Total synthesis and biological evaluation of viscolin, a 1,3-diphenylpropane as a novel potent anti-inflammatory agent

Article abstract of DOI:10.1016/j.bmcl.2006.09.046

Total synthesis of viscolin, an anti-inflammatory 1,3-diphenylpropane isolated from Viscum coloratum, employing the Wittig reaction is reported. Key steps in the synthesis of viscolin depend on the selection of protecting groups to maintain the para hydroxyl group that is the most critical chemical structure influencing the biological activity of viscolin and the utilization of microwave-assisted Wittig olefination reaction. Anti-inflammatory potency of the synthetic viscolin, its precursor product 16, and its analogue 17, through their effects on reactive oxygen species (ROS), nitric oxide (NO), and pro-inflammatory cytokine production in leukocytes and microglial cells were evaluated. Excellent inhibition of ROS and NO production in inflammatory cells could confer the synthetic viscolin to be a potent anti-inflammatory agent for the treatment of oxidative stress-induced diseases.

Full text of DOI:10.1016/j.bmcl.2006.09.046

Bioorganic & Medicinal Chemistry Letters 16 (2006) 6155–6160
Total synthesis and biological evaluation of viscolin,
a 1,3-diphenylpropane as a novel potent anti-inflammatory agent
Chung-Ren Su,a, Yuh-Chiang Shen,b, Ping-Chung Kuo,a Yann-Lii Leu,c
Amooru G. Damu,a Yea-Hwey Wangd and Tian-Shung Wua,b,
*
aDepartment of Chemistry, National Cheng Kung University, Tainan 701, Taiwan
bNational Research Institute of Chinese Medicine, Taipei 112, Taiwan
cGraduate Institute of Natural Products, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan
dInstitute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
Received 25 July 2006; revised 13 September 2006; accepted 15 September 2006
Available online 12 October 2006
Abstract—Total synthesis of viscolin, an anti-inflammatory 1,3-diphenylpropane isolated from Viscum coloratum, employing the
Wittig reaction is reported. Key steps in the synthesis of viscolin depend on the selection of protecting groups to maintain the para
hydroxyl group that is the most critical chemical structure influencing the biological activity of viscolin and the utilization of
microwave-assisted Wittig olefination reaction. Anti-inflammatory potency of the synthetic viscolin, its precursor product 16,
and its analogue 17, through their effects on reactive oxygen species (ROS), nitric oxide (NO), and pro-inflammatory cytokine
production in leukocytes and microglial cells were evaluated. Excellent inhibition of ROS and NO production in inflammatory cells
could confer the synthetic viscolin to be a potent anti-inflammatory agent for the treatment of oxidative stress-induced diseases.
Ó 2006 Published by Elsevier Ltd.
Inflammation contributes to play an important pathoge-
netic role in many inflammatory disorders including
asthma, gout, rheumatoid arthritis, multiple sclerosis,
ischemia-reperfusion injury, etc.1 During inflammation,
production of free radicals [e.g., hydrogen peroxide
(H2O2), superoxide anion (O2À)] and nitric oxide (NO)
plays a pivotal role for microorganism killing and also
signals the activation of leukocytes and macrophage.
Conversely, over-production of these toxic reactive oxy-
gen and nitrogen metabolites/species (ROS/RNS) may
cause more damage of the surrounding tissues than the
microbe per se.1,2 Besides, activated leukocytes are pref-
erentially to secrete cytokines [e.g., interleukin-2 (IL-2),
interferon-c (IFN-c), and tissue necrosis factor-a (TNF-
a)] for recruitment of inflammatory cells (e.g., neutro-
phils, macrophages, and microglial cells) to vascular
endothelium and subsequently transmigrate/infiltrate
to injured tissue where they release hydrolytic enzymes
and enormous quantities of free radicals (ROS/RNS)
that result in remarkable tissue damage and immuno-
pathogenesis.3 Thus, anti-inflammatory and anti-oxi-
dant therapies are also comprehensive pharmacological
approaches in the treatment of these inflammation-relat-
ed disorders.4,5 One of these important strategies is to
look for natural compounds and/or their synthetic
derivatives that are capable of inhibiting oxidative stress
for the prevention of free radicals- and cytokine-induced
cellular damage by inflammatory cells infiltrating to the
injured tissue.
Viscolin 1 (Fig. 1) is a naturally occurring 1,3-diphenyl-
propane that was isolated from the Viscum coloratum,6
a hemiparasite herb used in Chinese medicine as a
curative for a number of ailments such as hemorrhage,
pleurisy, gout, heart disease, epilepsy, arthritis, and
OCH3
HO
OCH3
OH
Keywords: Viscolin; Cytokine; Free radicals; Leukocyte; Microglial
cells; Nitric oxide.
OCH3
OCH3
*
Corresponding author. Tel.: +886 6 2747538; fax: +886 2 2740552;
e-mail: tswu@mail.ncku.edu.tw
These authors contributed equally to this work.
1
Figure 1. Viscolin.
0960-894X/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2006.09.046

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C.-R. Su et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6155–6160
hypertension.7,8 This compound displayed potent and
selective activity in the inhibition of superoxide anion
generation in human neutrophils activated with N-for-
myl-methionyl-leucyl-phenylalanine combined with
cytochalasin B, and it also exhibited DPPH radical-scav-
enging property. Both these actions could mediate its
anti-inflammatory activity. We began a program to ex-
plore the therapeutic potential of viscolin and its ana-
logues. The initial goal was to design a total synthesis
that is capable of producing gram quantities of 1 suitable
for more indepth in vitro and in vivo studies with the
flexibility to produce analogues for exploration of the
structure-activity relationships. Herein, we disclose our
approach toward the first total synthesis and biological
evaluation of viscolin.
hydroxyl group essential for bioactivity. Compound 4
was expected to be accessible using slight modification
of known methods.
With confidence that the total synthesis of viscolin 1
could be achieved in the above-mentioned manner, the
preparation of a specific embodiment of differentially
protected aldehyde 10 was commenced according to
the reaction sequence shown in Scheme 2.
In anticipation of the Baeyer–Villiger oxidation, it was
necessary to protect the hydroxyl group of o-vanillin 5.
For this purpose, we examined several protective re-
agents such as trimethylsilyl bromide, tert-butyldimeth-
ylsilyl bromide, methoxymethyl bromide, and isopropyl
bromide, and only isopropyl bromide gave the desired
product. The other protective groups would induce per-
oxidation or unsuccessful deprotection in the sequence.
Thus, treatment of 5 with isopropyl bromide gave the
protected vanillin in 94% yield, which was subjected to
Baeyer–Villiger oxidation using m-CPBA, and the
resulting formate ester was hydrolyzed in alkaline condi-
tion to yield the desired phenol 6 in 82% yield over two
steps.12 After protecting the phenolic hydroxyl group of
6 by benzyl chloride followed by selective deprotection
of the isopropyl group by BCl3, 7 was obtained.13 Grat-
ifyingly, H5IO6 and CrO3 in aqueous acetonitrile oxi-
dized phenol 7 to the corresponding benzoquinone 8
in high yield.14 Compound 8 was reduced with Na2S2O4
In the past, the most widely employed strategy for the
synthesis of 1,3-diphenylpropanes involves the catalytic
hydrogenation of the appropriate chalcones followed
by subsequent Clemmensen reduction which often re-
quires harsh conditions and long reaction time and suf-
fers from poor yields.9,10 The retrosynthetic analysis of
viscolin 1 is shown in Scheme 1. The synthetic work be-
gan with preparation of component molecules 3 and 4
required for the convergent approach toward the pro-
jected key intermediate 2 en route to the target com-
pound 1 involving Wittig olefination reaction and
hydrogenation.11 The most critical aspect for the synthe-
sis is in construction of 3 without altering the para
OCH3
OCH3
OCH3
OCH3
OH
HO
OCH3
CHO
HO
OCH3
OH
HO
OCH3
OH
2
1
+
3
OCH3
OCH3
OCH3
OCH3
-IPh3+P
OCH3
1
2
3
4
Scheme 1. Retrosynthetic analysis.
CHO
OH
OBn
OH
OiPr
OH
iii, iv
i, ii
OCH3
OCH3
OCH3
5
6
7
OCH3
O
O
BnO
OCH3
BnO
OCH3
vi, vii
v
OCH3
8
9
OCH3
BnO
OCH3
CHO
Viii
OCH3
10
Scheme 2. Reagents and conditions: (i) (CH3)2CHBr, K2CO3, DMF, 94%; (ii) 1—m-CPBA, CH2Cl2; 2—NaOH, CH3OH, 82%; (iii) BnCl, KI,
K2CO3, acetone, 85%; (iv) BCl3, CH2Cl2, 91%; (v) H5IO6, CrO3, CH3CN, 91%; (vi) Na2S2O4, H2O, 83%; (vii) (CH3)2SO4, NaOH, H2O, 86%; (viii)
POCl3, DMF, 58%.

C.-R. Su et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6155–6160
6157
and the unstable diol thus obtained was immediately
treated with (CH3)2SO4 in the alkaline solution to afford
fully methylated product 9.15 Subsequently formylation
of 9 with POCl3 and DMF finally furnished the desired
aldehyde 10.
reduction of the olefin moiety of 16, accompanied by
removal of the benzyl protecting groups, upon Pd/C cat-
alyzed hydrogenation, furnished viscolin 1 in 73%
yield.18 Importantly, analytical and spectral data ob-
tained for synthetic 1 are in excellent agreement with
those reported for the desired natural material. In order
to evaluate the impact of double bond or hydroxyl
groups on biological activity, benzylated viscolin 17 is
prepared by treating viscolin with benzyl chloride.
(Scheme 4).
For the construction of the other component molecule 4,
vanillin 11 was treated with benzyl chloride and the
ensuing protected product was subjected to Wittig olef-
ination to provide 13. Unfortunately, all of the condi-
tions applied for the Wittig reaction gave either a
mixture of products or the undesired polymers. After
considerable experimentation, however, it was realized
that, to our delight, the required olefination could be
achieved with high degree efficiency under microwave-
assisted conditions.16 Hydroboration of 13 followed by
the treatment with H2O2 and NaOH produced the pri-
mary alcohol 14,17 which was converted to phosphoni-
um salt 15 by a successive treatment with I2 in the
presence of PPh3 and then with PPh3 in toluene.
(Scheme 3).
To examine the efficacy of the synthetic viscolin 1, its
pro-drug product 16, and its analogue 17 on the sup-
pression of reactive oxygen species (ROS), nitric oxide
(NO), and cytokine production in activated leukocytes
or microglial cells for the use as an anti-inflammatory
agent, we set up in vitro models by exposing peripheral
human neutrophils (PMN), mononuclear cells (MNC),
and murine microglial cells (BV2) to phorbol-12-myris-
tate-13-acetate (PMA, a protein kinase c(PKC) activa-
tor), N-formyl-methionyl-leucyl-phenylalanine (fMLP,
a G-protein-coupled activator), or lipopolysaccharide
(LPS) for the induction of ROS, NO, and cytokines.
Their effects on ROS, NO, and cytokines production
in human leukocytes and murine microglial cells were
elucidated.
The final stage of total synthesis is shown in Scheme 4.
Wittig reaction of triphenylphosphonium salt 15 pro-
ceeded well in the presence of n-BuLi to afford the prod-
uct 16 having the basic skeleton of viscolin. Finally,
CHO
CHO
i
ii
HO
BnO
BnO
OCH3
OCH3
OCH3
13
11
12
P+Ph3I-
OH
iv, v
iii
BnO
BnO
OCH3
OCH3
15
14
Scheme 3. Reagents and conditions: (i) BnCl, KI, K2CO3, acetone, 87%; (ii) CH3P+Ph3IÀ, NaH, THF, microwave, 200 W, 10 min, 77%; (iii) 1—I2,
NaBH4, THF; 2—H2O2, NaOH, 75%; (iv) PPh3, imidazole, I2, CH2Cl2, 85%; (v) PPh3/toluene, quantitative.
P+Ph3I-
OCH3
OCH3
BnO
OCH3
CHO
BnO
OCH3
OBn
i
+
BnO
OCH3
OCH3
OCH3
OCH3
15
10
16
OCH3
OCH3
OCH3
HO
OCH3
OH
OCH3
BnO
OCH3
OBn
OCH3
iii
ii
OCH3
1
17
Scheme 4. Reagents and conditions: (i) n-BuLi, THF, 71%; (ii) H2, Pd/C, 73%; (iii) BnCl, KI, K2CO3, acetone, 85%.

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C.-R. Su et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6155–6160
In human leukocytes, fMLP and PMA both induced
large amounts of ROS production in PMN and MNC,
predominantly through a receptor/G-protein coupling
pathway or the protein kinase c(PKC)-dependent path-
way, respectively.3,19 Viscolin significantly suppressed
fMLP- and PMA-induced ROS production both in
PMN and MNC. The IC50 values were comparable with
that of quercetin (QC), a potent anti-inflammatory com-
pound of the plant origin (Table 1). Viscolin is 3–10
times more effective in the inhibition of ROS production
induced by fMLP than that of PMA, indicating that a
G-protein coupling pathway could be the major site tar-
geted by viscolin. Although less potent than viscolin,
products 16, and 17 showed a minor to mediocre activity
in the inhibition of fMLP- and PMA-induced ROS pro-
duction with a maximum inhibition percentage of
around 37–47% and 20–42% at 25 lM, respectively,
indicating that the hydroxyl groups of 1,3-diphenylpro-
pane derivatives are important for targeting the ROS
producing enzyme systems in human leukocytes. The
viscolin (a 1,3-diphenylpropane derivative) is a new class
of chemical compound with anti-oxidative activity. Acti-
vation of PKC as well as the quick intracellular calcium
mobilization (a down steam signal for G-protein activa-
tion) displays two important signaling pathways for the
ROS production in human leukocytes induced by PMA
and fMLP, respectively.19 Viscolin concentration-depen-
dently reduced PKC activity and interfered fMLP-in-
duced intracellular calcium mobilization (Table 2)
indicating that interference of PKC- and G-protein-cou-
pled signaling were both responsible for viscolin’s effect.
Microglial cells are also important free radical-produc-
ing cells in the central nervous system. We have ob-
served rapid production of ROS by NADPH oxidase
(NOX) and nitric oxide (NO) by NO synthase (NOS)
in microglial cells.20 We further evaluated whether visc-
olin, 16, and 17 could inhibit NOX-dependent ROS and
NOS-dependent NO production in microglial cells. Visc-
olin concentration-dependently suppressed ROS and
NO production in microglial cells. The viscolin was less
potent than diphenyleneiodonium (DPI), a specific
NOX inhibitor, in the inhibition of ROS production,
but was more potent than L-NAME, a specific NOS
inhibitor, in the inhibition of NO production (Table
3). Products 16 and 17 showed effectiveness in the inhi-
bition of NOS activity with IC50 value of around 19 and
20 lM, respectively, but they did not significantly target
the NOX activity (Table 3), suggesting that the hydroxyl
groups on the 1,3-diphenylpropane skeleton are impor-
tant for targeting NOX activity but not essential for tar-
geting NOS activity.
Pro-inflammatory cytokines produced by leukocyte and/
or macrophage play pivotal roles in mediating the acti-
vation and recruitment of inflammatory cells during
inflammation. Beside, drugs with anti-inflammatory
activity could modulate the cytokine production.21
Among these pro-inflammatory Th1-type cytokines,
interleukin-2 (IL-2) released by CD4+ Th cells, and
interferon-c (IFN-c) and tissue necrosis factor-a
(TNF-a) produced by CD8+ leukocytes and microglial
cells were examined in this study in the presence of visc-
olin, 16, and17. We used PMA combination with iono-
mycin, or LPS to induce cytokine production in human
leukocytes and microglial cells, respectively. No signifi-
cant inhibition of the cytokine production was observed
by viscolin or products 16 and 17, except at relatively
high concentration (25 lM) viscolin significantly inhibit-
ed the TNF-a production in microglial cells (Table 4),
indicating that viscolin, 16, and17 are not potent chem-
icals for the inhibition of cytokine production.
Table 1. Summary of the IC50 values for the inhibition of fMLP- and
PMA-induced ROS production by viscolin in human peripheral
leukocytes
Drugs
IC50 (lM) in PMN
IC50 (lM) in MNC
PMA
fMLP
PMA
fMLP
Viscolin
16
17
12.0 0.9*
ND
ND
1.4 0.1
ND
ND
8.3 2.2*
ND
ND
2.5 0.2
ND
ND
QC
5.5 1.8
2.5 0.3
3.1 0.8
4.0 1.4
The anti-inflammatory property of viscolin, but not
products 16 and 17, was partially due to its direct free
radical-scavenging activity with IC50 of around 49 lM.
Data were calculated as 50% inhibitory concentration (IC50). Values
represent means SEM of 3–5 experiments performed on different
days using cells from different donors. ND, values not detectable.
* P < 0.05 as compared with QC (quercetin), respectively.
Table 3. Summary of the effects of viscolin on NADPH oxidase
(NOX) and nitric oxide synthase (NOS) activity in murine microglial
cells
Table 2. Summary of the inhibitory effect of viscolin on protein kinase
activity and fMLP-induced calcium mobilization in human peripheral
leukocytes
Drugs
IC50 (lM) in NOX
IC50 (lM) in NOS
Drugs
Inhibition (%)
Viscolin
16
17
29.2 6.5*
ND
ND
24.0 1.0*
19.0 1.4*
20.0 2.2*
ND
PKA
PKC
fMLP-induced [Ca2+
]
i
Viscolin (5 lM)
Viscolin (25 lM)
ND
ND
34.4 2.7
48.8 6.8
36.7 3.5
53.5 4.6
DPI
L-NAME
10.2 0.6
ND
36.0 3.8
The activity of cyclic AMP-dependent protein kinase (PKA) and
protein kinase c (PKC) was determined in the presence or absence of
viscolin by an ELISA kit. Intracellular calcium mobilization ([Ca2+]i)
was determined by Fura-2 pre-loaded cells in the presence of 2 lM
fMLP. Data were calculated as percentage (%) of inhibition by taking
the values of protein kinase activity or calcium increment in drug-free
samples as 100%. Values represent means SEM of 3 experiments
performed on different days using cells from different donors. ND,
values not detectable.
NOX and NOS activity were measured by ROS and NO production,
respectively, in the presence of 1–50 lM of drugs. DPI (diphenylenei-
odonium, a NOX inhibitor) and L-NAME (a NOS inhibitor) were
included as positive controls. Data were calculated as 50% inhibitory
concentration (IC50) and expressed as means SEM from 5 to 6
experiments performed on different days using cells from different
passages.
* P < 0.05 as compared with relative positive control, respectively.

C.-R. Su et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6155–6160
6159
Table 4. Summary of the inhibitory effects of viscolin on cytokine
production in human leukocytes and murine microglial cells
References and notes
Drugs (lM)
IL-2/CD4+ IFN-c/CD8+ TNF-a/BV2
MCF MCF MCF
Control (drug free) 47
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2. Casimir, C. M.; Teahan, C. G. In Immunopharmacology of
Neutrophils; Hellewell, P. G., Williams, T. J., Eds.;
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3. Wardlaw, A. J.; Walsh, G. M. In Immunopharmacology of
Neutrophils; Hellewell, P. G., Williams, T. J., Eds.;
Acedemic Press: San Diego, 1994; p 134.
4. Cuzzocrea, S.; Riley, D. P.; Caputi, A. P.; Salvemini, D.
Pharmacol. Rev. 2001, 53, 135.
5. Middleton, E., Jr.; Kandaswami, C.; Theoharides, T. C.
Pharmacol. Rev. 2000, 52, 673.
6
17
82
67
72
65
2
32
3
Activator
+Viscolin (25)
+Viscolin (5)
+16 (25)
111 13
112 20
2
1
1
2
185
7
121 10*
155 14
155 17
164 23
154 22
164 25
99
7
103 19
101 12
102 11
100 22
+16 (5)
+17 (25)
+17 (5)
60 12
65 32
59 09
6. Leu, Y. L.; Hwang, T. L.; Chung, Y. M.; Hong, P. Y.
Chem. Pharm. Bull. 2006, 54, 1063.
7. Chiu, S. T.; Flora of Taiwan; 2nd ed.; Editorial Committee
of the Flora of Taiwan, Taipei, Taiwan, 1996; Vol. II, pp
282–285.
Data are expressed as means SEM from 3 to 5 experiments per-
formed on different days using cells from different donors or passages.
MCF, mean channel fluorescence of the intracellular cytokine staining.
* P<0.05 as compared with activator alone, respectively.
8. Chiu, S. T.; Medicinal Resource of Formosan Mistletoes;
In Proceedings of International Symposium on Plant
Biodiversity and Development of Bioactive Natural Prod-
ucts; Nov. 18–20, Taichung.
9. Schwartz, M. A.; Rose, F. F.; Holton, R. A.; Scott, S. W.;
Vishnuvajjala, B. J. Am. Chem. Soc. 1977, 99, 2571.
10. Iinuma, M.; Matoba, Y.; Tanaka, T.; Mizuno, M. Chem.
Pharm. Bull. 1986, 34, 1656.
Table 5. Summary of the effects of viscolin on DPPH free radical-
scavenging activity in cell free system and cytotoxicity on microglial
cells
Drugs
DPPH scavenging Cytotoxicity (% of dead cells)*
(IC50lM)
25 lM
10 lM
5 lM
11. Chen, C. C.; Huang, Y. L.; Shiao, Y. J.; Huang, R. L.; Fu,
T. T.; Shen, C. C. Chin. Pharm. J. 2003, 55, 381.
12. Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc. 2003, 125,
4680.
16
17
ND
ND
10.0 3.9 8.1 3.2
8.6 3.0
9.6 2.6 8.9 2.6 14.6 5.6
14.6 5.6 8.9 2.6 9.6 2.6
ND ND ND
Viscolin 49.2 1.1
Trolox 40.5 3.0
13. Iinuma, M.; Iwashima, K.; Tanaka, T.; Matsuura, S.
Chem. Pharm. Bull. 1984, 32, 4217.
14. Yamazaki, S. Tetrahedron Lett. 2001, 42, 3355.
15. Baker, W. J. Chem. Soc. 1941, 662.
* For cytotoxicity study, all drugs were examined at the concentration
as indicated in the table. The background cell death in the solvent
control (0.5% DMSO) was 8.5 2.7%. Trolox, an antioxidant
included as a control. Data are expressed as means SEM from 3 to
5 experiments performed on different days using cells from different
passages. ND, values not detectable.
16. Synthesis of 1-Benzyloxy-2-methoxy-4-vinylbenzene (13).
To a suspension of NaH (60% in paraffin oil, 840 mg,
21 mmol) in THF (20 mL) was added dropwise a solution of
methyl triphenyl phosphonim iodide (3.9 g, 9.8 mmol) in
THF (10 mL), followed by a solution of 12 (1.7 g, 7 mmol)
in THF (20 mL). The mixture was stirredfor 10 min at 80 °C
under MW irradiation (200 W). After cooling, the solution
was quenched byadding H2O in ice-water bath. The mixture
was extracted with EtOAc, washed with brine, and dried
over Na2SO4. The organic solvent was evaporated and the
residue was purified by silica gel column chromatography
(n-hexane/EtOAc 9:1) to give 13 (1.3 g, 77.2%); mp 45–
46 °C; IR (KBr) cmÀ1: 1598, 1576, 1513; HREIMS m/z:
240.1149 (calcd for C16H16O2: 240.1150); EIMS m/z: 240
Viscolin, 16, and 17 did not show significant cytotoxic
effect (Table 5).
In summary, the present work provides the first total
synthesis of viscolin and affirmed the structure originally
reported. We demonstrated in the study for the first time
that viscolin, a 1,3-diphenylpropane derivative, exhibits
leukocyte inhibitory activity by suppressing free radi-
cals, possibly through modulation of PKC activity and
calcium mobilization, and NO production with moder-
ate free radical-scavenging effects that give viscolin the
potential to be anti-inflammatory agent for the treat-
ment of oxidative stress-induced diseases. On the basis
of this route, further studies directed toward the synthe-
sis of artificial congeners of viscolin as well as evaluation
of anti-inflammatory properties will be reported in due
course.
1
(M+, 90), 91 (100); H NMR (300 MHz, CDCl3) d: 7.26–
7.45 (5H, m, ArH), 6.99 (1H, d, J = 1.6 Hz), 6.88 (1H, dd,
J = 8.3, 1.6 Hz), 6.83 (1H, d, J = 8.3 Hz), 6.64 (1H, dd,
J = 17.6, 10.6 Hz), 5.61 (1H, d, J = 17.6 Hz), 5.16 (1H, d,
J = 17.6 Hz), 5.16 (2H, s, OCH2), 5.15 (1H, d, J = 10.6 Hz),
3.92 (3H, s, OCH3); 13C NMR (75 MHz, CDCl3) d: 149.6,
148.0, 137.0, 136.4, 131.2, 128.4, 127.7, 127.1, 119.2,
113.8,111.9, 109.1, 70.9, 55.9.
17. Prasad, A. S. B.; Kanth, J. V. B.; Periasamy, M.
Tetrahedron 1992, 48, 4623.
18. Data for viscolin 1: white powder: mp 123–124 °C (lit.
1
118–121 °C)6; IR (KBr): 3418 (OH), 2937, 1599, 1515; H
NMR (CDCl3, 300 MHz): d 6.82 (1H, d, J = 8.6 Hz), 6.71
(1H, s), 6.70 (1H, d, J = 8.6 Hz), 6.30 (1 H, s), 5.63 (1H, br
s, D2O-exchangeable, OH), 5.45 (1H, br s, D2O-exchan-
geable, OH), 3.87 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.81
(3H, s, OCH3), 3.73 (3H, s, OCH3), 2.60 (2H, t,
J = 6.5 Hz), 2.58 (2H, t, J = 6.0 Hz), 1.77 (2H, tt,
J = 6.5, 6.0 Hz); 13C NMR (CDCl3, 300 MHz): d 154.3,
151.2, 147.4, 146.2, 143.4, 134.8, 133.5, 120.9, 116.1, 114.0,
111.0, 94.2, 60.9, 60.6, 55.9, 55.7, 35.7, 31.9, 23.2; EI-MS
Acknowledgments
We acknowledge the financial supports, in part, from
Grants of NSC-94-2113-M-006-008, NSC-94-2320-B-
077-007, NRICM94-DBCMR-09, and 94-T21 from
National Science Council and National Research Insti-
tute of Chinese Medicine to Y. C. Shen and T. S. Wu,
respectively.

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C.-R. Su et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6155–6160
m/z (rel. int.%): 348 (M+, 16), 197 (59), 137 (100); HR-
20. Wang, Y. H.; Wang, W. Y.; Chang, C. C.; Liou, K. T.;
Sung, Y. J.; Liao, J. F.; Chen, C. F.; Chang, S.; Hou, Y.
C.; Chou, Y. C.; Shen, Y. C. J. Biomed. Sci. 2006, 13, 127.
21. Suzuki, J. I.; Ogawa, M.; Futamatsu, H.; Kosuge,
H.; Tanaka, H.; Isobe, M. J. Mol. Cell Cardiol.
2006, 40, 688.
EIMS calcd for C19H24O6 (M+) 348.1573. Found
348.1575. EA calcd for C19H24O6: C, 65.50, H, 6.92.
Found C, 65.27, H, 6.94.
19. Shen, Y. C.; Chiou, W. F.; Chou, Y. C.; Chen, C. F. Eur.
J. Pharmacol. 2003, 465, 171.