Isolation and biomimetic synthesis of anti-inflammatory stilbenolignans from Gnetum cleistostachyum

Article abstract of DOI:10.1248/cpb.54.1053

One new stilbenolignan, gnetucleistol F (1), and four known stilbenolignans, gnetofuran A (2), lehmbachol D (3), gnetifolin F (4) and gnetumontanin C (5) were isolated from the lianas of Gnetum cleistostachyum C. Y. CHENG (Gnetaceae). Their structures and relative configurations were determined by means of spectroscopic evidence. Compounds 1, 2, 3 and 4 were synthesized for the first time on the basis of their biogenetic pathway, and their possible biomimetical synthetic mechanisms were discussed. The pharmacological activities of all stilbenolignans have been tested. Among them, 1, 2, 3, 4 and 5 showed moderate inhibitory activities on TNF-α and 1 also showed potent inhibitory activity on malondialdehyde.

Full text of DOI:10.1248/cpb.54.1053

July 2006
Notes
Chem. Pharm. Bull. 54(7) 1053—1057 (2006)
1053
Isolation and Biomimetic Synthesis of Anti-inflammatory Stilbenolignans
from Gnetum cleistostachyum
b
Chun-Suo YAO,a,b Mao LIN,*,b and Lin WANG
a Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine (Ministry of Education),
Peking Union Medical College; Beijing 100050, P.R. China: and b Institute of Materia Medica, Chinese Academy of
Medical Sciences & Peking Union Medical College; Beijing 100050, P.R. China.
Received February 19, 2006; accepted April 10, 2006
One new stilbenolignan, gnetucleistol F (1), and four known stilbenolignans, gnetofuran A (2), lehmbachol D
(3), gnetifolin F (4) and gnetumontanin C (5) were isolated from the lianas of Gnetum cleistostachyum C. Y.
CHENG (Gnetaceae). Their structures and relative configurations were determined by means of spectroscopic evi-
dence. Compounds 1, 2, 3 and 4 were synthesized for the first time on the basis of their biogenetic pathway, and
their possible biomimetical synthetic mechanisms were discussed. The pharmacological activities of all stilbeno-
lignans have been tested. Among them, 1, 2, 3, 4 and 5 showed moderate inhibitory activities on TNF-a and 1
also showed potent inhibitory activity on malondialdehyde.
Key words Gnetum cleistostachyum; Gnetaceae; gnetucleistol F; TNF-a activity; stilbenolignan
To seek for more potent anti-inflammatory active compo- chemistry of 1 was established on the basis of NOESY spec-
nents, we investigated the chemical constituents of Gnetum trum (Fig. 2b). The key correlations between H-7b/H-2(6)b,
cleistostachyum C. Y. CHENG (Gnetaceae). One new stilbeno- H-9b; H-8b/H-2(6)b, H-9b suggested a trans orientation of
lignan named gnetucleistol F (1), four known stilbenolig- H-7b and H-8b.1) The correlations between the methoxyl sig-
nans, gnetofuran A (2), lehmbachol D (3), gnetifolin F (4) nal at d 3.90 and H-2a, the signal at d 3.82 and H-2(6)b indi-
and gnetumontanin C (5), together with shegansu B (6), gne- cated that the methoxyls should be located at C-3a, C-3b and
tupendin B, gnetol and daucosterol were isolated from this C-5b respectively. Accordingly, the relative stereochemistry
plant. In order to confirm the structures and obtain enough of 1 was elucidated as depicted in 1 (Fig. 1).
samples for pharmacological test, a biomimetically synthetic
Lehmbachol D (3) was isolated as a pale white amorphous
route for the stilbenolignans was designed and compounds 1, powder, its planar structure was reported previously.2) In
2, 3 and 4 were synthesized successfully by oxidative cou- order to clarify its relative stereochemistry, the NOESY ex-
pling reaction. On the basis of the biogenetic pathway, their periment was carried out (Fig. 3). The NOE interactions be-
possible mechanisms were discussed. Pharmacological tests
for 1, 2, 3, 4 and 5 indicated that 1—5 showed moderate anti-
inflammatory activities, and compound 1 also showed potent
anti-oxidant activity.
Table 1. 1H- and 13C-NMR Data of 1 (d in ppm and J in Hz)a)
Position
1H
13C
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a
1b
2b
3b
4b
5b
140.2
111.3
144.6
148.7
129.9
115.8
128.9
126.6
131.5
105.0
158.9
102.3
158.9
105.1
132.6
103.8
148.1
136.0
148.1
103.8
88.3
Results and Discussion
7.11 s
Gnetucleistol F (1) was obtained as a pale white amor-
phous powder. Its HR-EI-MS m/z 466.1601 [Mꢀ] (C26H26O8
requires 466.1628) suggested a molecular formula of
C26H26O8. The characteristic absorption bands of hydroxyl
(3350 cmꢁ1, broad) and aromatic moieties (1608, 1518,
1464 cmꢁ1) were observed in the IR spectrum. The UV spec-
trum [lmaxꢂ310 (sh) (4.24), 327 (4.29) nm] revealed the
presence of a strong conjugated system in the structure. The
1H-NMR spectrum (Table 1) exhibited two signals of three
methoxyls, two signals of a dihydrobenzofuran moiety; a sig-
nal of an oxymethylene, and two trans olefinic protons. The
1H-NMR spectrum also showed one set of signals of AB2
system for ring D, two meta-coupled signals for ring C; a sig-
nal of two symmetric protons for ring A. Its 13C-NMR spec-
trum (Table 1) revealed the presence of three aliphatic car-
bons and three methoxyl carbons besides 20 aromatic and
olefinic carbons. These evidence suggested that the skeleton
of 1 was similar to that of 2.1) In the HMBC spectrum (Fig.
2a), the significant long-range correlations between H-7b/C-
4a, C-5a, C-1b, C-2(6)b, C-8b, C-9b; H-8b/C-4a, C-5a, C-1b,
C-7b, C-9b; H-7a/C-1a, C-2a, C-6a, C-8a indicated the pla-
nar structure of 1 as illustrated in Fig. 1. The relative stereo-
7.12 s
7.07 d, 16.2
6.95 d, 16.2
6.54 d, 2.4
6.27 t, 2.4
6.54 d, 2.4
6.75 d, s
6b
7b
8b
9b
OCH3
OCH3
OCH3
6.75 d, s
5.58 d, 6.9
3.58 d, 6.9
3.90 m
3.82 s
3.82 s
54.2
63.8
56.0
56.0
3.90 s
55.8
a) Measured in CD3COCD3 at 300 MHz for 1H-NMR and 75 MHz for 13C-NMR.
∗ To whom correspondence should be addressed. e-mail: linmao@imm.ac.cn
© 2006 Pharmaceutical Society of Japan

1054
Vol. 54, No. 7
Fig. 1. Stilbenolignans from Gnetum cleistostachyum
Fig. 2. Important Correlations of 1 in HMBC (a) and NOESY Spectra (b)
ferulic acid (or sinapinic acid) and isorhapontigenin (10) as
starting materials was designed and four stilbenolignans 1, 3
and 2, 4 were obtained, besides the isorhapontigenin dimer 6.
Esterification of ferulic acid (7a) afforded methyl ferulate
(8a) in 96% yield, which was converted to phenylpropenol
(9a) in 87% yield by reduction with lithium aluminium hy-
dride. Oxidative coupling reaction of 9a and 10 yielded com-
pounds 2, 4 and 6. Similarly, sinapinic acid (7b) was con-
verted to phenylpropenol (9b) in 29% yield, which afforded
compounds 1, 3 and 6 (Fig. 4) by oxidative coupling with 10.
The properties of the synthetic products 1—4 were in all as-
pects identical to those of the natural products except for the
Fig. 3. Important Correlations of 3 in NOESY Spectrum
tween H-8a/H-8b indicated a cis orientation of H-8a and H- optical rotation.
8b; between H-8b/H-2(6)b, and H-7b/H-2(6)b established a
The possible formation mechanisms of 1, 2, 3 and 4 may
trans orientation of H-8b and H-7b; between H-7a/H-2a, H- be rationalized as follows: in the course of oxidative coupling
6a, H-14a and H-8a/H-2a, H-2(6)b revealed a trans orienta- reaction, 10 was presumably converted into the free radicals
tion of H-7a and H-8a. Thus, the relative configuration of 3 ·R4, ·R5 and ·R8, while 7a (or 7b) provided the radicals ·Rꢀ
4
was established as depicted in Fig. 1.
(or ·R4ꢃ) and ·Rꢀ (or ·Rꢃ8) respectively (as shown in Fig. 5).
8
The other seven known compounds, including gnetofuran Coupling of ·Rꢀ (or ·R8ꢃ) and ·R5 produced an unstable
8
A (2),1) gnetifolin F (4),3) gnetumontanin C (5),4) gnetu- bisquinone intermediate 11a (or 11b), which generated 2 (or
pendin B,5) shegansu B (6),6) gnetol and daucosterol,7,8) were 1) via spontaneous intramolecular cyclization as shown in
readily identified by comparison of physical and spectro- Fig. 6. A Cb–Cb coupling of ·R8 and ·Rꢀ (or ·R8ꢃ) afforded
8
scopic data with values found in the literature.
an unstable bisquinone intermediate 12a (or 12b), which
From the biogenetic viewpoint, it was presumed that 1, 3 generated 4 (or 3) via spontaneous intramolecular cycliza-
(or 2, 4) should be formed by oxidative coupling of sinapyl tion. The formation mechanisms were closely in agreement
alcohol (or coniferol alcohol) and isorhapontigenin. In order with the assumption on the biogenesis pathway of stilbeno-
to support the hypothesis and obtain these stilbenolignans in lignans.
sufficient quantities, a route of biomimetic synthesis with
Pharmacological activities of compounds 1—5 have been

July 2006
1055
Fig. 4. Biomimetic Synthesis Routes of Compounds 1, 2, 3, 4 and 6
Fig. 5. Possible Free Radicals in the Oxidative Coupling Reaction
Fig. 6. Postulated Intermediates in the Formation of Compounds 1, 2, 3 and 4
tested (Table 2). Among them, 1—5 showed inhibition on 1.10ꢄ10ꢁ5 mol lꢁ1, 0.92ꢄ10ꢁ5 mol lꢁ1 and 2.46ꢄ10ꢁ5
TNF-a production by murine peritoneal macrophages with mol lꢁ1. Compound 1 obtained by biomimetic synthesis also
IC50 values of 1.03ꢄ10ꢁ5 mol lꢁ1, 1.09ꢄ10ꢁ5 mol lꢁ1, exhibited inhibition on malondialdehyde (MDA) with IC50

1056
Vol. 54, No. 7
Table 2. Pharmacological Activities of Compounds 1—5
drous ether (100 ml) and added to a suspension of lithium aluminium hy-
dride (2.96 g, 77.89 mmol). After stirring for 12 h at room temperature, the
mixture was poured into water and extracted with ether. Removing of the
solvent yielded 9a (6.0 g, 87%). 8b (1.0 g, 94%) and 9b (0.24 g, 29%) were
obtained by the same method using 7b (1.0 g) as starting material.
TNF-a inhibitory activity MDA inhibitory activity
Compounds
IC50 (10ꢁ5 M)
IC50 (10ꢁ6 M)
1
1
2
3
4
5
1.03
1.09
1.10
0.92
2.46
0.10
6.36
Methyl Ferulate 8a: H-NMR (300 MHz in CD3COCD3) d: 8.13 (s, OH),
7.60 (1H, d, Jꢂ15.9 Hz), 7.32 (1H, br s), 7.14 (1H, br d, Jꢂ8.1 Hz), 6.87
(1H, d, Jꢂ8.1 Hz), 6.41 (1H, d, Jꢂ15.9 Hz), 3.91 (3H, s, OCH3), 3.71 (3H,
s, COOCH3). EI-MS m/z: 208 (Mꢀ).
1
Methyl Sinapate 8b: H-NMR (300 MHz in CD3COCD3) d: 7.54 (1H, d,
Dexamethasonea)
Vitamin Ea)
Jꢂ15.9 Hz), 7.01 (2H, s), 6.44 (1H, d, Jꢂ15.9 Hz), 3.88 (6H, s, OCH3), 3.71
1.0
(3H, s, COOCH3). EI-MS m/z: 238 (Mꢀ).
Coniferol Alcohol (9a): 1H-NMR (300 MHz in CD3COCD3) d: 7.60 (s,
OH), 7.04 (1H, d, Jꢂ1.8 Hz), 6.86 (1H, dd, Jꢂ8.4, 1.8 Hz), 6.77 (1H, d,
Jꢂ8.4 Hz), 6.52 (1H, d, Jꢂ15.9 Hz), 6.25 (1H, dt, Jꢂ15.9, 5.4 Hz), 4.20
(2H, m), 3.85 (3H, s, OCH3). EI-MS m/z: 180 (Mꢀ).
a) Positive control.
value of 6.36ꢄ10ꢁ6 mol lꢁ1. The results suggested that 1, 2,
3, 4 and 5 has moderate anti-inflammatory activities, and 1
has potent anti-oxidant activity.
Sinapyl Alcohol (9b): 1H-NMR (300 MHz in CD3COCD3) d: 7.28 (s,
OH), 6.72 (2H, br s, Jꢂ15.9 Hz), 6.45 (1H, d, Jꢂ15.9 Hz), 6.27 (1H, dt,
Jꢂ15.9, 5.4 Hz), 4.19 (2H, m), 3.82 (6H, s, OCH3). EI-MS m/z: 210 (Mꢀ).
Biomimetic Synthesis of Compounds 1, 2, 3, 4 and 6 Silver oxide
(2 g, 8.62 mmol) was added to a solution of 9a (1 g, 5.56 mmol) and 10
(2.3 g, 8.91 mmol) in acetone (50 ml), the mixture was stirred at room tem-
perature for 8 h. After filtration, the filtrate was evaporated to dryness and
the residue was chromatographied on silica gel column eluted with hexane–
acetone (5 : 1—1 : 1) to afford 2 (250 mg), 4 (19.3 mg) and 6 (44.2 mg), to-
gether with the unreacted starting material 10 (100 mg). A solution of 9b
(240 mg, 1.14 mmol) and 10 (300 mg) in acetone (50 ml) was treated in the
same way as described above to afford 1 (4.5 mg), 3 (13.5 mg), 6 (11 mg)
and the unreacted starting material 10 (20 mg). The spectral data of the syn-
thetic compounds 1—4 and 6 were identical to those of natural products in
all respects except for the optical rotation.
Experimental
General Procedures Optical rotations were determined on a Perkin-
Elmer digital polarimeter. UV spectra were taken on a Shimadzu UV-300
spectrophotometer. IR spectra were run on a Perkin-Elmer 683 infrared
spectrometer recorded in KBr pellets. NMR spectra were recorded on a
Bruker AM-500 NMR spectrometer and a Varian Mercury-300 NMR spec-
trometer using TMS as internal standard. EI-MS and HR-EI-MS were ob-
tained using an Autospec-Ulma-Tof mass spectrometer.
Plant Material The lianas of Gnetum cleistostachyum C. Y. CHENG
(Gnetaceae) were collected in Hekou county of Yunnan province, People’s
Republic of China, in October 2001. The plant was identified by Dr. Y. M.
Shui of Kunming Institute of Botany, Chinese Academy of Sciences, China,
where a voucher specimen (No. 39795) was deposited.
Extraction and Isolation The dried and pulverized lianas of Gnetum
cleistostachyum (35 kg) were extracted with 65% EtOH (3ꢄ30 l) under re-
flux. After removing the solvent under vaccum, the residue (3.0 kg) was ex-
tracted with CHCl3 (3ꢄ4 l), EtOAc (3ꢄ4 l), Me2CO (3ꢄ4 l) and MeOH
(3ꢄ4 l) successively. The EtOAc soluble fraction (185 g) was subjected to
silica gel column chromatography (10ꢄ150 cm, 100—200 mesh, 2.5 kg)
eluted with a gradient system of CHCl3–MeOH to provide six fractions A—
F. Fraction E (62.3 g) was further subjected to silica gel column chromatog-
raphy (5ꢄ150 cm 140—180 mesh, 1 kg) eluted with a gradient system of cy-
clohexane–acetone to give fractions E1—E7. Fraction E5 (16 g) was then
further divided into Er1—Er5 by silica gel chromatography [5ꢄ80 cm
140—180 mesh, cyclohexane–acetone (4 : 1—1 : 2)]. Compound 3 (48 mg)
and 4 (30 mg) were obtained from fraction Er3 (800 mg) by silica gel col-
umn chromatography (3ꢄ30 cm 140—180 mesh, 50 g) eluted with
CHCl3–MeOH (25 : 1). Gnetol (80 mg) was obtained from fraction Er4
(0.30 g) by MPLC with MeOH–H2O (3 : 7) as eluent. Er5 (1.6 g) was sub-
jected to a silica gel column chromatography (3ꢄ40 cm, 200—300 mesh,
80 g) eluted with cyclohexane–acetone (3 : 1) to provide compounds 1
(34 mg) and 2 (26 mg). E3 (5.10 g) was subjected to column chromatography
on Rp-18 (35—75 mm, 350 g) eluted with MeOH–H2O system (1 : 1, 4 l) to
afford compound 5 (60 mg). Fraction D (8.0 g) was applied to a silica gel
column chromatography (5ꢄ80 cm, 200—300 mesh, 450 g) using cyclo-
hexane–acetone (4 : 1—1 : 1) as eluent to provide fraction D1—D4. Fraction
D2 (900 mg) was subjected to silica gel column chromatography (3ꢄ30 cm,
200—300 mesh, 50 g) eluted with petrol ether–acetone (3 : 1) to provide
gnetupendin B (16 mg) and 6 (200 mg). The MeOH insoluble fraction of D3
(1.5 g) provided daucosterol (500 mg).
1
Gnetofuran A (2): A pale white amorphous powder. H-NMR (300 MHz
in CD3COCD3) d: 7.10 (1H, d, Jꢂ2.0 Hz), 7.12 (1H, br s), 7.02 (1H, d,
Jꢂ16.5 Hz), 6.94 (1H, d, Jꢂ16.5 Hz), 6.53 (2H, d, Jꢂ2.0 Hz), 6.26 (1H, t,
Jꢂ2.0 Hz), 7.04 (1H, d, Jꢂ2.0 Hz), 6.82 (1H, d, Jꢂ8.0 Hz), 6.89 (1H, dd,
Jꢂ8.0, 2.0 Hz), 5.59 (1H, d, Jꢂ7.0 Hz), 4.16 (1H, t, Jꢂ5.5 Hz), 3.86 (1H, t,
Jꢂ5.5 Hz), 3.56 (1H, q, Jꢂ7.0 Hz), 3.88 (3H, s), 3.82 (3H, s). 13C-NMR
(300 MHz in CD3COCD3) d: 140.7 (C-1a), 111.9 (C-2a), 145.2 (C-3a),
149.3 (C-4a), 130.5 (C-5a), 116.4 (C-6a), 129.5 (C-7a), 127.1 (C-8a), 131.9
(C-9a), 105.5 (C-10a, 14a), 159.5 (C-11a, 13a), 102.6 (C-12a), 134.2 (C-1b),
110.4 (C-2b), 147.2 (C-3b), 148.3 (C-4b), 115.5 (C-5b), 119.5 (C-6b), 88.6
(C-7b), 54.6 (C-8b), 64.5 (C-9b), 56.3 (OCH3), 56.2 (OCH3). IR (KBr)
cmꢁ1: 3300, 2954, 2924, 2852, 1603, 1464, 1377, 1271, 1122, 960. UV lmax
(MeOH) nm (log e): 220 (sh) (4.61), 287 (sh) (4.12), 328 (4.26). EI-MS m/z:
436 (Mꢀ); HR-EI-MS m/z: 436.1501 (Calcd for C25H24O7: 436.1522). [a]D25
0° (cꢂ0.1, MeOH).
1
Gnetifolin F (4): A pale white amorphous powder. mp 144—147 °C; H-
NMR (300 MHz, in CD3COCD3) d: 7.02 (1H, d, Jꢂ1.8 Hz, H-2a), 6.82 (1H,
d, Jꢂ8.1 Hz, H-5a), 6.89 (1H, dd, Jꢂ8.1, 1.8 Hz, H-6a), 4.70 (1H, d,
Jꢂ4.5 Hz, H-7a), 3.75 (1H, dd, Jꢂ8.4, 4.5 Hz, H-8a), 6.26 (1H, d, Jꢂ2.1 Hz,
H-12a), 6.34 (1H, d, Jꢂ2.1 Hz, H-14a), 6.72 (1H, d, Jꢂ2.1 Hz, H-2b), 6.66
(1H, d, Jꢂ8.1 Hz, H-5b), 6.49 (1H, dd, Jꢂ8.1, 2.1 Hz, H-6b), 4.17 (1H, br s,
H-7b), 3.04 (1H, q, Jꢂ8.4 Hz, H-8b), 3.49 (1H, t, Jꢂ8.4 Hz, H-9ba), 4.45
(1H, t, Jꢂ8.4 Hz, H-9bb), 3.73 (3H, s), 3.85 (3H, s). 13C-NMR (300 MHz in
CD3COCD3) d: 135.5 (C-1a), 110.4 (C-2a), 148.3 (C-3a), 146.7 (C-4a),
115.3 (C-5a), 119.6 (C-6a), 88.3 (C-7a), 59.6 (C-8a), 147.9 (C-9a), 122.7
(C-10a), 159.7 (C-11a), 102.5 (C-12a), 155.8 (C-13a), 103.1 (C-14a), 138.0
(C-1b), 111.8 (C-2b), 148.3 (C-3b), 145.5 (C-4b), 115.4 (C-5b), 120.2 (C-
6b), 50.9 (C-7b), 55.8 (C-8b), 74.4 (C-9b), 56.1 (OCH3), 56.0 (OCH3). EI-
MS (m/z): 466 (Mꢀ). [a]2D0 0° (cꢂ0.021, MeOH).
Shegansu B (6): A yellowish amorphous powder. IR (KBr) cmꢁ1: 3302,
1603, 1514, 1462, 1340, 1279, 1155, 1005, 837. UV lmax (EtOH) nm
(log e): 285 (sh) (4.21), 328 (4.48); FAB-MS m/z: 515 (Mꢀ1)ꢀ. [a]2D0 0°
(cꢂ0.048, MeOH). Its 1H-NMR spectral data (300 MHz, in CD3COCD3)
were in agreement with those repored in the literature.6)
Gnetucleistol F (1): A pale white amorphous powder. UV lmax (MeOH)
nm (log e): 235 (sh) (4.29), 310 (sh) (4.24), 327 (4.29). IR (KBr) cmꢁ1
:
3350, 2954, 2924, 2852, 1608, 1518, 1464, 1377, 1213, 1115, 1009, 957,
837. 1H- (300 MHz) and 13C-NMR (75 MHz) see Table 1. [a]2D0 ꢀ4.67°
(c=0.1, MeOH). EI-MS m/z: 466 (Mꢀ). HR-EI-MS m/z: 466.1601 (Calcd for
C26H26O8, 466.1628).
Anti-inflammation and anti-oxidant activity tests were carried out in ac-
cord with the methods discussed in the literature.9,10)
Lehmbachol D (3): A pale white amorphous powder. EI-MS m/z: 466
(46%) (Mꢀ); HR-EI-MS m/z: 466.1610 (Calcd for C26H26O8, 466.1628). Its
spectral data were in agreement with those reported in the literature.2)
Acknowlegements The authors are grateful to Prof. Gui-Fang Cheng
Preparation of Coniferol Alcohol (9a) and Sinapyl Alcohol (9b) 7a and Prof. Geng-Tao Liu for the pharmacological test, and the Department of
(8 g, 41.24 mmol) was dissolved in methanol saturated with hydrochloric Instrumental Analysis of our institute for the measurement of UV, IR, MS,
acid (50 ml) and the solution was kept at room temperature for 48 h. Re- 1H-, 13C-NMR and 2D NMR spectra. The authors would also like to thank
moval of the solvent yielded 8a (8.2 g, 96%), which was dissolved in anhy- Prof. Lian-Niang Li of our institute for the constructive suggestions.

July 2006
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