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中国科技论文在线 http://www.paper.edu.cn Send Orders of Reprints at [email protected] 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, resvera- trol 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 deriva- tives 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 /13 $58.00+.00 © 2013 Bentham Science Publishers 1875-533X 转载 中国科技论文在线 http://www.paper.edu.cn 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 chun- ganenol (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