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Current Medicinal Chemistry, 2013, 20, 1005-1017 1005

From Resveratrol to Its Derivatives: New Sources of Natural Antioxidant

Shan He*,1 and Xiaojun Yan*,2

1School of Marine Sciences, Ningbo University, Ningbo 315211, China; 2Key Laboratory of Applied Marine Biotechnology (Ningbo University), Ministry of Education, Ningbo 315211, China Abstract: Resveratrol, a star natural product from red wine, has attracted increasing attention around the world. In recent years, resveratrol derivatives (including its oligomers) have shown amazing chemical diversity and biological activities. They have been emerging to be promising new sources of natural antioxidant. This review summarizes recent finding on antioxidant activities of resveratrol derivatives and the structure-activity relationship for the first time. Scientific evidences have highlighted their potential as therapeutic agents for cerebral and cardiovascular diseases. In our opinion, more effort should be devoted to the synthesis of resveratrol oligomers. Based on the structure-activity relationship, screening for resveratrol derivatives with higher antioxidant activity than trans-resveratrol is war- ranted, and these molecules may have greater therapeutic potential in future investigations. Keywords: Antioxidant, Biological Activity, Chemical Diversity, Derivative, Resveratrol, Structure-Activity Relationship

1. INTRODUCTION Loes. fil.) in 1940 [8]. Now most of the commercial resveratrol Reactive oxygen species (ROS), including superoxide anion products are isolated and purified from a traditional Chinese and Japanese medicine, the roots of Polygonum cuspidatum [9]. Initially (O2 ), hydroxyl radical ( OH), peroxyl radicals (ROO ), and sin- 1 characterized as a phytoalexin of grapevines (Vitis vinifera) [10], glet oxygen ( O2), are highly reactive molecules generated during cellular respiration and normal metabolism, which play a dual role resveratrol attracted little interest until 1992, when it was linked to as both deleterious and beneficial species [1]. Beneficial effects of the low incidence of heart diseases in some regions of France–the ROS occur at low/moderate concentrations and involve physiologi- so-called “French paradox”, that is, despite a high fat intake, mor- cal roles in cellular responses to noxia, in the function of a number tality from coronary heart disease is lower due to the regular con- of cellular signaling pathways, and the induction of a mitogenic sumption of red wine [11]. In 1997, a seminal paper reporting the response [2]. However, overproduction of ROS results in oxidative cancer chemopreventive activity of resveratrol [12] has triggered stress (OS), a state of imbalance between ROS production, and the considerable attention on this natural polyphenol. The past 15 years ability of cell’s endogenous antioxidants to defend against them, have witnessed intense research devoted to the biological activities, leading to progressive oxidative damage to cell structures, including especially the antioxidant activity, of this star natural product [13], lipids and membranes, proteins, and nucleic acids [3]. Therefore, which has become a dietary supplement and a candidate for drug ROS have been implicated as being important causative agents of development, and its biological activities have been extensively aging and various human diseases, such as stroke, cancer, heart reviewed [14]. Its potent antioxidant activity is empowered by its diseases, multiple sclerosis, Parkinson's disease, and autoimmune unique structure. It has recently become clear that the three phenol disease [4]. For example, in the past 20 years, the study of ROS groups with remarkable H-transfer capacity [15] and the tran- dependent damage to DNA has become a major thrust of carcino- sisomery of the double bond [16] are responsible for its antioxidant genesis research. ROS are able to attack the bases or the deoxyribo- activity (Fig. (2)). syl backbone of DNA, or attack other cellular components such as Since ROS play an important role in carcinogenesis, antioxi- lipids to generate reactive intermediates that couple to DNA bases. dant activities of 700 plant extracts were assessed by J. M. Pez- The resulted endogenous DNA lesions are genotoxic and induce zuto's Lab in 1990s, to discover and characterize natural antioxi- mutations that can contribute to the development of cancer [5]. dants with cancer chemopreventive activity. Bio-assay guided isola- In the normal physiological state, ROS are regulated by cellular tion of the 28 plant extracts found active in the primary screening endogenous antioxidants both enzymatically and non- resulted in the characterization of many potent antioxidants. Among enzymatically, which constitute a complex and efficient antioxida- them, resveratrol and its derivative piceatannol showed the highest tive defense system. Enzymatic antioxidants include superoxide cancer chemopreventive activities determined by a 7,12- dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), dimethylbenz[a]anthrancene (DMBA)-induced preneoplastic lesion while non-enzymatic antioxidants are represented by glutathione formation in mammary gland organ culture model [17]. This report (GSH), ascorbic acid (Vitamin C), -tocopherol (Vitamin E), caro- indicated that resveratrol derivatives may offer comparable or even tenoids, flavonoids, and other antioxidants. Under normal condi- stronger biological activities. Other investigation also demonstrated tions, there is a balance between ROS and the intracellular levels of that some derivatives exhibited higher antioxidant activities than these antioxidants, which is essential for the survival of living or- resveratrol [18]. In recent years, research interests are shifting from ganisms and their health [6]. However, under OS the impaired anti- resveratrol to its derivatives (including its oligomers), which are oxidative defense system is unable to control the level of ROS, and emerging to be promising new sources of natural antioxidant. This demand exogenous supplement of antioxidant to scavenge exces- review summarizes findings in the past 15 years, which docu- sive ROS to restore the original state of cellular “redox homeosta- mented the discovery of resveratrol derivatives as new antioxidants sis” [7]. Therefore, antioxidants that effectively scavenge these and their therapeutic applications, with special attention to the ROS are potential preventive or therapeutic agents against ROS- structure-activity relationship (SAR). mediated diseases. 2. CHEMICAL DIVERSITY Resveratrol (3,5,4’-trihydroxystilbene; Fig. (1)) was first iso- Resveratrol and its derivatives belong to a group of plant poly- lated from the roots of white hellebore (Veratrum grandiflorum phenolic compounds “stilbene”, which are distributed in particular families of plants including Vitaceae, Dipterocarpaceae, Gnetaceae, *Address correspondence to these authors at the 818 Fenghua Road, Ningbo Univer- Cyperaceae, and Leguminosae [19]. The stilbene nucleus is based sity, Caoguangbiao Sci&Tech Hall, Ningbo 315211, China; Tel: +86 574 87600458; on a 14-carbon skeleton composed of two phenyl rings linked by an Fax: +86 574 87600570; E-mail: [email protected] and Ningbo University, Post Box ethylene bridge. Stilbenes are derived from the general phenylpro- 71, Ningbo 315211, China; Tel: +86 574 87600738; Fax: +86 574 87600590; E-mail: [email protected] panoid pathway, starting from phenylalanine. The biosynthesis of

1006 Current Medicinal Chemistry, 2013, Vol. 20, No. 8 He and Yan

R1 R2 R3 R4 R5 1 resveratrol H H OH H OH 2 isorhapontigenin H OMe OH H OH HO 3 oxyresveratrol OH H OH H OH 1 2 R R 4 piceatanol H OH OH H OH B 5 rhapontigenin H OH OMe H OH A R3 6 gnetol OH H H OH OH 7 R5 piceid H H OH H OGlu 8 4 pinosylvin H H H H OH R 9 astringin H OH OH H OGlu 10 rhapontin H OH OMe H OGlu

Fig. (1). Chemical structures of resveratrol and its natural monomeric derivatives.

resveratrol in plant is catalyzed by stilbene synthase via a single from 2 to 8. Representative structures of oligomers with differ- reaction. Stilbene synthase uses three malonyl-CoA and one p- ent DPs are shown in Fig. (5). Dimers, trimers and tetramers coumaroyl-CoA as substrates and synthesize a linear tetraketide constitute the major members of resveratrol oligomers. Highly intermediate, which is then cyclized via an aldol condensation, condensed stilbene oligomer (HCSO), which was composed of followed by an additional decarboxylation to afford resveratrol more than five stilbene monomers, is rare. Hitherto, there have (Fig. (3)) [20]. Then further modifications, including glycosylation only been six HCSOs discovered from the plant kingdom, [21], methylation [22], oligomerization [23], isomerization [24], namely vaticanol D [27], vaticanols H-J [28], vateriaphenol A and isoprenylation [25], generate various resveratrol derivatives [29], and chunganenol [30]. All of them are resveratrol oli- with intriguing chemical diversity (Fig. (4)). gomers from Dipterocarpaceous plants, with exception of chunganenol (Fig. (5)), which was the first resveratrol hexamer from HO Vitaceae family [30]. Vateriaphenol A (Fig. (5)), a resveratrol B octamer from Vateria indica has the highest DP ever reported. A C (2) Variety of skeleton. Resveratrol oligomers are produced by OH oxidative coupling between resveratrol monomers via different HO patterns, thus generating distinct skeletons. Ten patterns have been reported when two monomeric units linked by only one Fig. (2). The meta-hydroxyl groups (A), the para-hydroxyl group (C) and C–C or C–O–C bond (with two linkage points). Another ten transisomery of the double bond (B) are essential for the potent antioxidant patterns have been found, when two monomeric units linked by activities of resveratrol against different ROS. two C–C or C–O–C bonds (with four linkage points), com- monly forming a ring. Seven patterns have been observed, There have been several reviews concerning the chemical di- when two monomeric units linked by three C–C or C–O–C versity of natural stilbenes [26]. From 1995 to 2008, about 400 new bonds (with six linkage points), usually forming two rings. And naturally occurring stilbenes have been isolated and characterized there are only two patterns discovered, when two monomeric [26d]. To the best of our knowledge, there are at least 500 natural units linked by four C–C or C–O–C bonds (with eight linkage stilbenes reported, most of which are resveratrol oligomers. The points) [26d]. In sum, there are at least 29 different patterns, chemical diversity of resveratrol oligomers mainly lies in the fol- leading to the formation of dozens of skeletons. Some examples lowing aspects: with different linkage points are shown in Fig. (6). Readers are encouraged to consult the recent review by Dr. H. X. Lou’s lab (1) Degree of polymerization (DP). DP is the number of units of for further details [26d]. It is worth noting that chunganenol, resveratrol monomers forming an oligomer, which could range

PAL C4H 4CL OH OH HO OH HO S-CoA

H2N O O O O phenylalanine cinnamic acid p-coumaric acid p-coumaroyl-CoA

STS 3 malonyl-CoA

HO OH STS

OH aldol condensation CoA-S HO trans-resveratrol O O O O tetraketide intermediate

Fig. (3). Biosynthesis of resveratrol. PAL, phenylalanine ammonia lyase; C4H, cinnamate 4-hydroxylase; 4CL, hydroxycinnamoyl CoA ligases; STS, stilbene synthase. 中国科技论文在线 http://www.paper.edu.cn

From Resveratrol to Its Derivatives Current Medicinal Chemistry, 2013, Vol. 20, No. 8 1007

HO MeO

OH OH GluO MeO trans-piceid pterostilbene

glycosylation methylation

HO HO HO isomerization OH OH HO trans-resveratrol cis-resveratrol

oligomerization isoprenylation

HO HO O OH

HO OH HO arachidin-3 OH

OH trans--viniferin

Fig. (4). Common modifications of resveratrol.

which was discovered in our lab, features a unique skeleton developed to generate chemical diversity synthetically (for review, interunit lingkage where two stilbene units are connected by a see [33]). Even though considerable achievement has been made in methylene bridge (Fig. (5)) [30]. recent years [34], the synthesis of resveratrol oligomers remains a (3) Complex stereochemistry. The planar structures of monomeric great challenge due to their chemical complexity as discussed resveratrol derivatives do not possess any chiral carbon. When above. Advance in organic chemistry to provide a general and facile two monomeric units couple to form an oligomer, opening of approach is still highly needed at the following points: (1) Enanti- the ethylene bridge could generate asymmetry. For example, oselective or diastereoselective oligomerization. (2) Regioselective catalyzed by horseradish peroxidase (HRP), dimerization of coupling at specific location. (3) Regioselectivity in forming spe- resveratrol yields the racemic mixture of resveratrol-trans- cific coupling pattern. dehydrodimer (Fig. (7)) [31]. As the largest resveratrol oli- 3. ANTIOXIDANT ACTIVITY gomeric molecule, the octamer vateriaphenol A have 16 chiral carbons. In most cases, hydrogens from the same ethylene 3.1. DPPH (1,1-Diphenyl-2-Picrylhydrazyl) Radical bridge located as trans configuration in oligomers. All the natu- DPPH is a stable free radical, which has been widely used for ral resveratrol oligomers with chiral centers are optically active, the evaluation of antioxidant activities of natural products in the indicating that biosyntheses of them in plants are enantioselec- micromolar range [35]. The DPPH assay is simple and rapid, thus tive (formation of dimer) or diastereoselective. Some of these highly suitable for in vitro screening for antioxidants [36]. Resvera- selectivities are family specific. For instance, (+)- -viniferin trol and its derivatives with DPPH scavenging activities are summa- (Fig. (4)), a resveratrol dimer, and (+)-hopeaphenol, a resvera- rized in (Table 1). Apparently, resveratrol is not the best DPPH trol tetramer, are isolated from Vitaceaeous plants, however scavenger. Many derivatives showed comparable or stronger DPPH their enantiomers are from other families such as Dipterocar- scavenging activities than resveratrol. They are astringin, as- paceae and Gnetaceae. Based on the biomimetic transformation tringinin, piceatannol, scirpusin A, quadrangularin A, parthenocis- from (+)- -viniferin to many other oligomers, Takaya et al. fur- sin A, laetevirenol A, laetevirenol B, chunganenol, -viniferin, and ther proposed that the stereochemistry of resveratrol oligomers vitisin A. Among them, laetevirenol A, laetevirenol B, and chun- from Vitaceaeous plants may be originated from the stereo- ganenol with novel structures were discovered in our lab [37]. chemistry of (+)- -viniferin [32]. There seems to be a relationship between DP and DPPH scavenging The amazing chemical diversity of resveratrol derivatives activity, and the average activities of different DPs follow the order: shows again the great imagination of nature. Synthesis of mono- monomer dimer > tetramer > trimer [38]. It is also observed that meric resveratrol derivatives has been a hot topic in both organic the antioxidant activity of the same compound could vary signifi- and medicinal chemistry. A number of catalytic methods have been cantly under different assay conditions. Normally, lower DPPH 中国科技论文在线 http://www.paper.edu.cn

1008 Current Medicinal Chemistry, 2013, Vol. 20, No. 8 He and Yan

HO HO HO OH OH HO OH HO OH

H O O O OH OH HO HO OH

HO OH OH OH HO HO OH

Parthenocissin A OH (Dimer) O

OH OH Parthenocissin B Kobophenol A (Trimer) (Tetramer)

HO HO HO OH HO OH OH HO H OH OH HO H O HO

OH O HO OH OH OH H HO HO O HO O OH HO

HO HO O O OH OH

Amurensin E Chunganenol OH (Pentamer) (Hexamer)

HO HO HO OH OH HO HO HO H O HO H OH HO O O H H H HO HO HO OH OH OH HO OH HO HO OH OH H H O H OH HO HO HO H O H HO HO HO OH HO HO OH O HO OH OH

Vaticanol J Vateriaphenol A OH (Heptamer) (Octamer) Fig. (5). Chemical structures of typical resveratrol oligomers with different DPs. 中国科技论文在线 http://www.paper.edu.cn

From Resveratrol to Its Derivatives Current Medicinal Chemistry, 2013, Vol. 20, No. 8 1009

OH MeO H OH HO OH OH HO H OH HO O HO H OH H OH H HO OH HO H OH OH O HO OH H OH OH HO OH OH Amurensin A Parthenostilbenin A Pallidol Betulifol A (Two linkage points) (Four linkage points) (Six linkage points) (Eight linkage points) Fig. (6). Chemical structures of representative resveratrol oligomers with different linkage points.

HO HO

HO O O horseradish peroxidase

HO + HO OH H2O2 OH OH HO OH OH OH OH Fig. (7). Dimerization of resveratrol to give resveratrol-trans-dehydrodimer.

concentration, longer reaction time and higher temperature would amer [27]. In 2002, trans--viniferin, the major dimer of resvera- decrease IC50 value. We strongly recommend that future investiga- trol, isolated from Vitis vinifera (grape), exhibited stronger superox- tion of resveratrol derivatives should include trans-resveratrol as ide anion scavenging activity than resveratrol and some of its positive control, so that data from different reports could be com- monomeric derivatives [47]. In 2003, resveratrol along with ten pared. derivatives were isolated from Gnetum gnemon. Most of them showed potent scavenging activities toward O2 [48]. Two years 3. 2. Hydroxyl Radical later, Kim et al. reported superoxide anion scavenging activity of twelve stilbenes from Parthenocissus tricuspidata, where piceatan- The hydroxyl radical has a high reactivity, making it a very nol exerted the best activity among the isolates [40]. The scaveng- 9 dangerous radical with a very short half-life of approximately 10 s ing activities of resveratrol and its derivatives against O2 are in vivo [43]. Resveratrol has been reported to scavenge hydroxyl listed in (Table 2). It is worth noting that superoxide anion scaveng- radical as determined by electron paramagnetic resonance (EPR) ing effect can differ with the test used, and there are more determin- spin-trapping technique [13d], which is the most accurate and reli- ing factors in the assay condition and measurement than the DPPH able method for measuring scavenging effect against ROS. Leonard assay. 2+ 3+ et al. used the Fenton reaction (Fe H2O2Fe OHOH ) as a source of hydroxyl radical, which was trapped by DMPO to 3.4. Peroxyl Radicals generate DMPO-OH adducts, a much more stable free radical de- tectable by EPR. Resveratrol was found to scavenge hydroxyl radi- Another ROS derived from oxygen is peroxyl radicals(ROO). cal in a dose dependant manner with reaction rate constant calcu- They can initiate fatty acid peroxidation, which is detrimental to lated as 9.45108 M-1s-1 [13d]. However, as we look into the data cell structure and function [49]. Therefore, it is very important to presented in Ref 13d, addition of 1.3 mM resveratrol only caused evaluate an antioxidant’s capacity to inhibit lipid peroxidation [50]. 40% inhibition of hydroxyl radical signals in EPR spectrum. This Antioxidant activities of resveratrol and its monomeric derivatives result has been confirmed in our recent investigation [44]. We have have been assessed by their capacity to prevent Fe2+-induced lipid screened many resveratrol derivatives for hydroxyl radical scaven- peroxidation in microsomes or Cu2+-induced lipid peroxidation in ger by EPR spin-trapping technique, however, none of them low-density lipoproteins (LDL). Astringin and astringinin (also showed potent scavenging effect (unpublished data). known as “piceatannol”) showed similar or even stronger effect than resveratrol in both assay system [18b]. This result has been 3.3. Superoxide Anion Radical confirmed in another investigation where twelve stilbenes were evaluated for their lipid peroxidation inhibitory activity in rat liver Molecular oxygen has a unique electronic configuration and is homogenates [40]. 4,4'-Dihydroxystilbene has been reported to itself a radical. The addition of one electron to molecular oxygen exert 81.5% inhibition in a -carotene bleaching assay, which was forms the superoxide anion radical (O2 ) [1a]. Although it is less comparable to that of -tocopherol (Vitamin E) tested in the same reactive than hydroxyl radical, O2 is considered the “primary” conditions [47]. Eight stilbenes derivatives from Gnetum gnemon ROS, and can further interact with other molecules to generate showed better lipid peroxide inhibition than that of resveratrol [48]. much more toxic “secondary” ROS, such as H2O2, OH, and ROO In our previous report, the antioxidant activities of quadrangularin [45]. It has been implicated in the pathology of various diseases A and parthenocissin A, two isomeric resveratrol dimers, were [46]. O2 is usually generated using a xanthine/xanthine oxidase markedly stronger than that of vitamin C, as determined by - system and measured spectrophotometrically or using ESR spin- carotene bleaching assay [51]. In addition, there are a handful syn- trapping technique. Leonard et al. have reported the superoxide thetic resveratrol monomeric derivatives are effective antioxidants anion scavenging effect of resveratrol in a dose dependant manner against lipid peroxidation. These results are discussed in the latter [13d]. In 2000, vaticanol D, a novel resveratrol hexamer isolated “structure-activity relationship” section. (Table 3) summarizes in- from Vatica rassak, showed a scavenging activity of super oxide at hibitory effects of naturally occurring resveratrol derivatives toward IC50 = 7.4 M. It was also the first occurrence of resveratrol hex- lipid peroxidantion. 中国科技论文在线 http://www.paper.edu.cn

1010 Current Medicinal Chemistry, 2013, Vol. 20, No. 8 He and Yan

Table 1. DPPH Scavenging Activities of Resveratrol and Its Derivatives.

Compounds DPs Assay Condition IC50 Refs.

trans-Resveratrol 1 74.0 M cis-Resveratrol 1 97.0 M 100 M DPPH trans-Piceid 1 200 M Reaction time = 10 min [16b] cis-Piceid 1 Trolox IC50 = 10.1 M 140 M Astringin 1 30.6 M Astringinin 1 29.0 M 94.6 g/ml trans-Resveratrol 1 300 M DPPH Piceatannol 1 Reaction time = 10 min 68.4 g/ml [15] Temperature = 37 oC Scirpusin A 2 78.0 g/ml ,-Dihydrorhaponticin 1 40 g/ml DPPH 8.98 g/ml Reaction time = 30 min o [37] 6’’-O-(7,8-Dihydrocaffeoyl)- ,-dihydrorhaponticin 1 Temperature = 25 C 9.04 g/ml Ascorbic acid IC50 = 2.29 g/ml Resveratrol 1 12.9 g/ml Piceatannol 1 7.42 g/ml 100 M DPPH Pallidol 2 Reaction time = 30 min 36.1 g/ml o [38] Parthenocissin A 2 Temperature = 37 C 43.9 g/ml Quercetin IC50 = 3.37 g/ml Piceid 1 44.2 g/ml Cyphostemmin B 2 34.9 g/ml Resveratrol 1 71.9 M Quadrangularin A 2 66.9 M Parthenocissin A 2 57.9 M Laetevirenol A 2 150 M DPPH 38.4 M Reaction time = 30 min Laetevirenol B 3 37.3 M [35a] Temperature = 37 oC Laetevirenol C 3 Vitamin E IC50 = 28.3 M 110.8 M Laetevirenol D 3 128.0 M Laetevirenol E 3 158.2 M Parthenocissin B 3 172.7 M Chunganenol 6 37.3 M Amurensin B 3 188 M [35b] Gnetin H 3 251 M 150 M DPPH -Viniferin 2 Reaction time = 30 min 62.2 M o Amurensin G 3 Temperature = 37 C 138 M Vitamin E IC50 = 33.6 M Vitisin A 4 42.4 M [39] Hopeaphenol 4 115 M Resveratrol 1 73.2 M Wilsonol A 3 103.5 M Wilsonol B 3 195.4 M Wilsonol C 4 182.2 M Diviniferin B 4 175.3 M Resveratrol 1 75.2 M Pallidol 2 146.8 M 150 M DPPH -Viniferin 2 Reaction time = 30 min 127.3 M o [40] Ampelopsin B 2 Temperature = 37 C 194.7 M Vitamin C IC50 = 32.3 M Ampelopsin D 2 96.9 M Miyabenol C 3 89.7 M Dividol A 3 175.0 M Hopeaphenol 4 94.3 M Gnetin H 3 184.5 M Heyneanol A 4 144.6 M 中国科技论文在线 http://www.paper.edu.cn

From Resveratrol to Its Derivatives Current Medicinal Chemistry, 2013, Vol. 20, No. 8 1011

(Table 1) contd….

Compounds DPs Assay Condition IC50 Refs.

Ampelopsin G 3 149.3 M Amurensin G 3 277.2 M trans-Resveratrol 1 24.5 M cis-Resveratrol 1 24.1 M 60 M DPPH trans-3,5-Dihydroxy-4'-methoxystilbene 1 48.6 M [41] Reaction time = 60 min trans-3,5-Dimethoxy-4'-hydroxystilbene 1 30.1 M ,-Dihydroresveratrol 1 106.8 M

Table 2. Superoxide Anion Radical Scavenging Activities of Resveratrol and Its Derivatives.

Compounds DPs IC50 Refs.

Vaticanol D 6 7.4 M [25] trans--Viniferin 2 140 M Resveratrol 1 950 M 4-Hydroxystilbene 1 1100 M [46] 4,4'-Dihydroxystilbene 1 820 M 3,5-Dihydroxystilbene 1 1680 M Gnemonol K 3 69 M Gnemonol L 3 59 M -Viniferin 2 20 M Gnetol 1 66 M Isorhapontigenin 1 29 M [47] Resveratrol 1 15 M Latifolol 3 68 M Gnemonol B 3 79 M Gnemonol I 3 57 M Resveratrol 1 37.9 g/ml Piceatannol 1 0.45 g/ml Tricuspidatol 2 38.7 g/ml Pallidol 2 42.5 g/ml [38] Parthenocissin A 2 39.9 g/ml Betulifol A 2 22.1 g/ml -Viniferin 3 19.8 g/ml Cyphostemmin B 2 24.7 g/ml

3.5. Singlet Oxygen have been ignored, until our investigation demonstrated that palli- 1 Singlet oxygen (1O ) is molecular oxygen in its first excited dol (Fig. (6)), a resveratrol dimer from red wine, is a O2 oxygen 2 quencher in 2009 [58]. Pallidol showed strong quenching effects on singlet state, generated by the transfer of energy to ground state 1 O2 at very low concentrations in aqueous system with IC50 = 5.5 (triplet) molecular oxygen [52]. It is formed readily on exposure of a range of endogenous and exogenous sensitizers, including por- M, which was even stronger than EGCG (Epigallocatechin gallate, a famous antioxidant from green tea with IC50 = 14.5 M). Our phyrins and dye molecules such as Rose Bengal, to ultraviolet and 1 1 kinetic study has revealed that the reaction of pallidol with O2 had visible light [53]. O2 reacts with a wide range of cellular targets 10 an extremely high rate constant (ka = 1.71 10 ). It is recom- including proteins, DNA, RNA, lipids, and sterols [54]. Among 1 these important biological molecules, proteins, Cys, Met, Trp, Tyr mended to be used as a preventive agent in O2-mediated diseases, 1 which may contribute to the health beneficial effects of red wine. In and His residues are major targets for O2, since the rate constants for reaction of 1O with proteins side-chains are higher than that the same year, another two novel resveratrol tetramers, laetevire- 2 nols F and G, from Parthenocissus laetevirens has been emerged as with the others, and proteins are present at higher concentrations 1 1 effective O2 quencher with IC50 = 5.4 M and 6.3M respectively, within cells [55]. Dr. M. J. Davies has estimated that 68.5% of O2 generated within cells may be consumed by proteins [56]. It has which were comparable with pallidol and stronger than EGCG [59]. been postulated to play a role in the development of a number of In another investigation in our lab, three resveratrol oligomers have light-induced diseases including cataract, sunburn and some skin been isolated and purified from Vitis chunganensis by high-speed cancers [57]. Therefore, antioxidants with potent 1O quenching counter-current chromatography (HSCCC). Among them, vitisin A, 2 a resveratrol tetramer, showed similar selective quenching effect effects may have potential in the treatment and prevention of these 1 1 against O2 with IC50 = 6.9 M [41]. Furthermore the novel resvera- diseases. For a long time, the O2 quenching effects of stilbenes 中国科技论文在线 http://www.paper.edu.cn

1012 Current Medicinal Chemistry, 2013, Vol. 20, No. 8 He and Yan

Table 3. Lipid Peroxidation Inhibitory Activity of Resveratrol and Its Derivatives

Compounds DPs IC50 Refs.

3.0 Ma trans-Resveratrol 1 b 2.6 M 18.1 Ma cis-Resveratrol 1 b 19.0 M 21.3 Ma trans-Piceid 1 19.3 Mb [16b] 16.0 Ma cis-Piceid 1 b 16.6 M 1.9 Ma Astringin 1 b 3.1 M 1.0 Ma Astringinin 1 b 1.9 M

Gnemonol K 3 19 M Gnemonol L 3 7 M -Viniferin 2 33 M Gnetol 1 61 M Isorhapontigenin 1 45 M [47] Resveratrol 1 75 M Latifolol 3 32 M Gnemonol B 3 50 M Gnemonol I 3 25 M Resveratrol 1 9.03 g/ml Piceatannol 1 2.67 g/ml Tricuspidatol 2 46.40 g/ml Pallidol 2 12.46 g/ml Parthenocissin A 2 10.86 g/ml [38] Betulifol A 2 19.8 g/ml -Viniferin 3 16.43 g/ml Cyphostemmin B 2 11.04 g/ml Parthenostilbenin A 2 20.35 g/ml Parthenostilbenin B 2 18.68 g/ml

a Fe2+-induced lipid peroxidation in microsomes b Cu2+-induced lipid peroxidation in LDL Table 4. Singlet Oxygen Quenching Effects of Resveratrol and Its Derivatives.

Compounds DPs IC50 Refs.

Pallidol 2 5.5 M [57] Laetevirenols F 4 5.4 M [58] Laetevirenols G 4 6.3 M Vitisin A 4 6.9 M [39] Chunganenol 6 1.4 M [28] Amurensin G 3 5.2 M [43] Wilsonol A 3 12.3 M Wilsonol B 3 23.8 M Wilsonol C 4 7.6 M [40] Diviniferin B 4 6.2 M Resveratrol 1 18.5M

1 trol hexamer chunganenol has exhibited the hitherto highest O2 than resveratrol, especially chunganenol with at least 10-fold higher quenching activity (IC50 = 1.4 M) [30]. (Table 4) summarizes than the monomer. 1 quenching effects of resveratrol and its derivatives against O2. It is Our previous investigations have proved that resveratrol and its observed that most of resveratrol oligomers assayed are stronger 1 derivatives are potent O2 quenchers, therefore we conducted a 中国科技论文在线 http://www.paper.edu.cn

From Resveratrol to Its Derivatives Current Medicinal Chemistry, 2013, Vol. 20, No. 8 1013

mechanistic study in 2010 [44]. In order to understand the mecha- assessed in the transient rat middle cerebral artery occlusion nism under the quenching effect, our priority was to find out the (MCAO) model to mimic the onset of ischemic stroke. Oxyresvera- 1 active functional group(s) that may react with O2. A mimetic trol was administered twice intraperitoneally: immediately after HPLC/ESI-MS2 assay was designed to identify the product(s) of occlusion and at the time of reperfusion. Oxyresveratrol has dra- 1 reaction between resveratrol and O2. Based on detailed analysis of matically reduced the brain infarct volume of MCAO rats at the the MS fragmentation data, we were able to characterize the major dosages of 10 or 20 mg/kg. The neurological deficits induced by product as resveratrol quinone (Fig. (8)). Additional analyses of the I/R have also been improved by oxyresveratrol treatment. His- reaction products between resveratrol oligomers (Pallidol and tological analysis of apoptotic markers in the ischemic brain area 1 Amurensin G) and O2 have lead to the identification of corre- has indicated that oxyresveratrol treatment inhibited cytochrome c sponding quinone structures, revealing that resveratrol and its de- release and caspase-3 activation in MCAO rats, and the number of 1 rivatives undergo a similar reaction with O2. The reaction take apoptotic nuclei in ischemic brain was also reduced by oxyresvera- place at the resorcinol group, that is the 3,5-dihydroxylbenzene trol treatment. The dose dependent neuroprotective effect of moiety. The first step of the reaction involves a 1,4-cycloaddition of oxyresveratrol suggests that it is a potent neuroprotectant in vivo, 1 O2 to the resorcinol ring, yielding the endoperoxide intermediate and is potentially useful in the treatment of stroke [62]. IM-1. Then the subsequent reaction step diverts into two pathways: In the next year, isorhapontigenin (trans-3-methoxy-3',4,5'- Pathway A undergo an intramolecular H-abstraction of IM-1 to tetrahydroxystilbene) has been reported to attenuates cardiac hyper- generate IM-2; Pathway B involves hydrolysis and then consecu- trophy via blocking oxidative stress-mediated pathways [63]. tive loss of a molecular water to give an unstable hydroperoxide Isorhapontigenin inhibited angiotensin II (Ang II)-induced cardiac IM-2' and then IM-2. The two pathways maintain a competitive hypertrophy, which was associated with a decrease in ROS levels dynamic equilibrium. Our further theoretical calculation, performed and intracellular malonaldehyde content and an increase of activi- with PM3 semiempirical molecular orbital calculations, indicated ties of endogenous antioxidants such as SOD and GPx. Ang II in- that pathway B played a predominant role in the second step. Fi- duced phosphorylation of PKC, Erk1/2, JNK, and p38 was inhibited nally, the intramolecular loss of H2O in IM-2 yield resveratrol qui- 1 by isorhapontigenin. In addition, PKC-dependent PI3K–Akt– nones (Fig. (8)) [44]. The O2 quenching effect of resveratrol has GSK3/p70S6K pathway was also blocked by this resveratrol ana- been corroborated by Jung et al.’s recent report. Resveratrol has log. Pretreatment with isorhapontigenin dramatically inhibited Ang shown a protective effect on the methylene blue sensitized pho- II-mediated NF-B through regulating the degradation and phos- tooxidation of -terpinene, which explains the mechanism of how phorylation of IB and the activity of IKK and AP-1 activation resveratrol protects tissues and cells from photosensitized oxidation by affecting the expression of c-Fos and c-Jun proteins. These re- in biological systems [60]. sults were supported by further in vivo evidence. In an aortic- banded rat model, isorhapontigenin treatment significantly attenu- 4. THERAPEUTIC POTENTIAL ated heart weight/body weight ratio by approximately 25%, de- In the past 15 years, numerous publications have proved the creased posterior wall thickness and left ventricle diastolic and therapeutic potential of resveratrol in various diseases including systolic diameters, increased 10% fractional shortening, and re- cancer, heart disease, diabetes and stroke [14c]. However, its ex- duced cardiac myocyte size and systolic blood pressure. Therefore tremely low bioavailability and rapid clearance from the circulation isorhapontigenin could prevent the development of cardiac hyper- have laid down some limitation in its applications. As Dr. D. A. trophy through an antioxidant mechanism involving inhibition of Sinclair demonstrated in the review, “developing analogues with different intracellular signaling transduction pathways. It may be improved bioavailability, or finding new, more potent compounds used as a supplemental pharmacological agent for the prevention that mimic its effects will become increasingly important” [14c]. and treatment of cardiac hypertrophy [63]. Although still scarce, a few investigations have already revealed the Recently, we have studied the neuroprotective effects of therapeutic potential of resveratrol derivatives. parthenocissin A, a novel antioxidant and free radical scavenger, In 2001, Hung et al. have reported the beneficial effects of as- using a transient MCAO model in rats, which was the first in vivo tringinin (3,3',4',5-tetrahydroxystilbene, also known as “piceata- therapeutic evidence of resveratrol oligomer [64]. MCAO rats nol”) on the ischemia and reperfusion (I/R) damage in rat heart treated with parthenocissin A showed dose-dependent reductions in [61]. Astringinin with an additional hydroxyl group in its structure brain infarction size with improved neurological and motor out- have shown stronger antioxidant activity than resveratrol in differ- come. Parthenocissin A treatment inhibited lipid peroxidation and ent investigations. In the study, astringinin has been introduced to restored SOD activity in brain tissue. Furthermore, I/R induced examine its cardioprotective effects in ischemia or I/R, where the elevation of NO production and nitric oxide synthase (NOS) activ- left main coronary artery was occluded by three different proce- ity in brain tissue was also inhibited by parthenocissin A treatment. dures: (i) 30 min occlusion, (ii) 5 min occlusion followed by 30 min These findings indicated that the beneficial effect of parthenocissin reperfusion, and (iii) 4 h occlusion. Rats were infused with and A on neuroprotection was associated with a reduction of oxidative without astringinin before coronary artery occlusion to evaluate its stress and an inhibition of NO production. Our results have opened preventive effects. Pretreatment of astringinin has significantly new vistas in the potential use of resveratrol oligomers in stroke reduced the incidence and duration of ventricular tachycardia and prevention and therapy [64]. ventricular fibrillation. Astringinin could completely prevent the mortality of animals during ischemia or I/R at the dosages of 2.5 5. STRUCTURE-ACTIVITY RELATIONSHIP 10-5 and 2.5 10-4 g/kg. During the same period, astringinin pretreatment has also increased nitric oxide (NO) and decreased lactate Investigation of the SAR of resveratrol and its derivatives is dehydrogenase (LDH) levels in the carotid blood. Therefore, as- important for the understanding of their mechanism of antioxidative tringinin is a potent antiarrhythmic agent with cardioprotective action and provide basis for designing compounds with better anti- activity. It is also observed that the beneficial effects of astringinin oxidant activities. It has been the subject attracting medicinal chem- are related to its antioxidant activity and upregulation of NO pro- ists around the world in the past 15 years. As early as 1997, the duction [61]. number and position of hydroxyl groups have been revealed to play an important role in the antioxidant activity of stilbenes [18b]. In In 2004, another resveratrol derivative, oxyresveratrol (trans- 2001, there were two reports appeared almost at the same time con- 2,3',4,5'-tetrahydroxystilbene), has been indicated as a neuroprotec- cerning the structural determinants of the antioxidant activity of tive agent, which inhibits the apoptotic cell death in transient cere- resveratrol. In the stationary -radiolytic experiments in liposomes bral ischemia [62]. The neuroprotective effect of oxyresveratrol was 中国科技论文在线 http://www.paper.edu.cn

1014 Current Medicinal Chemistry, 2013, Vol. 20, No. 8 He and Yan

HO HO OH HO 1 O2 H2O O2 OH OH OH Pathway B HO HO HO OOH trans-resveratrol IM-1 IM-2'

- H O Pathway A 2

O O

- H2O OH OH HO OOH HO O IM-2 resveratrol quinone

1 Fig. (8). Proposed mechanism of reaction between resveratrol and O2. and pulse radiolytic experiments in aqueous solutions, trans- In 2002, Dr. Z. L. Liu’s lab has conducted a SAR investigation resveratrol and 4-hydroxy-trans-stilbene (4-HS) showed almost the using more resveratrol analogs. 4-HS, 3,5-DHS, 4,4’-dihydroxy- same effect and were much stronger than 3,5-dihydroxy-trans- trans-stilbene (4,4’-DHS), 3,4-dihydroxy-trans-stilbene (3,4-DHS), stilbene (3,5-DHS) (Fig. (9)). Thus, Stojanovi et al. demonstrated 3,4,5-trihydroxy-trans-stilbene (3,4,5-THS) and 3,4,4’-trihydroxy- that the para-hydroxyl group (Fig. (10)) made greater contribution trans-stilbene (3,4,4’-THS) have been synthesized (Fig. (9)). Their to the peroxyl radical scavenging activity of resveratrol than the antioxidant activities against the peroxidation of linoleic acid have meta-hydroxyl groups (resorcinol group, Fig. (10)) [65]. This con- been studied in sodiumdodecyl sulfate (SDS) and cetyltrimethyl clusion has been supported by Caruso et al.’s study using ab initio ammonium bromide (CTAB) micelles to mimic the microenviron- calculations and crystal structure of resveratrol. Their results dem- ment of biomembranes. In both assay systems, 3,4-DHS, 3,4,5-THS onstrated that the para-hydroxyl group is more acidic than the other and 3,4,4’-THS with ortho-dihydroxyl functionality showed two meta-hydroxyl groups, and H-atom transfer is the dominant stronger inhibition on linoleic acid peroxidation than resveratrol mechanism by which resveratrol and its derivatives scavenge free and molecules bearing no such functionality, which unveiling the radicals [66]. In another investigation, the SAR study has been exceptional antioxidant power of ortho-dihydroxyl group (Also extended to the stereoisomery and saturation of the stilbenic double known as “catechol group” (Fig. (10)). We herein propose a name bond of resveratrol. First, the important role of the para-hydroxyl “ortho-dihydroxyl rule” for this phenomenon). This can be under- group has been confirmed in this study. Nevertheless, it is clearly stood because the ortho-hydroxyl phenoxyl radical, the oxidation not the sole determinant for antioxidant activity. The double bond intermediate, is more stable due to the intramolecular hydrogen in the stilbenic skeleton and its transisomery are also important, bonding interaction, supported by both experiments [67] and theo- since the cis-form and the derivative, in which the double bond is retical calculations [68]. Furthermore, it is easier for the ortho- reduced, are significantly less effective than trans-resveratrol. In hydroxyl phenoxyl radical to form the stable ortho-quinone in the addition, partial methylation decreases the antioxidant activity of oxidation process. It is for a similar reason, that para-hydroxyl resveratrol, while complete methylation could cause significant loss group increase antioxidant activity by stabilizing the semiquinone of antioxidant activity, indicating that phenolic hydroxyl group is radical-anion intermediate via resonance through the trans double required [16]. These observations have been supported by another bond. That is the reason why the antioxidant activity of 3,4,4’-THS, study, where stilbenes with para-hydroxyl group showed better bearing both functionalities, was the best among the tested com- antioxidant activities in both -carotene bleaching assay and super- pounds. Interestingly, resveratrol and its derivatives can work alone oxide anions scavenging assay, while resveratrol analogs without or synergistically with -tocopherol in the antioxidative action by phenolic hydroxyl group did not have any antioxidative effect [47]. trapping the propagating lipid peroxyl radical and reducing the - R tocopheroxyl radical to regenerate -tocopherol [69]. In another 3' investigation from the same lab, antioxidant activities of 4-HS, 3,5- R 3 DHS, 4,4’-DHS, 3,4-DHS, along with resveratrol, have been evalu- R 4' ated for the free radical-induced peroxidation of rat liver micro- R4 somes in vitro. And the activity sequence follows the order: 3,4- R5' DHS > 4,4’-DHS > resveratrol > 4-HS > 3,5-DHS. Again, 3,4-DHS R5 with catechol group showed superior activity, which confirmed their previous conclusion [70]. The ortho-dihydroxyl rule is not R3 R4 R5 R3' R4' R5' Resveratrol OH H OH H OH H restricted in the antioxidant activity against lipid peroxidation, a 4-HS H OH H H H H SAR study by Murias et al. has proved that it can also be applied to 3,5-DHS OH H OH H H H the O2 and DPPH scavenging activities. Stilbenes with catechol 4,4'-DHS H OH H H OH H group or 3,4,5-trihydroxylbenzene group (pyrogallol group, Fig. 3,4-DHS OH OH H H H H (10)), including 3,3',4',5-tetrahydroxy-trans-stilbene (3,3',4',5- 3,4,5-THS OH OH OH H H H TTHS, IC50=2.69 M), 3,4,4',5-tetrahydroxy-trans-stilbene 3,4,4'-THS OH OH H H OH H (3,4,4',5-TTHS, IC50=41.5 M) and 3,3',4,4',5,5'-hexahydroxy- 3,3',4',5-TTHS OH H OH OH OH H trans-stilbene (3,3',4,4',5,5'-HHS, IC =5.02 uM), exhibit a more 3,4,4',5-TTHS OH OH OH H OH H 50 3,3',5,5'-TTHS OH H OH OH H OH than 6600-fold higher antiradical activity than resveratrol and its 3,3',4,5,5'-PHS OH OH OH OH H OH two other analogues, including 3,3’,5,5’-tetrahydroxy-trans-stilbene 3,3',4,4',5,5'-HHS OH OH OH OH OH OH (3,3’,5,5’-TTHS) and 3,3’,4,5,5’-pentahydroxy-trans-stilbene (3,3’,4,5,5’-PHS) (Fig. (9)). Interestingly hydroxystilbenes with Fig. (9). Monomeric trans-stilbenes for SAR investigations. catechol group or pyrogallol group exerted a more than three-fold 中国科技论文在线 http://www.paper.edu.cn

From Resveratrol to Its Derivatives Current Medicinal Chemistry, 2013, Vol. 20, No. 8 1015

OH OH OH HO OH OH HO OH

R R R R para-hydroxyl group resorcinol group catechol group pyrogallol group

Fig. (10). Major functionalities of stilbenes with different hydroxylation patterns.

higher cytotoxic activity than other analogs without the functionali- gations of their applications in light-mediated diseases includ- ties in HL-60 leukemic cells, because oxidation of ortho-dihydroxyl ing cataract, sunburn and skin cancers, are highly recom- group yield ortho-semiquinones, which undergo redox-cycling mended. thereby consuming additional oxygen and forming cytotoxic oxygen radicals. These findings suggest that the cytostatic activities of CONFLICT OF INTEREST resveratrol and its derivatives are linked to their antioxidant activities [71]. The author(s) confirm that this article content has no conflicts of interest. Furthermore, Mikulski et al. have recently reported the quantitative structure–antioxidant activity relationship of resveratrol and ACKNOWLEDGEMENTS its derivatives, including seven oligomers and five glucosides [15]. Their free radical scavenging activities have been calculated using We thank support from Qianjiang Talent Plan (2012R10068), the density functional theory. According to the results, all oligomers Zhejiang Marine Biotechnology Innovation Team (2012R10029-2), and glucosides studied exhibit stronger antioxidant activity than Ningbo Marine Algae Biotechnology Team (2011B81007), Talent trans-resveratrol. A dimer of 4,4'-DHS is stronger than its mono- Plan of Ningbo University (RCL2011718), and K.C.Wong Magna mer. The H-atom transfer mechanism is more preferable than the Fund in Ningbo University. single-electron transfer mechanism, and all the antioxidants showed higher ability to donate electron in water medium than in the gas ABBREVIATIONS phase. Although these theoretical results still await future experi- mental verification, the report has again highlighted the remarkable ROS = Reactive oxygen species antioxidant activity of resveratrol derivatives and their potential therapeutic applications [15]. OS = Oxidative stress SOD = Superoxide dismutase CONCLUSION GPx = Glutathione peroxidase In the past 15 years, we have witnessed the research outbreak of CAT = Catalase resveratrol, a natural antioxidant from red wine and grape, which is GSH = Glutathione under multiple clinical trials. Resveratrol has provided an entrance to the medicinal investigations of an important group of plant poly- DMBA = 7,12-Dimethylbenz[a]anthrancene phenols “stilbene”, where resveratrol derivatives have shown in- SAR = Structure-activity relationship triguing chemical diversity. Numerous reports have proved resvera- PAL = Phenylalanine ammonia lyase trol derivatives to be a promising source of potent antioxidants, while some have shown higher activity than resveratrol. In recent C4H = Cinnamate 4-hydroxylase years, in vivo studies of resveratrol derivatives have highlighted 4CL = Hydroxycinnamoyl CoA ligases their therapeutic potential in the treatment in cerebral and cardiovascular diseases, which is linked to their remarkable antioxidant STS = Stilbene synthase activities. They may also be used as functional food supplements DP = Degree of polymerization owing to their powerful antioxidant capacities. Finally, we would HCSO = Highly condensed stilbene oligomer like to propose the following points to be considered in future investigations: HRP = Horseradish peroxidase (1) Screening of antioxidant capacity of resveratrol derivatives DPPH = 1,1-Diphenyl-2-picrylhydrazyl should include trans-resveratrol as a screening criteria. More EPR = Electron paramagnetic resonance interest should be directed towards compounds with higher activity than trans-resveratrol. LDL = Low-density lipoproteins (2) SAR studies have revealed the so-called “ortho-dihydroxyl EGCG = Epigallocatechin gallate rule”, that stilbenes with ortho-dihydroxyl group possess higher HSCCC = High-speed counter-current chromatog- antioxidant activities. These compounds may have greater raphy therapeutic potential in future investigations. I/R = Ischemia and reperfusion (3) Different mechanisms have been observed when stilbenes react NO = Nitric oxide with different ROS. For example, the resorcinol group plays a predominant role in the quenching effect of resveratrol, while LDH = Lactate dehydrogenase the para-hydroxyl group is more effective in scavenging per- MCAO = Middle cerebral artery occlusion oxyl radicals. Results from these mechanistic studies will provide a basis for future screening and drug design. Ang II = Angiotensin II (4) Our previous reports have shown that resveratrol derivatives, NOS = Nitric oxide synthase 1 especially oligomers, are potent O2 quenchers. Further investi- SDS = Sodiumdodecyl sulfate 中国科技论文在线 http://www.paper.edu.cn

1016 Current Medicinal Chemistry, 2013, Vol. 20, No. 8 He and Yan

CTAB = Cetyltrimethyl ammonium bromide Sinclair, D. A. Therapeutic potential of resveratrol: the in vivo evidence. Nat. Rev. Drug Discov., 2006, 5, 493-506. 4-HS = 4-Hydroxy-trans-stilbene [15] Mikulski, D.; Molski, M. Quantitative structure–antioxidant activity relationship of trans-resveratrol oligomers, trans-4,4-dihydroxystilbene 3,5-DHS = 3,5-Dihydroxy-trans-stilbene dimer, trans-resveratrol-3-O-glucuronide, glucosides: Trans-piceid, cis- 4,4’-DHS = 4,4’-Dihydroxy-trans-stilbene piceid, trans-astringin and trans-resveratrol-4-O--D-glucopyranoside. Eur. J. Med. Chem., 2010, 45, 2366-2380. 3,4-DHS = 3,4-Dihydroxy-trans-stilbene [16] Stivala, L.A.; Savio, M.; Carafoli, F.; Perucca, P.; Bianchi, L.; Maga, G.; Forti, L.; Pagnoni, U. M.; Albini, A.; Prosperi, E.; Vannini, V. Specific 3,4,5-THS = 3,4,5-Trihydroxy-trans-stilbene structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol. J. Biol. Chem., 2001, 276, 22586-22594. 3,4,4’-THS = 3,4,4’-Trihydroxy-trans-stilbene [17] Lee, S.K.; Mbwambo, Z.H.; Chung, H.; Luyengi, L.; Gamez, E. J.; Mehta, R. 3,3',4',5-TTHS = 3,3',4',5-Tetrahydroxy-trans-stilbene G.; Kinghorn, A.D.; Pezzuto, J.M. Evaluation of the antioxidant potential of natural products. Comb. Chem. High. Throughput Screen., 1998, 1, 35-46. 3,4,4',5-TTHS = 3,4,4',5-Tetrahydroxy-trans-stilbene [18] (a) Wang, M.; Jin, Y.; Ho, C.T. Evaluation of resveratrol derivatives as potential antioxidants and identification of a reaction product of resveratrol 3,3',4,4',5,5'-HHS = 3,3',4,4',5,5'-Hexahydroxy-trans- and 2, 2-diphenyl-1-picryhydrazyl radical. J. Agric. Food. Chem., 1999, 47, stilbene 3974-3977. (b) Fauconneau, B.; Waffo-Teguo, P.; Huguet, F.; Barrier, L.; Decendit, A.; Merillon, J.M. 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Received: July 29, 2012 Revised: October 04, 2012 Accepted: October 10, 2012