH Radical Scavenging Activity of Compounds 1—4
was separated by silica gel column chromatography using a gradient of
hexane–EtOAc (from 30 : 1 to 5 : 1), then EtOAc–MeOH (from 20 : 1 to
1 : 1), to yield five fractions (E1—E5) according to their TLC profiles. Frac-
tion E4 (0.8 g) was chromatographed over silica gel column using a gradient
of EtOAc–MeOH (from 10 : 1 to 5 : 1), to yield five subfractions E4.1—
E4.5. The E4.3 fraction was further purified by semi preparative HPLC [RS
Tech Optima Pak C18 column (10ꢅ250 mm, 10 mm particle size); mobile
phase MeOH–H2O (85 : 15); flow rate 2 ml/min; UV detection at 254 nm] to
obtain compound 1 (8.3 mg; tRꢂ26.4 min), and 3 (5.6 mg, tRꢂ31.4 min). The
E5 fraction was separated by reversed-phase C18 (RP-18) column chro-
matography using a stepwise gradient of MeOH–H2O (from 50 : 50 to 100 : 0
for each step), to afford ten subfractions (E5.1—E5.10). Fraction E5.3 was
purified by semi preparative HPLC using the same condition above except
that the gradient of mobile phase (50 to 100% MeOH in water over 50 min)
to afford compound 2 (14.1 mg, tRꢂ18.2 min). Fraction E5.5 was purified by
semi preparative HPLC using the same condition with that employed for
compound 2 to afford compound 4 (12.7 mg, tRꢂ22.8 min).
Sample
IC50 (mM)a)
1
2
3
22.8
117.2
27.1
4
105.8
20.1
a-Tocopherolb)
a) IC50 values were calculated from regression lines using five different concentra-
tions in triplicate. b) Positive control.
comparing the 1D and 2D NMR spectra, including HMBC
(Fig. 2), with those of (2S)-8-formyl-5-hydroxy-7-methoxy-
6-methylflavanone isolated from the same plant.2) Thus, the
structure of 3 was determined as (2S)-8-formyl-6-methyl-
naringenin.
3ꢃ-Formyl-4ꢃ,6ꢃ,4-trihydroxy-2ꢃ-methoxy-5ꢃ-methylchalcone (1): Yellow
amorphous powder; UV lmax (MeOH) nm (e): 280 (4.12), 321 (3.87); IR
(KBr) cmꢁ1: 3452, 2873, 2758, 1620, 1547, 1465, 780, 705; ESI-MS m/z:
329 [MꢀH]ꢀ; HR-ESI-MS m/z: 329.1813 [MꢀH]ꢀ (Calcd for C18H16O6:
329.1820); for 1H- and 13C-NMR spectral data, see Table 1.
Compound 4 was obtained as a white amorphous pow-
der. The HR-ESI-MS spectrum showed the [MꢀH]ꢀ peak at
m/z 477.2594, which established a molecular formula of
C23H24O11, indicating that it was a glycosylated derivative of
3ꢃ-Formyl-6ꢃ,4-dihydroxy-2ꢃ-methoxy-5ꢃ-methylchalcone 4ꢃ-O-b-D-Glu-
copyranoside (2): Yellow amorphous powder; [a]D22 ꢁ125.5 (cꢂ0.2,
MeOH); UV lmax (MeOH) nm (e): 285 (4.05), 325 (3.80); IR (KBr) cmꢁ1
:
1
3. In addition to all the signals assignable to 3, the H- and
3400, 2958, 2760, 1625, 1606, 1518, 1416, 1280, 1175, 1076 cmꢁ1; ESI-MS
m/z: 491 [MꢀH]ꢀ; HR-ESI-MS m/z: 491.1585 [MꢀH]ꢀ (Calcd for
C24H26O11: 491.1586); for 1H- and 13C-NMR spectral data, see Table 1.
(2S)-8-Formyl-6-methylnaringenin (3): Yellow amorphous powder; [a]D22
ꢀ58.8 (cꢂ0.2, MeOH); UV lmax (MeOH) nm (e): 232 (4.15), 270 (4.37),
385 (3.90); IR (KBr) cmꢁ1: 3425, 2870, 2770, 1686, 1630, 1527, 1385,
1278, 1090; ESI-MS m/z: 315 [MꢀH]ꢀ; HR-ESI-MS m/z: 315.2788
[MꢀH]ꢀ (Calcd for C17H14O6: 315.2790); for 1H- and 13C-NMR spectral
data, see Table 2.
13C-NMR spectra of 4 showed seven and six characteristic
signals of a sugar moiety in the region ranging from d 3.27
to 4.96 and from d 62.5 to 101.6, respectively. The sugar was
assigned as glucopyranose on the basis of NMR data and the
comparison of the Rf value with authentic glucose after enzy-
matic (naringinase) hydrolysis of 4. The absolute configura-
tion was determined to be D-glucose by GC. The JH,H value
(7.5 Hz) of the anomeric proton (H-1ꢄ) indicated that glucose
was linked via a b-linkage. The location of glucose was con-
firmed by HMBC correlation between H-1ꢄ and C-7 (Fig. 2).
On the basis of these data, the structure of 4 was assigned as
(2S)-8-formyl-6-methylnaringenin 7-O-b-D-glucopyranoside.
Compounds 1—4 were tested for their in vitro antioxidant
activity using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radi-
cal scavenging assay (Table 3). Compounds 1 and 3 exhibited
DPPH radical scavenging activity with inhibitory concentra-
tion (IC50) values of 22.8 and 27.1 mM, respectively, while
compounds 2 and 4 exhibited weak activity with IC50 values
of 117.2 and 105.8 mM, respectively.
(2S)-8-Formyl-6-methylnaringenin 7-O-b-D-Glucopyranoside (4): Yellow
amorphous powder; [a]D22 ꢁ120.7 (cꢂ0.2, MeOH); UV lmax (MeOH) nm
(e): 230 (4.08), 272 (4.35), 335 (3.85); IR (KBr) cmꢁ1: 3430, 2870, 2770,
1685, 1640, 1529, 1380, 1276, 1086; ESI-MS m/z 477 [MꢀH]ꢀ; HR-ESI-
1
MS m/z 477.2590 [MꢀH]ꢀ (Calcd for C23H24O11: 477.2594); for H- and
13C-NMR spectral data, see Table 2.
Enzymatic Hydrolysis of 2 and 4 Naringinase (100 mg, from Penicil-
lium decumbens) was added to a suspension of 2 and 4 (5 mg) in 50 mM ac-
etate buffer (pH 5.5), and the mixture was stirred at 37 °C for 5 h. The reac-
tion mixture was extracted with EtOAc (10 mlꢅ3), and the organic layer was
evaporated to dryness. The residue was chromatographed on a preparative-
TLC with CHCl3–MeOH (9 : 1) to give 1 (1.5 mg, Rf, 0.62) and 3 (1.8 mg, Rf
0.55). The water layer was checked by silica gel TLC (EtOAc–MeOH–
H2O–AcOH, 65 : 20 : 15 : 15). The spot on the TLC plate was visualized by
an anisaldehyde–H2SO4 reagent. The configuration of glucose was deter-
mined by a GC method,15) and the sugar derivative thus obtained showed a
retention time of 21.30 min, identical with that of authentic D-glucose.
1,1-Diphenyl-2-picrylhydrazyl (DPPH) Radical Scavenging Activity
The DPPH radical-scavenging activity was measured using a method de-
scribed previously.16) Briefly, 10 ml of each sample dissolved in DMSO was
prepared in 96-well plates, and then 190 ml of 200 mM ethanolic DPPH solu-
tion was added. The mixture was incubated at room temperature for 30 min,
and the absorbance of the reaction mixture was measured at 517 nm.
Experimental
General Experimental Procedures Optical rotations were measured
with a JASCO DIP 1000 digital polarimeter. UV spectra were recorded on a
JASCO V-530 spectrophotometer, and CD spectra were recorded on a
JASCO J-715 CD/ORD spectropolarimeter. IR spectra were obtained on a
JASCO FT/IR 300-E spectrometer. NMR experiments were conducted on
1
a Varian Unity INOVA 400 spectrometer. H- and 13C-NMR spectra were
recorded at 400 and 100 MHz, respectively, and tetramethylsilane was used
as the internal standard. ESI-MS and HR-ESI-MS analyses were performed
on a Micromass QTQF2 mass spectrometer. EI-MS spectra were obtained
on a JEOL JMS-SX102A spectrometer. TLC was carried out on Merck
silica gel F254-precoated glass plates and RP-18 F254S plates. HPLC was
performed on a Waters 600E multisolvent delivery system connected to a
UV detector using Supelco Supelcosil LC-SI (5 mm, 10ꢅ250 mm) and Isco
Allsphere ODS-2 (10 mm, 10ꢅ250 mm) semipreparative columns.
Plant Material The buds of Cleistocalyx operculatus were purchased in
Dong Xuan herbarium market, Hanoi, Vietnam, in July 2007 and identified
by Professor Pham Thanh Ky, Department of Pharmacognosy, Hanoi Col-
lege of Pharmacy. A voucher specimen (HN-0160) was deposited in the
herbarium of the Hanoi College of Pharmacy.
Acknowledgements The authors acknowledge the financial support
provided by Hanoi University of Pharmacy, Hanoi, Vietnam and Gyeongbuk
Regional Innovation Agency (2007), Korea.
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Vol. 56, No. 12
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