Structure-activity relationship of trans-resveratrol and its analogues

Abstract

Cancer is one of the main causes of death in both men and women, claiming over 6 million people each year worldwide. Chemoprevention in combination with anti-cancer treatment is therefore important to reduce morbidity and mortality. Stilbene-based compounds have over the years attracted attention of many researchers due to their wide ranging biological activities. One of the most relevant and extensively studied stilbenes is trans-resveratrol, a phytoalexin present in grapes and other foods. One of the most striking biological activities of trans-resveratrol soundly investigated during recent years has been its cancer-chemopreventive potential. It has been found that the biological activity of trans-resveratrol and its analogues depends significantly on the structural determinants, which are (i) number and position of hydroxyl groups, (ii) intramolecular hydrogen bonding, (iii) stereoisomery and (iv) double bond. The observation that trans-stilbene compounds having 4 -hydroxy group, double bond and bearing ortho-diphenoxyl or para-diphenoxyl functionalities possess remarkably higher chemopreventive activity than trans-resveratrol gives us useful information for further chemopreventive drug design.

Full text

Structure-activity relationship of trans-resveratrol and its analogues
*
Minireview
Z. OVESNÁ, K. HORVÁTHOVÁ-KOZICS
Laboratory of Mutagenesis and Carcinogenesis, Cancer Research Institute, e-mail: zdenka.ovesna@savba.sk, Slovak Academy of Sciences,
833 91 Bratislava, Slovak Republic
Received May 12, 2005
Cancer is one of the main causes of death in both men and women, claiming over 6 million people each year worldwide.
Chemoprevention in combination with anti-cancer treatment is therefore important to reduce morbidity and mortality.
Stilbene-based compounds have over the years attracted attention of many researchers due to their wide ranging biological
activities. One of the most relevant and extensively studied stilbenes is trans-resveratrol, a phytoalexin present in grapes and
other foods. One of the most striking biological activities of trans-resveratrol soundly investigated during recent years has
been its cancer-chemopreventive potential. It has been found that the biological activity of trans-resveratrol and its ana-
logues depends significantly on the structural determinants, which are (i) number and position of hydroxyl groups, (ii)
intramolecular hydrogen bonding, (iii) stereoisomery and (iv) double bond. The observation that trans-stilbene compounds
having 4’-hydroxy group, double bond and bearing ortho-diphenoxyl or para-diphenoxyl functionalities possess remark-
ably higher chemopreventive activity than trans-resveratrol gives us useful information for further chemopreventive drug
design.
Key words: trans-resveratrol, piceatannol, structure-activity relationship, chemopreventive activity, antioxidant activity
In recent years, the development of more effective and
safer agents has been intensively required for chemopre
-
vention of human cancer, and natural products from plants
have been expected to play an important role in creating new
and better chemopreventive agents. There is a growing inter
-
est in biological properties of natural products as the means
to identify novel small compounds that could have potential
in clinical medicine [31, 32].
trans-Resveratrol (3,4’,5-trihydroxy-trans-stilbene; t-RES)
is a polyphenolic compound accounting to the stilbene class
(Fig. 1). It has been found in high concentrations in a wide
variety of plants, including grapes, peanuts, berries, pines
and traditional oriental medicine plants [4]. Thus, relatively
high concentrations of this compound are present in grape
juice and, especially, in red wine [1, 16]. In plants t-RES is
synthesized in response to stress conditions such as trauma,
exposure to ozone and fungal infection, and thus it can be
considered to be a phytoalexin, a class of antibiotics of plant
origin [39, 40]. Other abiotic elicitors, such as ultraviolet rays
and heavy metals, can trigger t-RES production [1]. t-RES
has been reported to be a phytoestrogen due to its structural
450 NEOPLASMA, 52, 6, 2005
*
This work was supported by the grant of the Slovak Grant Agency of
SAS VEGA No. 2/4005/04 and by the National Program of Research and
Development Use of Cancer Genomics to Improve the Human Population
Health No. 2003SP51/0280800/0280801.
Compounds 3 4 5 3’ 4’ 5’
trans-resveratrol OH OH OH
piceatannol OH OH OH OH
pterostilbene OCH
3
OCH
3
OH
3’-hydroxypterostilbene OCH
3
OCH
3
OH OH
Figure 1. Chemical structures of trans-resveratrol, piceatannol, ptero
-
stilbene and 3’-hydroxypterostilbene

similarity to the estrogenic agent diethylstilbestrol [24]. In re
-
cent years, it has been shown to exhibit estrogenic activity in
mammals [3,18]. t-RES has been reported to have both
anti-carcinogenic and cardioprotective activities, which
could be attributed to its antioxidant and anti-coagulant prop
-
erties [13, 42]. Besides these effects, t-RES has been reported
to be effective in inhibiting platelet aggregation and lipid
peroxidation, altering eicosanoid synthesis, modulating lipo
-
protein metabolism [8, 23, 33], and exhibiting vasorelaxing
and anti-inflammatory activities [16, 40]. In different rodent
species as well as in humans, t-RES is well absorbed, distrib
-
uted to various organs, and metabolized to trans-res
-
veratrol-3-O-glucuronide and trans-resveratrol-3-O-sulfate
[19, 44, 47].
The anti-cancer activity of t-RES was first revealed by its
ability to reduce incidence of carcinogen-induced develop
-
ment of cancers in experimental animals [10, 22]. It has since
been demonstrated that it possesses chemopreventive and
cytostatic properties via the inhibition of tumor initiation,
promotion and progression [22]. It causes cell arrest in the S
and G
2
phases of the cell cycle [36] and is capable of inducing
differentiation and apoptosis in a multitude of tumor cell
lines, such as human leukemic, colonic, breast, prostate and
esophageal cells via CD95-dependent or independent mecha-
nisms or through activation of caspase 3 or cleavage of
poly(ADP-ribose) polymerase [9, 17, 27, 35, 38, 48]. It has
also been demonstrated that t-RES inhibits the ribonucleotide
reductase catalyzing the rate limiting step of de novo DNA
synthesis [14]. t-RES also demonstrates non-selective
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)
inhibition [28].
Structure-activity relationship of t-RES
In order to establish the influence of the spatial position of
the hydroxyl groups on the radical-scavenging effect of
t-RES,
STOJANOVIC et al [42] compared the activity of t-RES
with activities of its analogues 4-hydroxy-trans-stilbene and
3,5-dihydroxy-trans-stilbene. All three stilbenes efficiently
suppressed formation of the lipid hydroperoxides, but t-RES
and 4-hydroxy-trans-stilbene were found to be more reactive
than 3,5-dihydroxy-trans-stilbene. The fact, that t-RES and
4-hydroxy-trans-stilbene show almost the same antioxidant
effect, indicates that the radical-scavenging activity of t-RES
depends on the position of the hydroxyl groups. Therefore,
for t-RES it can be concluded that its para-hydroxyl group
dominates in the radical-scavenging efficiency whereas its
meta-hydroxyl groups show only minor reactivity. Using the
pulse radiolysis, reactions of t-RES and its analogues with
trichloromethylperoxyl radicals (CCl3OO.) were studied.
Spectral and kinetic properties of the transients showed great
similarity between t-RES and 4-hydroxy-trans-stilbene
which seems to confirm that para-hydroxyl group of t-RES
scavenges free radicals more effectively than its meta-hydro
-
xyl groups.
FANG et al [12] studied the antioxidant effect of t-RES and
its analogues, which are 4-hydroxy-trans-stilbene, 3,5-di
-
hydroxy-trans-stilbene, 4,4’-dihydroxy-trans-stilbene, 3,4-di
-
hydroxy-trans-stilbene, 3,4,5-trihydroxy-trans-stilbene and
3,4,4’-trihydroxy-trans-stilbene, against the peroxidation of
linoleic acid in sodium dodecyl sulfate and cetyltrimethyl
ammonium bromide micelles. They found that the antioxi
-
dant activity of t-RES analogues depends significantly on the
position of the hydroxyl groups. Molecules with ortho-di
-
hydroxyl and/or para-hydroxyl functionalities possessed
highest antioxidative activity. This can be understood be
-
cause the ortho-hydroxyl phenoxyl radical, the oxidation in
-
termediate for more active species (3,4-dihydroxy-trans-stil
-
bene, 3,4,5-trihydroxy-trans-stilbene and 3,4,4’-trihydroxy-
trans-stilbene), is more stable due to the intramolecular hy
-
drogen bonding interaction, as evidenced from both experi
-
ments [15] and theoretical calculations [46]. In addition, it
should be easier to further oxidize the ortho-hydroxyl
phenoxyl radical and/or ortho-semiquinone radical anion to
form the final ortho-quinone. The 4’-hydroxy group also en
-
hanced the activity, since the 4’-hydroxy group can stabilize
the semiquinone radical-anion intermediate by resonance
through the trans double bond. Therefore, the antioxidative
activity of 3,4,4’-trihydroxy-trans-stilbene is so high [12].
Later,
CAI et al [5] studied the same structure/activity rela-
tionship in biological systems. They investigated the
antioxidative effect of t-RES and related trans-stilbene ana-
logues, that were 3,4-dihydroxy-trans-stilbene, 4,4’-di-
hydroxy-trans-stilbene, 4-hydroxy-trans-stilbene, and 3,5-di-
hydroxy-trans-stilbene, on free radical-induced peroxidation
of rat liver microsomes. They found, that t-RES and its ana-
logues, especially 3,4-dihydroxy-trans-stilbene, are good an-
tioxidants for both peroxyl radical- and hydroxyl radical-ini
-
tiated peroxidation of rat liver microsomes. The antioxidant
mechanism may involve trapping the initiating peroxyl radi
-
cals and/or hydroxyl radicals and reducing α-tocopheroxyl
radical (TO°) to regenerate the endogenous α-tocopherol.
STIVALA et al [41] have investigated whether antioxidant
and anti-proliferative activities of t-RES are dependent on (i)
the stereoisomery, (ii) the position of the different phenolic
hydroxyl groups, and (iii) the stilbenic double bond of the
molecule. For this purpose, the cis-form was obtained by UV
irradiation of t-RES; three different derivatives were synthe
-
sized in which the hydroxylic functions were selectively pro
-
tected by methyl groups: 3,5-dihydroxy-4’-methoxy-trans-
stilbene, 3,5-dimethoxy-4’-hydroxy-trans-stilbene, and
3,4’,5-trimethoxy-trans-stilbene; and the α,β-dihydro
-
xo-3,4’,5-trihydroxystilbene was obtained by reduction of
the stilbenic double bond. The antioxidant activity of these
compounds was evaluated by measuring the inhibition of cit
-
ronellal thermo-oxidation, or the reduction of 2,2-diphen
-
yl-1-picrylhydrazyl radical. In addition, the protection
against lipid peroxidation was determined in rat microsomes,
and in human primary cell cultures. The anti-proliferative ac
-
tivity was evaluated by a clonogenic assay, and by analysis of
TRANS-RESVERATROL AND ITS ANALOGUES 451

cell cycle progression and DNA synthesis. The results
showed that (i) 4’-hydroxy group in trans-conformation
(hydroxystyryl moiety) is not the sole determinant for antiox
-
idant properties, while it is absolutely required for
anti-proliferative activity. (ii) There is a direct correlation,
from a structural point of view, between the anti-proliferative
effect and the ability to inhibit DNA pol α and β. Thus, a
mechanism underlying the inhibition of cell cycle progres
-
sion is the interaction between the 4’-hydroxystyryl moiety
of t-RES and DNA polymerases.
MATSUOKA et al [25] reported that t-RES is negative in the
bacterial reverse mutation assay but in high concentrations
induces micronuclei and sister chromatid exchanges in vitro
(10–87 µmol/l; 48 h treatment). Later, they synthesized six
analogues of t-RES differing in number and position of
hydroxyl groups, and they investigated structure-activity re
-
lationship in chromosomal aberration, micronucleus and sis
-
ter chromatid exchange tests in a Chinese hamster cell line.
Of the six t-RES analogues, only 3,4’-dihydroxy-trans-stil
-
bene and 4-hydroxy-trans-stilbene were clearly positive in a
concentration-dependent manner in all the cytogenetic stud
-
ies performed. Both were equal to, or stronger than t-RES in
genotoxicity. The 4’-hydroxy-trans-stilbene had the simplest
chemical structure and was the most genotoxic. The other an-
alogues did not have a 4’-hydroxy group. Their results sug-
gest, that the 4’-hydroxy group is essential to the geno-
toxicity of stilbenes [26].
OHGUCHI et al [30] studied the inhibitory effect on
tyrosinase activity of stilbene derivatives, which are t-RES
oligomers ranging from monomer to tetramer (t-RES,
dihydroresveratrol, (-)-ε-viniferin, (+)-α-viniferin, vatica-
nol, (-)-hopeaphenol), isolated from Dipterocarcaceae
plants. The structure-activity relationship obtained in this
study suggest that the double bond in the parent stilbene skel
-
eton is necessary for the tyrosinase inhibitory activity, and
also that the whole molecular size is important for the inhibi
-
tion. The inhibitory potency of the t-RES oligomers was
strongly reduced by increasing polymerization.
From the experimental crystal structure and ab initio cal
-
culations on t-RES and its derivatives, structural features of
mechanistic importance were described. The molecular
structure reveals relative coplanarity of the trans-stilbene
skeleton, and the molecular packing in the solid state showed
an extensive hydrogen bond network that elucidates the
flip-flop motion of the three hydroxyl groups that alternately
form break hydrogen bonds with each of the neighboring
phenolic oxygens. The dynamic behavior provoked by the al
-
ternation of hydrogen bond formation and breaking can re
-
sult in the ready mobility of up to three hydrogen atoms per
t-RES molecule that can be transferred to reactive oxidants
that are rich in electron density. In addition, theoretical stud
-
ies confirm the planarity of t-RES as well as for half of the
molecule of a condensation dimeric derivative of t-RES,
trans-σ-viniferin. Furthermore, these studies show the
para-4’-hydroxy group to be more acidic compared to the
other two meta-hydroxyl groups. These features correlate
with the biological activity of t-RES as an antioxidant and
support earlier studies showing hydrogen atom transfer to be
the dominant mechanism by which phenolic antioxidants in
-
tercept free radicals [7].
Higher hydroxylated analogues of t-RES
In contrast to the detailed knowledge of t-RES activities in
biological systems much less is known about the effects of
higher hydroxylated stilbens. t-RES undergoes cytochrome
P450 catalyzed hydroxylation to piceatannol (3,3’,4’,5-tetra
-
hydroxy-trans-stilbene; PCA; Fig. 1) and to two other un
-
identified mono- and dihydroxy-t-RES analogues. It demon
-
strates that a natural dietary cancer preventative agent can be
converted to a compound with known chemopreventive and
anticancer activity by an enzyme CYP1B1, which is
overexpressed in a wide variety of human tumors. Impor
-
tantly, this result gives insight into the functional role of the
cytochrome P450 enzyme CYP1B1 and provides evidence
for the concept that CYP1B1 in tumors may be functioning as
a growth suppressor enzyme [34]. As t-RES, PCA displays
cytotoxic activity in acute leukemia and lymphoma cells and
anti-proliferative activity in colorectal cancer cell lines [45].
PCA differs from t-RES by possessing an additional
hydroxyl group and it is more water-soluble than t-RES. PCA
has been isolated together with t-RES from grapes and wine.
Stilbene synthesis in grapes depends on different viticultural
factors such as the grape variety, the environment and cul-
tural practices. Concerning the grape variety, red
berry-grapes have higher stilbene levels than white
berry-grapes. With regard to climate, preliminary results sug-
gest a positive correlation between vineyard elevation and
stilbene grape concentrations. Quality-oriented cultural prac
-
tices produce grapes with high levels of stilbenes [1]. Besides
stilbenes, wine contains other polyphenolic compounds
(flavonoids: flavonols, catechins, anthocyanins). All of these
compounds exhibit interesting properties which may account
in part for the so-called “French paradox,” i.e. the fact that the
incidence of heart infarction in Southern France is 40% lower
than in the rest of Europe despite the population’s high-fat
diet [13].
CAI et al [6] compared the inhibiting activities of t-RES and
seven other hydroxylated trans-stilbenes with respect to an
azo compound-induced peroxidation of linolic acid in vitro
and to induced apoptosis in cultured HL-60 and Jurkat hu
-
man leukemia cells. They found that both antioxidant and
apoptotic activities of the analogues containing 3,4-dihydro
-
xyl groups namely 3,4-dihydroxy-trans-stilbene, 3,4,4’-tri
-
hydroxy-trans-stilbene and 3,4,5-trihydroxy-trans-stilbene
were significantly higher than those of t-RES and the other
analogues. These data were supported by other investigators
who also found free radical scavenging activity that was
several times better, along with a higher growth-inhibitory
activity of PCA and 3,4,4’,5-tetrahydroxy-trans-stilbene
452 OVESNÁ, HORVÁTHOVÁ-KOZICS

compared to t-RES in tumor cells [20]. t-RES and its hydro
-
xylated derivatives may be oxidized in an enzymatic or
non-enzymatic manner via the one-electron pathway to a
phenoxyl radical (ArO°) and subsequently yiels quinone or
quinone-methine type prooxidant or alkylating products.
Several studies showed that the quinone products from oxi
-
dation of catecholic estrogen [2] and dopamine [11] are in
-
deed responsible for the observed apoptotic effects of these
drugs on cells.
HUNG et al [21] compared antioxidative and free radical
scavenging activities of t-RES and its analogues to their pro
-
tective effects on ischaemia-reperfusion induced injuries of
rat hearts. t-RES and PCA have been shown to be more po
-
tent inhibitors than other analogues against Cu
2+
-induced ox
-
idation of low-density lipoprotein (LDL). PCA was 2 to 25.5
fold more potent than t-RES in thiobarbituric acid-reactive
substance and 1,1-diphenyl-2-picryl-hydrazyl (DPPH) as
-
says. However, PCA was about 160 fold more potent than
t-RES in superoxide anion scavenging. Their results showed
the possible structural criteria important for the antioxidant
activities of these polyphenolic compounds. Deletion of the
hydroxyl group at the B-4 of t-RES reduces its antioxidant
activity. In contrast, the presence of ortho-dihydroxy struc-
ture in ring B (PCA) enhanced its activity to inhibit LDL
peroxidation and free radical trapping, especially superoxide
anion. Their results showed a positive correlation between
the antioxidation and cardioprotective activities among these
phenolic compounds. The effects of PCA on LDL oxidation
and DPPH scavenging observed here is consistent with the
report by
FAUCONNEAU et al [13].
MURIAS et al [29] studied structure-activity relationship
between pro-/antioxidant properties of t-RES, PCA and five
synthesized polyhydroxylated t-RES analogues. Radical
scavenging experiments with O
2
°- (5,5-dimethyl-1-pyrro
-
line-N-oxide/electron spin resonance) and 2,2-diphen
-
yl-1-picrylhydrazyl (DPPH°) revealed that 3,3’,4’,5-tetra
-
hydroxy-trans-stilbene, PCA and 3,3’,4,4’,5,5’-hexa-
hydroxy-trans-stilbene exerted a more than 6600-fold higher
anti-radical activity than t-RES and its two other analogues.
Furthermore, in HL-60 leukemic cells hydroxystilbens with
ortho-hydroxyl groups exhibited a more than three-fold
higher cytostatic activity compared to hydroxystilbenes with
other substitution patterns. Oxidation of ortho-hydroxy
-
stilbenes in a microsomal model system resulted in the exis
-
tence of ortho-semiquinones, which were observed by ESR
spectroscopy. Further experiments revealed that these inter
-
mediates undergo redox-cycling thereby consuming addi
-
tional oxygen and forming cytotoxic oxygen radicals. In con
-
trast to compounds with other substitution patterns
hydroxystilbenes with one or two resorcinol groups did not
show an additional oxygen consumption or semiquinone for
-
mation. Their findings suggest that the increased cytotoxicity
of ortho-hydroxystilbenes is related to the presence of
ortho-semiquinones formed during metabolism or auto
-
oxidation.
Methoxylated derivatives of t-RES
ROBERTI et al [37] have synthesized and tested a library of
compounds based on t-RES and have demonstrated the im
-
portance of a 3,5-dimethoxy motif in conferring
pro-apoptotic activity to stilbene based compounds. Later,
TOLOMEO et al [43] evaluated the ability of pterostilbene and
3’-hydroxypterostilbene (Fig. 1), natural 3,5-dimethoxy
analogs of t-RES and PCA, in inducing apoptosis in sensitive
and resistant leukemia cells. When tested in sensitive cells,
human myeloid leukemia cell line HL-60 and human T lym
-
phoma cell line HUT78, 3’-hydroxypterostilbene (3,5-di
-
methoxy analogue of PCA) was 50-97 times more potent
than t-RES in inducing apoptosis, while pterostilbene ap
-
peared barely active. However, both compounds, but not
t-RES and PCA, were able to induce apoptosis in the
Fas-ligand resistant lymphoma cell lines, HUT78B1 and
HUT78B3, and the multi drug-resistant leukemia cell lines
HL-60-R and K562-ADR (a Bcr-Abl-expressing cell line re
-
sistant to imatinib mesylate). Moreover, pterostilbene and
3’-hydroxypterostilbene, when used at concentrations that
elicit significant apoptotic effects in tumor cell lines, did not
show any cytotoxicity in normal hemopoietic stem cells.
In order to find more selective COX-2 inhibitors a series of
methoxylated and hydroxylated t-RES derivatives were syn-
thesized and evaluated for their ability to inhibit both en-
zymes using in vitro inhibition assays for COX-1 and COX-2
by measuring prostaglandin E
2
production. Hydroxylated but
not methoxylated t-RES derivatives showed a high rate of in-
hibition. The most potent t-RES compounds were PCA and
3,3’,4,4’,5,5’-hexahydroxy-trans-stilbene. Their selectivity
index was in part higher than celecoxib, a selective COX-2
inhibitor already established on the market. Effect of struc
-
tural parameters on COX-2 inhibition was evaluated by
quantitative structure-activity relationship (QSAR) analysis
and a high correlation was found with the topological surface
area TPSA. Docking studies on both COX-1 and COX-2 pro
-
tein structures also revealed that hydroxylated but not
methoxylated t-RES analogues are able to bind to the binding
sites of the enzymes [28].
Conclusion
It has been found that the biological activity of t-RES and
its analogues depends significantly on the structural determi
-
nants, which are (i) number and position of hydroxyl groups,
(ii) intramolecular hydrogen bonding, (iii) stereoisomery and
(iv) double bond. The observation that trans-stilbene com
-
pounds having 4’-hydroxy group, double bond and bearing
ortho-diphenoxyl or para-diphenoxyl functionalities possess
remarkably higher chemopreventive activity than t-RES
gives us useful information for further anti-cancer drug de
-
sign.
TRANS-RESVERATROL AND ITS ANALOGUES 453

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TRANS-RESVERATROL AND ITS ANALOGUES 455