Evaluation of resveratrol derivatives as potential antioxidants and identification of a reaction product of resveratrol and 2,2-diphenyl-1- picryhydrazyl radical

Article abstract of DOI:10.1021/jf990382w

Resveratrol (3,4',5-trihydroxy-trans-stilbene), an antioxidant from grapes, and five other polyhydroxystilbenes were synthesized. Their antioxidative properties were evaluated in two model systems [pure lipid oxidation using the Rancimat method and 2,2-diphenyl-1-picryhydrazyl (DPPH) free radical scavenging model.] 3,3',4,5'-Tetrahydroxystilbene, 3,3',4,5,5'- pentahydroxystilbene, and 3,4,4',5-tetrahydroxystilbene were found to be more active than resveratrol in both models. A dimer of resveratrol was identified as the major radical reaction product when resveratrol was reacted with DPPH radicals.

Full text of DOI:10.1021/jf990382w

3974
J. Agric. Food Chem. 1999, 47, 3974−3977
Eva lu a tion of Resver a tr ol Der iva tives a s P oten tia l An tioxid a n ts a n d
Id en tifica tion of a Rea ction P r od u ct of Resver a tr ol a n d
2,2-Dip h en yl-1-p icr yh yd r a zyl Ra d ica l
Mingfu Wang, Yi J in, and Chi-Tang Ho*
Department of Food Science, Rutgers University, 65 Dudley Road, New Brunswick, New J ersey 08901-8520
Resveratrol (3,4′,5-trihydroxy-trans-stilbene), an antioxidant from grapes, and five other polyhy-
droxystilbenes were synthesized. Their antioxidative properties were evaluated in two model systems
[pure lipid oxidation using the Rancimat method and 2,2-diphenyl-1-picryhydrazyl (DPPH) free
radical scavenging model.] 3,3′,4,5′-Tetrahydroxystilbene, 3,3′,4,5,5′-pentahydroxystilbene, and
3,4,4′,5-tetrahydroxystilbene were found to be more active than resveratrol in both models. A dimer
of resveratrol was identified as the major radical reaction product when resveratrol was reacted
with DPPH radicals.
Keyw or d s: Resveratrol derivatives; polyhydroxystilbene; antioxidant; 2,2-diphenyl-1-picryhydrazyl;
free radical scavenging
INTRODUCTION
(5), and 3,3′,4,5,5′-pentahydroxy-trans-stilbene (6). The
goal of this study was to find antioxidative stilbene
derivatives more active than resveratrol and to use them
to prevent free radical-related problems, either to
benefit pathological disturbance or to prevent lipid
oxidation. To examine the scavenging free radical
process of stilbene compounds, the stable radical ter-
mination product was purified and identified.
It was suggested recently that generation of free
radicals plays a major role in the progression of a wide
range of pathological disturbance such as brain dys-
function, cancer, and cardiovascular disease and inflam-
mation (Huong et al., 1998; Haraguchi et al., 1997). In
the food industry, free radicals are also found to be
responsible for lipid oxidation, which is a major deter-
minant in the deterioration of foods during processing
and storage (Nunez-Delicado et al., 1997; Chen and Ho,
1997; Dziedzic et al., 1985). Due to these facts, consider-
able interest has been given to the addition of antioxi-
dants in food and biological systems to scavenge free
radicals. A lot of natural compounds have been found
to be antioxidants, including vitamin E, flavonoids,
phenolic acids, chlorophyll derivatives, and carotenoids
(Larson 1988).
Recently resveratrol (3,4′,5-trihydroxy-trans-stilbene),
a natural product derived from grapes, was found to be
antioxidative, antimutagenic, and an inducer of phase
II drug-metabolizing enzymes (J ang et al., 1997). Res-
veratrol belongs to a class of compounds called stilbenes,
which are widely distributed in nature. Interest in the
synthesis of stilbene compounds stems from the discov-
ery of many natural stilbene compounds as antioxida-
tive, antifungal, ichthyotoxic, antinitotic, and antileu-
kemic agents (Pettit et al., 1989, 1995; Cushman et al.,
1991; Hata et al., 1979). In the present study, we
synthesized resveratrol and five other polyhydroxystil-
benes and evaluated their antioxidative properties. We
used the Rancimat method to test antioxidative activity
in pure lard and 2,2-diphenyl-1-picryhydrazyl (DPPH)
to test free radical scavenging activity. The six stilbene
compounds we studied were 3,5-dihydroxy-trans-stil-
bene (1), 3,4′,5-trihydroxy-trans-stilbene (2), 3,3′,4,5′-
tetrahydroxy-trans-stilbene (3), 3,4,4′,5-tetrahydroxy-
trans-stilbene (4), 3,3′,5,5′-tetrahydroxy-trans-stilbene
MATERIALS AND METHODS
Gen er a l P r oced u r es. 1H and 13C NMR spectra were
obtained on a Varian Gemini-200 instrument (Varian Inc.,
Melbourne, Australia) at 200 and 50 MHz, respectively. CH3-
OH-d4 was used as a solvent, and chemical shifts were
expressed in parts per million (δ). 13C NMR multiplicity was
determined by APT experiment. Chemical shifts were ex-
pressed in ppm. Electron impact (EI) mass spectra were
recorded on a Finnigan MAT-90 instrument (Finnigan Inc.,
San J ose, CA), and atmospheric pressure chemical ionization
(APCI)-MS was obtained from a Fisons/VG Plaform II mass
spectrometer. Thin-layer chromatograghy was performed on
Sigma-Aldrich silica gel TLC plates (250 µm thickness, 2-25
µm particle size; Aldrich, Milwaukee, WI) with compounds
visualized by spraying with 5% (v/v) H2SO4 in an ethanol solu-
tion. Benzyl alcohol, 4-methoxybenzyl alcohol, 3,4-dimethoxy-
benzyl alcohol, 3,5-dimethoxybenzyl alcohol, 3,5-dimethoxy-
benzaldehyde, 3,4-dimethoxybenzaldehyde, 3,4,5-trimethoxy-
benzaldehyde, triethyl phosphite, sodium methoxide, pyridine
hydrochloride, benzene, DMF, 2,2-diphenyl-1-picryhydrazyl
(DPPH), silica gel (130-270 mesh), and TLC plates were
purchased from Aldrich Chemical Co. (Milwaukee, WI), All
organic solvents and pure lard (pork fat) were obtained from
Fisher Scientific (Springfield, NJ ).
Gen er a l Syn th etic P r oced u r e for Resver a tr ol. All of
the stilbene derivatives were prepared by the method accord-
ing to literature (Bachelor et al., 1970; Drewes et al., 1973) as
shown in Figure 1.
Syn th esis of Resver a tr ol. 4-Methoxybenzyl alcohol (10 g)
was dissolved in dry benzene, and excess dry HBr was bubbled
into the solution with stirring over a period of 20 min. Then
the solution was heated to 78 °C and allowed to stand for 1 h.
Water (100 mL) was added to remove HBr, and the benzene
* Corresponding author (fax, 732-932-8004; e-mail, ho@
aesop.rutgers.edu).
10.1021/jf990382w CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/14/1999

Resveratrol Derivatives as Antioxidants
J. Agric. Food Chem., Vol. 47, No. 10, 1999 3975
F igu r e 1. General synthetic scheme for stilbene derivatives.
layer was dried by MgSO4. Evaporation of the benzene gave a
quantitative yield of slightly colored oil of 4-methoxybenzyl
bromide.
this experiment. Two micromoles (100 µL of 20 mM methanol
solution) of the above compounds was mixed with 2.5 g of lipid
in different glass cylinders. A total of 100 µL of methanol was
also added to all cylinders, including the control. The air supply
was maintained at 20 mL/min, and the temperature was kept
at 110 °C. All tests were run in triplicate, which were averaged
during data analysis.
Deter m in a tion th e Sca ven gin g Effect on DP P H Ra d i-
ca ls. In the 1.0 × 10-4 M ethanol solution of DPPH, test
compounds and six stilbenes were added, and their final
concentrations were 20 µM. Then the samples were shaken
vigorously and kept in the dark for 0.5 h. The absorption of
the samples was measured on a spectrophotometer (Milton
Roy, model 301) at 517 nm against a blank of ethanol without
DPPH. All tests were run in triplicate and averaged (Chen
and Ho, 1995).
4-Methoxybenzyl bromide (3.8 g) was heated with excess
triethyl phosphite (4.5 mL) to 130 °C until the evolution of
ethyl bromide had ceased. Then the solution was cooled to 0
°C, and 25 mL of DMF and 1.1 g of sodium methoxide were
added to it. To this solution 2.1 g of 3,5-dimethoxybenzalde-
hyde was added and allowed to stand at room temperature
for 1 h. The reaction mixture was then heated to 100 °C,
allowed to stand at this temperature for 1 h, and then kept at
room temperature overnight. Water-methanol (2:1, 40 mL)
was added, and the precipitated stilbene was collected by
filtration and washed with water. The purity of this stilbene
was detected by TLC (hexane:ethyl acetate 4:1); yield 3.2 g
(95%).
Excess pyridine hydrochloride (11 g) and 3,4′,5-trimethoxy-
stilbene (2 g) were mixed and heated to 190 °C for 4 h. The
hot dark syrup was poured into 50 mL of 2 N HCl, and the
reaction mixture was extracted with ethyl acetate (3 × 100
mL). The ethyl acetate layer was dried with MgSO4, and then
ethyl acetate was removed under reduced pressure. The
residual was purified by column chromatography on silica gel
eluted with chloroform-methanol (15:1) to get 3,4′,5-trihy-
droxystilbene 0.76 g (45%). MS m/z: 228 (M+), 211, 199, 181,
157, 115.
An a lysis of Ra d ica l Rea ction P r od u ct of DP P H a n d
Resver a tr ol. One millimole of resveratrol and 1 mmol of
DPPH were added to 50 mL of methanol. The mixture was
shaken vigorously and kept in the dark for 0.5 h. Then
methanol was removed under reduced pressure at 50 °C. The
residue was subjected to silica gel (50 g) chromatography,
which was performed with chloroform (200 mL), followed by
chloroform-methanol (20:1, 10:1, 7:1, 5:1, and 1:1 each 200
mL). The fraction obtained by using chloroform-methanol (7:
1) as the mobile phase and was further subfractionated by a
column chromatography (20 × 50 mm) on Sephadex LH-20
(50 g, Pharmacia Biotech, Piscataway, NJ ) using methanol as
the mobile phase. The major compound (40 mg) was obtained
after elution of 800 mL of methanol.
Other stilbene compounds were synthesized in the same
manner as 3,4′,5-trihydroxystilbene using the corresponding
benzyl alcohol and benzaldehyde instead of 4-methoxybenzyl
alcohol and 3,5-dimethoxybenzaldehyde.
1
1H NMR (200 MHz, in CD3OD): 7.36 (1H, d, J ) 8.4 Hz,
H-6D), 7.19 (1H, s, H-2D), 7.17 (2H, d, J ) 8.4 Hz, H-2A and
H-6A), 6.98 (1H, d, J ) 16.5 Hz, H-â), 6.82 (4H, m, H-3A, 5A,
5D, R), 6.46 (2H, d, J ) 2.1 Hz, H-2E, 6E), 6.22 (2H, m, H-4B,
4E), 6.14 (2H, d, J ) 2.1 Hz, H-2B and 6B), 5.39 (1H, d, J )
8.4 Hz, H-1C), 4.40 (1H, d, J ) 8.4 Hz). 13C NMR (50 MHz, in
CD3OD): 161.3 (s, C-4D), 160.2, 159.9 (4C, s, C-3B, 5B, 3E,
5E), 159.0 (s, C-4A), 146.7 (s, C-1B), 141.5 (s, C-1E), 133.1,
132.7, 132.6 (3C, s, C-1A, 1D, 3D), 129.7 (d, C-R), 129.0 (3C,
d, C-2A, 6A, 2D), 127.7 (d, C-â), 124.5 (d, C-6D), 116.6 (2C, d,
C-3A, 5A), 110.7 (d, C-5D), 108.1 (2C, d, C-2B, 6B), 106.1 (2C,
d, C-2E, 6E), 103.0; 102.8 (2C, d, C-4B, 4E), 95.2 (d, C-1C),
59.0 (d, C-2C).
3,5-Dihydroxystilbene (1). H NMR (CD3OD): 7.50 (2H, d,
J ) 7.3 Hz), 7.33 (2H, t, J ) 7.3 Hz), 7.22 (1H, t, J ) 7.3 Hz),
7.04 (1H, d, J ) 16.6 Hz), 7.00 (1H, d, J ) 16.6 Hz), 6.49 (2H,
d, J ) 2.1 Hz), 6.20 (1H, t, J ) 2.1 Hz). MS m/z: 212 (M+),
197, 165, 141, 115, 77.
1
3,3′,5, 5′-Tetrahydroxystilbene (3). H NMR (CD3OD): 6.86
(2H, s), 6,44 (4H, d, J ) 2.1 Hz), 6.18 (2H, t, J ) 2.1 Hz). MS
m/z: 244 (M+), 226, 197, 173, 160, 160, 141, 115.
3,3′,4,5′-Tetrahydroxystilbene (4). 1H NMR (CD3OD): 6.98
(1H, d, J ) 2.1 Hz), 6.88 (1H, d, J ) 16.3 Hz), 6.83 (1H, dd, J
) 2.1, 8.0 Hz), 6.73 (1H, d, J ) 16.3 Hz), 6.72 (1H, d, J ) 8.0
Hz), 6.44 (2H, d, J ) 2.1 Hz), 6.15 (1H, t, J ) 2.1 Hz). MS m/z:
244 (M+), 197, 173, 149, 123, 115.
3,4,4′,5-Tetrahydroxystilbene (5). 1H NMR (CD3OD): 7.30
(2H, d, J ) 8.4 Hz), 6.80 (1H, d, J ) 16.0 Hz), 6.74 (1H, d, J
) 8.4 Hz), 6.72 (1H, d, J ) 16.4 Hz), 6.50 (2H, s). MS m/z:
244 (M+), 197, 169, 141, 115.
RESULTS AND DISCUSSION
Sca ven gin g Effect on DP P H Ra d ica ls. The model
of scavenging DPPH free radicals is a simple method
to evaluate the antioxidative activity of antioxidants.
Antioxidants serve hydrogen to free radicals and scav-
enge radicals. The scavenging effect of six stilbenes is
shown in Table 1. All these compounds exhibited free
radicals scavenging ability at the concentration of 20
µM as compared with control samples without additives.
Specially 3,3′,4,5,5′-pentahydroxystilbene and 3,4,4′,5-
3,3′,4,5,5′-Pentahydroxystilbene (6). 1H NMR (CD3OD): 6.80
(1H, d, J ) 16.2 Hz), 6.69 (1H, d, J ) 16.2 Hz), 6.52 (2H, s),
6.41 (2H, d, J ) 2.1 Hz), 6.14 (1H, t, J ) 2.1 Hz). MS m/z:
260 (M+), 244, 213, 197, 123, 108, 80.
Eva lu a tion of th e In h ibitor y Effect on Lip id Oxid a tion
by th e Ra n cim a t Meth od . Pure lard (pork fat) was used as
the lipid substrate to evaluate the lipid oxidation inhibitory
activity of the six stilbene derivatives and BHT. A Metrohm
679 Rancimat instrument (Herisan, Switzerland) was used in

3976 J. Agric. Food Chem., Vol. 47, No. 10, 1999
Wang et al.
Ta ble 1. Sca ven gin g Effects of An tioxid a n ts on th e
2,2-Dip h en yl-1-p icr ylh yd r a zyl Ra d ica la
Ta ble 2. In d u ction Tim e of Lip id Oxid a tion Mea su r ed by
Ra n cim a t Meth od
absorption
induction time
at 517
inhibition
% (SD)
compounda
for lard (h) (SD)b
compound
nmb(SD)c
control
BHT
2.05 (0.10)
6.00 (0.20)
2.25 (0.10)
12.3 (0.65)
3.68 (0.20)
60.3 (1.5)
control
1.415 (0.001)
3,5-dihydroxystilbene (1)
0.994 (0.008) 29.8 (0.57)
0.636 (0.036) 55.1 (2.54)
0.757 (0.007) 46.5 (0.49)
0.465 (0.008) 67.1 (0.57)
0.100 (0.008) 92.9 (0.21)
3,5-dihydroxystilbene (1)
3,4′,5-trihydroxystilbene (2)
3,3′,5,5′-tetrahydroxystilbene (3)
3,3′4,5′-tetrahydroxystilbene (4)
3,4,4′,5-tetrahydroxystilbene (5)
3,3′,4,5,5′-pentahydroxy-stilbene (6)
3,4′,5-trihydroxystilbene (2)
3,3′,5,5′-tetrahydroxystilbene (3)
3,3′,4,5′-tetrahydroxystilbene (4)
3,4,4′,5-tetrahydroxystilbene (5)
43.0 (1.0)
48.1 (0.70)
3,3′,4,5,5′-pentahydroxystilbene (6) 0.100 (0.008) 92.9 (0.21)
a
a
The concentration of DPPH ethanolic solution was 1.0 × 10-4
The concentration of added compounds was 2 µmol in 2.5 g of
b
b
M. The concentration of compounds was 20 µM. c Each value is
the mean of triplicate measurement, and SD means standard
derivation of measurement.
lard. Each value is the mean of triplicate measurement, and SD
means standard derivation of measurement.
tetrahydroxystilbene exhibited 92.9% inhibition. As
shown in Table 1, 3,3′,4,5,5′-pentahydroxystilbene )
3,4,4′,5-tetrahydroxystilbene > 3,3′,4,5′-tetrahydroxy-
stilbene > 3,4′,5-trihydroxystilbene > 3,3′,5,5′-tetrahy-
droxystilbene > 3,5-dihydroxystilbene. It is well-ac-
cepted that the DPPH radical scavenging of phenolic
compounds is due to their hydrogen-donating ability;
the more the number of hydroxyl group, the higher the
possibility of free radicals scavenging ability (Chen et
al., 1995). Part of the explanation for this is that
pentahydroxystilbene is the most active antioxidant in
this model. Phenol compounds are not active as anti-
oxidants unless substitution at either the ortho or para
position has increased the electron density of the
hydroxyl group and lowered the oxygen-hydrogen bond
energy. The effect of this is to increase the reactivity
toward the free radicals (Madsen et al., 1997), so
3,4,4′,5-tetrahydroxystilbene and 3,3′,4,5′-tetrahydroxy-
stilbene are more reactive than 3,3′,5,5′-tetrahyydroxy-
stilbene. From the result of these tests, we also know
that just like the highest activities shown by flavonols
with group in the B ring with a 3′,4′,5′-substitution
(Larson et al., 1988), 3,3′,4,5,5′-pentahydroxystilbene
and 3,4,4′,5-tetrahydroxystilbene are the most active
antioxidants.
Eva lu a tion of th e In h ibitor y Effect on Lip id
Oxid a tion by th e Ra n cim a t Meth od . The Rancimat
method is a common method used to measure the
potential antioxidative abilities of synthetic and natural
antioxidants. The mechanism of this method is reported
to be based on measuring the changes of electrical
conductivity of water caused by the formation of short-
chain compounds when fats and oils are oxidized under
elevated temperature and accelerated aeration.
The effects of 2 µmol of stilbenes and BHT on the
oxidative stability of lard are shown in Table 2. The
effects in decreasing order were 3,3′,4,5′-tetrahydroxy-
stilbene > 3,3′,4,5,5′-pentahydroxystilbene > 3,4,4′,5-
tetrahydroxystilbene . 3,4′,5-trihydroxystilbene . BHT
> 3,3′,5,5′-tetrahydroxystilbene > 3,5-dihydroxystilbene.
3,3′,4,5′-Tetrahydroxystilbene, 3,3′,4,5,5′-pentahydroxy-
stilbene, and 3,4,4′,5-tetrahydroxystilbene showed higher
lipid oxidation activity. In this model, 3,3′,5,5′-tetrahy-
droxystilbene and 3,5-dihydroxystilbene showed poor
oxidation-inhibition activity, which suggests the im-
portance of the presence of either an ortho or a para
hydroxyl group in the tested compounds for their
antioxidative activity.
F igu r e 2. Structure of the oxidative dimerization product of
resveratrol.
compounds) (Chen and Ho, 1995, 1997). They all showed
excellent oxidation-inhibition activity. Specially, EGCG
and ECG showed the induction time of 55.30 and 55.30
h, respectively (Chen et al., 1995). In our test, we found
one compound (3,3′,4,5′-tetrahydroxystilbene) even bet-
ter than EGCG. It is also interesting to notice that this
compound is better than 3,3′,4,5,5′-pentahydroxystil-
bene. The present study showed that three compounds
(3,3′,4,5′-tetrahydroxystilbene, 3,3′,4,5,5′-pentahydrox-
ystilbene, and 3,4,4′,5-tetrahydroxystilbene) are more
active than resveratrol in both models; especially 3,3′,4,5′-
tetrahydroxystilbene deserves further investigation.
An a lysis of a Ra d ica l Rea ction P r od u ct. By using
chromatographic methods, one major compound was
isolated from the reaction between resveratrol and
DPPH free radicals. This compound was isolated as
white powders. The positive APCI-MS showed a molec-
ular peak at 455 [M + 1]+, suggesting that this
compound is a possible dimer of resveratrol. By compar-
1
ing the H and 13C NMR data with these known dimers
of resveratrol (Langcake and Pryce, 1977; Lins et al.,
1991; Sotheeswaran et al., 1985), the spectral data of
this compound were found to be identical with those of
a dimer formed during the oxidative dimerization of
resveratrol with horseradish peroxidase-hydrogen per-
oxide (Langcake and Pryce, 1977). The structure of this
compound is shown in Figure 2. The bioactivity and
toxicity of this compound still remain unknown. This
compound can be used to study the antioxidant mech-
anism.
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Received for review April 20, 1999. Revised manuscript
received J uly 23, 1999. Accepted J uly 26, 1999.
J F990382W