全 文 ：Received 20 Nov. 2003 Accepted 24 Jun. 2004
Supported by the National Natural Science Foundation of China (30070007) and Natural Science Foundation of Yunnan Province (99B0017G).
* Author for correspondence. Tel.: +86 (0)871 5223111; Fax: +86 (0)871 5150227; E-mail: .
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Acta Botanica Sinica
植 物 学 报 2004, 46 (9): 1122-1127
Antibacterial Activities of Neolignans Isolated from
the Seed Endotheliums of Trewia nudiflora
LI Guo-Hong2, ZHAO Pei-Ji1, SHEN Yue-Mao1*, ZHANG Ke-Qin2
(1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany,
The Chinese Academy of Sciences, Kunming 650204, China;
2. Laboratory for Conservation and Utilization of Bio-resource, Yunnan University, Kunming 650091, China)
Abstract: Five neolignans including four new ones were obtained from the seed endotheliums of Trewia
nudiflora L. Their structures were determined to be 9-methyl americanol A (1), 9-methyl isoamericanol A
(2), 9-ethyl americanol A (3), 9-butyl americanol A (4), and americanin (5). Two acetylated products 3,4-
diacetyl americanin (5a) and 3,4,9-triacetyl americanin (5b) had been prepared from compound 5. All of
these compounds were investigated on antibacterial assays when carbenicillin sodium, streptomycin
sulfate and rifampicin were used as positive controls. Compounds 4 and 5 exhibited antibacterial activities
against gram-positive bacterium Staphylococcus aureus and gram-negative bacterium Mycobacterium
tuberculosis at the minimum inhibitory concentrations (MIC) of 50 mg/mL and 100 mg/mL, respectively,
but 5a and 5b did not exhibit antibacterial activity at 200 mg/disk.
Key words: Trewia nudiflora ; seed endothelium; neolignan; antibacterial activity
Antimicrobial resistance is emerging in virtually all noso-
comial and community pathogen-antimicrobial
combinations, which highlights the need to stimulate fur-
ther research into strategies aimed at preserving the effec-
tiveness of currently available antibacterial agents and find-
ing new classes of antibacterial agents. Natural products
produced by higher plants evolved from selection for ac-
quisition of improved defense against microbial attacks
(Dixon, 2001), therefore, they are less likely to incur
resistance.
The genus Trewia (Euphorbiaceae) includes only one
species, which spread in India, Malaysia and China. Some
maytansinoids isolated from the Trewia nudiflora seeds
are tumor inhibitors (Powell et al., 1981; 1982). There were
no reports about the isolation of antibacterial components
from the seeds of T. nudiflora, particularly, from the seed
endotheliums. We report herein the isolation, structure
identification and the antibacterial activity against gram-
positive bacterium Staphylococcus aureus and gram-nega-
tive bacterium Mycobacterium tuberculosis of seven
neolignans including two acetyl derivatives.
1 Results and Discussion
Compound 1, the HRESIMS determined the molecular
formula to be C19H20O6 (m/z 367.116 7 [M + Na]+, calcd.
367.115 7). The IR (KBr) spectra of 1 revealed the presence
of the hydroxyl (3 430 cm-1), ether (1 274 cm-1), double
bond (1 615 cm-1) and aromatic (1 586, 1 507 cm-1)
functionalities, which was supported by the UV absorbance
at lmax 269.80 nm. The 1H-NMR spectrum indicated the
presence of a trans-double bound (d 6.49 (d, J = 15.9 Hz), d
6.13 (dd, J = 6.2, 15.8 Hz)), two 1,3,4-trisubtituted benzene
rings (d 6.85 (s), d 6.81 (d, J = 8.3 Hz), d 6.75 (d, J = 8.5 Hz) and
(d 6.94 (s), d 6.91 (d, J = 8.5 Hz), d 6.89 (d, J = 8.4 Hz)), and the
structure unit involving 1,4-dioxane ring (d 3.96 (m, 1H),
4.78 (d, J = 8.0 Hz)), indicating that 1 was a neolignan. The
HMBC experiments showed the 1H-13C long-range correla-
tions between the methoxyl protons at d 3.34 (H-10) and
the carbon at d 74.1 (C-9), and between the methylene
protons at d 4.01 (H-9) and the carbons at d 58.0 (OMe-9),
124.7 (C-8) and 133.6 (C-7), between the methine protons
at d 6.85 (H-2) and the carbons at d 120.4 (C-6) and 146.9 (C-
4), between the methine protons at d 6.81 (H-5) and the
carbons at d 129.4 (C-1) and 146.4 (C-3), between the methine
protons at d 6.94 (H-2) and the carbons at d 121.3 (C-6) and
145.1 (C-4), so determining the structure of the caffeyl al-
cohol moiety (Fig.1). The structure of the right nine-car-
bon moiety was determined by the HMBC correlations be-
tween the methylene protons at d 3.65 (H-9) and the carbon
at d 77.5 (C-7), and between the methine proton at d 4.78 (H-
7) and the carbons at d 62.0 (C-9), 79.8 (C-8), 129.4 (C-1) and
115.7 (C-2). The linkage of the two moieties was deter-
mined by the weak three-bond 1H-13C long-range correla-
tions between the methine proton at d 4.78 (H-7) and the
LI Guo-Hong et al.: Antibacterial Activities of Neolignans Isolated from the Seed Endotheliums of Trewia nudiflora 1123
carbon at d 145.1 (C-4). The ROESY experiment showed
1H-1H correlations between the protons at d 4.78 (H-7) and
at d 3.46 (H-9b) and 3.65 (H-9a), indicating the trans-form of
C-7/C-8 in the dioxane ring. Therefore, compound 1 was
de te rmined to b e 9 -me thoxy-7 -en-3 ,8 :4 , 7 -
diepoxyneolignan-3,4,9-triol, namely 9-methyl americanol
A (Fukuyama et al., 1992).
Compound 2, the HRESIMS determined the molecular
formula to be C19H20O6 (m/z 367.115 2 [M + Na]+, calcd.
367.115 7). The 1H- and 13C-NMR spectra of 2 showed
great similarities to those of compound 1. The ROESY
experiment showed 1H-1H correlations between the pro-
tons at d 4.83 (H-7) and at d 3.49 (H-9b), indicating the
trans-form of C-7/C-8 in the dioxane ring. Therefore, com-
pound 2 was determined to be 9-methyl-7-en-3,7:4,8-
diepoxyneolignan-3,4,9-triol, namely 9 -methyl
isoamericanol A (Fukuyama et al., 1992).
Compound 3, the HRESIMS determined the molecular
formula to be C20H22O6 (m/z 381.131 2 [M + Na]+, calcd.
381.131 4). The data of 1H- and 13C-NMR spectra of 3
showed great similarities to those of compound 1 except
for the replacement of methoxyl group with ethoxyl at C-9.
The HMBC experiments showed weak four-bond 1H-13C
long-range correlations between the proton at d 3.49 (H-9b)
and the carbon at d 144.5 (C-3), and the ROESY experiment
showed 1H-1H correlations between the protons at d 4.77
(H-7) and at d 3.71 (H-9a), indicating the trans-form of C-7/
C-8 in the dioxane ring. Therefore, compound 3 was deter-
mined to be 9-ethoxyl-7-en-3,8:4,7-diepoxyneolignan-3,4,
9-triol, namely 9-ethyl americanol A (Fukuyama et al., 1992).
Compound 4, the HRESIMS determined the molecular
formula to be C22H26O6 (m/z 409.161 4 [M + Na]+, calcd.
409.162 7). The 1H- and 13C-NMR spectra of 4 showed
great similarities to those of compound 1 except for the
replacement of methoxyl group with butoxyl at C-9. The
HMBC experiments showed 1H-13C long-range correlations
between the proton at d 4.79 (H-7) and the carbon at
d 145.3 (C-4), and weak four-bond 1H-13C long-range corre-
lations between the proton at d 3.48 (H-9b) and the carbon
at d 144.9 (C-3). Therefore, compound 4 was determined to
be 9-butoxyl-7-en-3,8:4,7-diepoxyneolignan-3,4,9-triol,
namely 9-butyl americanol A (Fukuyama et al., 1992).
Compound 5 was readily determined to be 9-aldehyde-
7-en-3, 7:4 8-diepoxyneolignan-3,4,9-triol (american) (Woo
and Kang, 1978) based on the NMR assignments, and the
HMBC correlations between the proton at d 4.85 (H-7) and
the carbon at d 145.7 (C-3) and the proton at d 3.51 (H-9b)
and the carbon at d 148.1 (C-4). The ROESY experiment
showed 1H-1H correlations between the protons at d 4.85
(H-7) and at d 3.51 (H-9b), indicating the trans-form of C-7/
C-8 in the dioxane ring.
Compounds 1-5 isolated from the seed endotheliums
and the two acetylated products of 5 were tested against S.
aureus and M. tuberculosis. The disk diffusion method
used in the preliminary screening showed that compounds
4 and 5 were active against the tested bacteria, but the
acetylated products of compound 5 were inactive at the
amount 200 mg/disk (Table 1). Except for compounds 4 and
5, other natural neolignans did not exhibit any antibacterial
activities at the amount 100 mg/disk. The minimum inhibitory
concentrations (MIC) of compounds 4 and 5 against S.
aureus and M. tuberculosis were 50 and 100 mg/mL,
respectively. The MIC of the positive control streptomycin
sulfate was 2 mg/mL.
Fig.1. The structures of compounds 1-5.
Acta Botanica Sinica 植物学报 Vol.46 No.9 20041124
Table 2 1H-NMR data of compounds 1-5
Position 1 2 3 4 5
2 6.85, s 6.85, s 6.80, s 6.85, s 6.87, d, 1.9
5 6.81, d, 8.3 6.81, d, 8.3 6.72, d, 8.5 6.80, d, 8.2 6.82, d, 8.2
6 6.75, d, 8.5 6.77, d, 8.5 6.74, d, 8.5 6.76, d, 8.5 6.80, dd, 1.9, 8.3
7 4.78, d, 8.0 4.83, d, 8.1 4.77, d, 8.2 4.79, d, 8.1 4.85, d, 8.1
8 3.96, m 4.02, m 3.92, br, s 3.99, m 4.09, ddd, 2.5, 4.5, 7.8
9 3.65, d, 11.4 3.71, d, 11.4 3.71, d, 11.4 3.67, d, 11.4 3.72, dd, 2.4, 12.4
3.46, dd, 3.7, 12.2 3.49, d, 12.2 3.49, dd, 3.7, 12.2 3.48, m 3.51, dd, 4.4, 12.4
3 6.94, s 7.05, s 6.93, s 6.94, s 7.24, d, 2.0
5 6.91, d, 8.5 6.99, d, 8.5 6.83, d, 8.3 6.91, d, 8.5 7.03, d, 8.3
6 6.89, d, 8.4 6.90, d, 8.4 6.84, d, 8.4 6.89, d, 8.4 7.23, dd, 2.0, 8.4
7 6.49, d, 15.9 6.53, d, 15.9 6.46, d, 16.0 6.50, d, 15.7 7.57, d, 15.8
8 6.13, dd, 6.2,15.8 6.16, dd, 6.2, 15.7 6.10, dd, 7.8, 14.0 6.16, dd, 6.2,15.8 6.65, dd, 7.8, 15.8
9 4.01, d, 6.1 4.04, m 4.07, d, 6.2 4.08, ddd, 6.1, 6.2, 6.2 9.58, d, 7.7
4.02, d, 6.2
RO-9 CH3O- CH3O- CH3CH2O- CH3CH2CH2CH2O-
3.34, s, 3H 3.34, s, 3H 3.48, q, 6.4, 2H 3.48, m, 2H
1.23, t, 6.3, 3H 1.57, m, 2H
1.40, q, 7.7, 2H
0.93, t, 7.3, 3H
1H-NMR, and HMBC, 1H-1H COSY and ROESY spectra were obtained at 500 MHz and recorded in CD3OD at room temperature, respectively.
Coupling constants are presented in Hz. Unless otherwise indicated, all proton signals integrate to 1H.
Table 3 13C-NMR data of compounds 1-5
Position 1 2 3 4 5
1 129.4 129.4 128.0 129.6 129.1
2 115.7 115.6 114.2 115.5 115.6
3 146.4 146.7 146.7 146.6 146.7
4 146.9 147.2 147.2 147.1 147.3
5 116.3 116.4 115.3 116.4 118.6
6 120.4 120.4 119.6 120.4 120.4
7 77.5 77.7 77.7 77.7 77.6
8 79.8 80.0 80.0 80.1 80.5
9 62.0 62.1 62.1 62.1 61.9
1 131.6 131.8 131.8 131.9 129.1
2 115.8 115.8 114.8 115.8 118.1
3 144.7 144.9 144.5 144.9 145.7
4 145.1 145.5 144.9 145.3 148.1
5 117.9 117.3 116.8 118.0 116.4
6 121.3 121.0 120.0 120.9 124.0
7 133.6 133.6 132.3 133.3 155.2
8 124.7 125.0 123.9 125.3 127.8
9 74.1 74.2 73.1 72.5 196.0
RO-9 58.0 58.0 65.6 71.5
15.0 32.9
20.3
14.2
13C-NMR spectra were obtained at 125 MHz and recorded in CD3OD at room temperature.
Table 1 The antibacterial activities of compounds 1-5, 5a and 5b, and positive controls (the diameters of inhibition zones in mm)
Tested organisms
Compounds Acetylated products
Positive controls
(100 mg/disk) (200 mg/disk)
1 2 3 4 5 5a 5b
Carbenicillin sodium Streptomycin sulfate Rifampicin
(10 mg/disk) (10 mg/disk) (0.2 mg/disk)
Mycobacterium tuberculosis - - - 8.5 7.5 - - 15.0 11.0 15.0
Staphylococcus aureus - - - 8.5 7.5 - - 12.0 10.0 15.0
-, no activities.
LI Guo-Hong et al.: Antibacterial Activities of Neolignans Isolated from the Seed Endotheliums of Trewia nudiflora 1125
Previous studies showed that neolignans had various
bioactivities including antitumour, antimitotic, antiviral
activity and specifically inhabiting certain enzymes (Macrae
and Towers, 1984), and Zacchino et al. (1999) reported that
8-O-4-neolignans had antifungal activity. But the
antibacterial activity of diepoxyneolignan was not reported
before our work. The four new neolignans 1-4 produced
remarkably different inhibitory zones in paper disc diffusion
assay (Table 1), indicating that the acyl substitution at C-9
affect the antibacterial activities. Compound 5 gave decent
activities against S. aureus and M. tuberculosis (MIC 100
mg/mL), while its acetylated products 5a and 5b were
inactive at 200 mg/disc, indicating that the free hydroxyl
groups contributed to the antibacterial activities in our
experiments as well.
Plant lignans including neolignans isolated in our work
are well established phytoalexins, and are widely distributed
in various plant tissues. Our experiments indicated the
diepoxyneolignan subtype of neolignans had evident
antibacterial activity, and showed primary structure-activity
relationships, revealing the need to carry out further
researches into this type of structures and indicating that
seed endotheliums may be unique resources of antimicrobial
products.
2 Experimental
2.1 General experimental procedures
Optical rotations were measured on a JASCO DIP-370
Digital Polarimeter. The IR spectra were measured on a
Perkin-Dlmer-577 spectrophotometer. UV spectra were
o b ta ined o n a Sh imad zu d oub le -beam 2 10 A
spectrophotometer. The NMR spectra were recorded on
Brucker DRX-500 spectrometers. EIMS, ESIMS and LC-
MS analysis were carried out on VG AutoSpec-3000 and
Finnigen LCQ Advantage spectrometer, respectively. TLC
was performed on plates precoated with silica gel (Qingdao
Marine Chemical Ltd., China). Reversed-phase C18 silica
gel for column chromatography was obtained from Merck.
Sephadex LH-20 for column chromatography was purchased
from Amersham Biosciences. Solvents were distilled be-
fore used.
2.2 Plant materials
The seeds of Trewia nudiflora L. were collected in
Xishuangbanna, Yunnan Province of China, December 1998.
A voucher specimen (No. K. M. Feng 20159) was deposited
at Kunming Institute of Botany, The Chinese Academy of
Sciences.
2.3 Extraction and isolation
The seed endotheliums of T. nudiflora (dry weight: 6.5
kg) were extracted three times with 70% ethanol. The etha-
nol extract was portioned between EtOAc and water. The
EtOAc extract was extracted with petroleum ether and chlo-
roform to produce two fractions PE and CH. Fraction CH
(105 g) was subjected to column chromatography over silica
gel (300 g, 200-300 mesh, Qingdao Marine Chemical Ltd.)
eluted with chloroform containing increasing amount of
methanol (10 L) to produce nine fractions (CH-1 to CH-9)
based on TLC results. Fractions 1-7 were determined to
mainly contain wax and lipids by TLC and LC-MS analysis,
which were free of lignans and did not show antimicrobial
activities in our experiments, therefore, were not subjected
to further isolation. Fraction CH-8 (1.84 g) was further
chromatographed on a silica gel (30 g) column and eluted
with chloroform first (60 mL) and then petroleum ether con-
taining increasing amount of acetone (3 L) to produce three
fractions (CH-8-1 to CH-8-3). Fraction CH-8-1 (0.643 g) was
subjected to column chromatography over Sephadex LH-
20 (30 g) eluting with methanol (200 mL) to produce three
factions (CH-8-1-1 to CH-8-1-3), and fraction CH-8-1-3
(0.263 g) was subjected to MPLC over reversed-phase C18
silica gel (24 g) eluting with MeOH-H2O (3:2, V/V, 2 L) to
afford compound 4 (175 mg). Fraction CH-8-2 (0.5 g) was
subjected to column chromatography over Sephadex LH-
20 (30 g) eluting with methanol (200 mL) to produce two
fractions (fraction CH-8-2-1 and CH-8-2-2), and fraction CH-
8-2-2 was subjected to column chromatography over re-
versed-phase C18 silica gel (50 g) eluting with MeOH-H2O
(1:1, V/V, 2.5 L) to afford compound 1 (128 mg). Fraction
CH-9 (15.838 g) was further chromatographed on silica gel
(80 g) column and eluted with chloroform containing in-
creasing amount of acetone (5 L) to produce six fractions
(CH-9-1 to CH-9-6). Fraction CH-9-5 (3.26 g) was subjected
to MPLC over reversed-phase C18 silica gel (130 g) and
eluted with MeOH-H2O (2:3, V/V, 2.5 L) to afford compound
5 (800 mg). Fraction CH-9-2 (0.5 g) was chromatographed
on Sephadex LH-20 column (30 g) eluting with methanol
and further subjected to column chromatography over re-
versed-phase C18 silica gel (50 g) eluting with MeOH-H2O
(1:1, V/V) to afford compound 3 (20 mg). Fraction CH-9-6
(2.15 g) was chromatographed on Sephadex LH-20 column
(30 g) eluting with methanol (300 mL) to produce four frac-
tions (CH-9-6-1 to CH-9-6-4). Fraction CH-9-6-2 (0.45 g)
was chromatographed on reversed-phase C18 silica gel col-
umn (50 g) and eluted with MeOH-H2O (1:1, V/V, 1.8 mL)
containing increasing amount of methanol to produce com-
pound 2 (5 mg).
2.4 Acetylation of compound 5
Compound 5 (300 mg) was dissolved in 20 mL acetic
Acta Botanica Sinica 植物学报 Vol.46 No.9 20041126
anhydride and pyridine (1:1, V/V) and warmed at 60 oC for
10 min and stayed at ambient temperature over night. The
mixture after being dried with flow nitrogen was subjected
to column chromatography over silica gel (30 g) and eluted
with chloroform containing increasing amount of acetone
(1 L) to produce 5a (200 mg) and 5b (100 mg), respectively.
2.5 Identification
Compound 1 White powder. [a]23D -6.67o (c 0.30,
MeOH). UV lMeOH nm: 204, 269, 356; EIMS m/z (rel. Int):
344 [M]+ (68), 312 (8), 191 (26), 166 (93), 148 (92), 123 (100),
91 (48), 77 (23); IR n KBr cm-1: 3 437, 1 615, 1 586, 1 506, 1 436,
1 274. See the 1H- and 13C-NMR data in Table 2 and Table
3, respectively.
Compound 2 White powder. [a]23D -40.00o (c 0.05,
MeOH)/-19.17o (c 0.30, MeOH). UV lMeOH nm: 206, 270,
380; EIMS m/z (rel. Int): 344 [M]+ (21), 312 (4), 191 (6), 166
(76), 148 (36), 123 (100), 91 (51), 77 (26); IR n KBr cm-1: 3 432,
2 925, 1 630, 1 507, 1 442, 1 273. See the 1H- and 13C-NMR
data in Table 2 and Table 3, respectively.
Compound 3 Yellow powder. [a]23D -1.67o (c 0.60,
MeOH). UV lMeOH nm: 206, 270, 380; EIMS m/z (rel. Int):
358 [M]+ (31), 344 [M-CH3] (54)，312 (8), 191 (22), 166
(100), 148 (90), 123 (95), 91 (52), 77 (26); IR n KBr cm-1:
3 441, 1 612, 1 587, 1 508, 1 449, 1 276. See the 1H- and 13C-
NMR data in Table 2 and Table 3, respectively.
Compound 4 Yellow powder. [a]23D -7.86o (c 1.40,
MeOH). UV lMeOH nm: 206, 270, 380; EIMS m/z (rel. Int): 386
[M]+ (60), 312 (15), 166 (100), 148 (85), 123 (80), 91 (36), 77
(14); IR n KBr cm-1: 3 423, 2 933, 1 612, 1 587, 1 507, 1 450,
1 274. See the 1H- and 13C-NMR data in Table 2 and Table
3, respectively.
Compound 5 Yellow crystal. EIMS m/z (rel. Int): 228
[M]+ (100), 310 (21), 166 (50), 148 (49), 123 (70), 91 (28), 77
(23). See the 1H- and 13C-NMR data in Table 2 and Table 3,
respectively.
Compound 5a Yellow oil, [a]23D -8.6o (c 0.70, MeOH),
ESIMS m/z: 455 [M+1]+.
Compound 5b Yellow oil, [a]23D -10.9o (c 0.55, MeOH),
ESIMS m/z: 413 [M+1]+.
2.6 Antibacterial assay
The preliminary screening of the antibacterial activity
was assessed against S. aureus and M. tuberculosis by
using disk diffusion method (Jorgensen et al., 1999). Car-
benicillin sodium (10 mg), streptomycin sulfate (10 mg) and
rifampicin (0.2 mg) were used as the positive controls,
respectively. The minimum inhibitory concentration (MIC)
of compounds 4 and 5 was evaluated using agar dilution
technique (Jorgensen et al., 1999) in Petri dishes (containing
beef extract, peptone and agar). Different concentrations
of the two compounds were dissolved in dimethyl sulfox-
ide (DMSO) to give serious twofold dilutions that were
added to each dish, resulting in the concentrations of test-
ing compounds ranging from 25 to 400 mg/mL, and strepto-
mycin sulfate was used as positive control.
Acknowledgements: The authors are grateful to Mr. HE
Yi-Neng and Ms. LIANG Hui-Ling in the State Key Labora-
tory of Phytochemistry and Plant Resources in West China,
Kunming Institute of Botany, The Chinese Academy of
Sciences, for measuring NMR and MS data, respectively.
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(Managing editor: WANG Wei)
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