Keywords

1 Introduction

The term “stilbenoids” was proposed by Gorham in 1980 [1, 2], which refers to a class of plant phenolics with 1,2-diphenylethylene or 1,2-diphenylethane nucleus in their structures. Stilbenoids are regarded as plant phytoalexins and have been a hot research topic for their intricate structures and diverse biological activities. The phytochemical research concerning the stilbenoids developed quickly in recent years. More than 1,000 compounds belonging to this group have been discovered, compared with just over 100 listed in 1980 and about 300 in 1995 [2]. Recent advances in analytical and spectroscopic techniques, especially the NMR methods, speed up the discovery and elucidation of the intricate structures of stilbenoids. The intricate structures and stereochemistry of oligostilbenes and bisbibenzyls were established based on the modern techniques. Furthermore, these compounds demonstrated diverse biological activities, including antitumor, antimicrobial, antioxidant effects, antiplatelet aggregation, phytotoxicity, etc. These bioactive compounds and their derivatives are of great interest for drug research and development as a result of their potential in therapeutic or preventive applications, exemplified by resveratrol and combretastatin A-4. In this chapter, we will give an overview of structural features, occurrence, phytochemical aspects, biosynthesis, and biological activities of the stilbenoids.

2 Phytochemical Aspects

According to their structural characteristics, stilbenoids are mainly divided into five categories, stilbenes, oligostilbenes, bibenzyls, bisbibenzyls, and phenanthrenes. In the section of phytochemical aspects, the structural characteristic, distribution, typical representatives, and their structures of each group are introduced.

2.1 Stilbenes

Stilbenes possess a skeleton with two aromatic rings joined by a methylene bridge. The simple stilbene nucleus is generally substituted by different groups of hydroxyl, methyl, methoxy, prenyl, geranyl, etc., and combined with sugars to form glycosides. The double bonds in naturally occurring stilbenes are usually E-configuration, but stilbenes with Z-configuration are also observed. The compounds of this group highlight the chemical structural diversity through the modification of above styles on the nucleus. About 125 new stilbenes have been discovered between the year of 1995 and 2008 [3]. They mainly occur in the families of Aceraceae, Anchinoidae, Asteraceae, Bombycidae, Burseraceae, Combretaceae, Cyperaceae, Dipterocarpaceae, Euphorbiaceae, Gnetaceae, Hepaticae, Iridaceae, Leguminosae, Lejeuneaceae, Liliaceae, Meliaceae, Moraceae, Ophioglossaceae, Orchidaceae, Polygonaceae, Rosaceae, Stemonaceae, Vitaceae, and Zingiberaceae.

Resveratrol 1 is the most famous representative of this group and occurs in Polygonum cuspidatum root and Vitis species. It is a phytotoxin produced by several plants in response to infection or other stresses and attracted attention for its cardioprotective effect in red wine. In addition, it is the most important unit for the construction of oligomeric stilbenes.

Combretastatins, a series of bioactive stilbenes (combretastatin A series), bibenzyls (B series), phenanthrenes (C series), and macrocyclic lactone (D series), were obtained from the African willow tree Combretum caffrum (Combretaceae). Among them, the A series of combretastatins belonging to stilbenes, including combretastatins A-1 to A-6 2–7, are found to be tubulin polymerization inhibitors.

Typical stilbenes substituted with hydroxyls, methyl, methoxy, menthane groups, and their origin were listed as follows. Trans-4-[2-(3,5-dimethoxyphenyl)ethenyl]-1,2-benzenediol 8 was isolated from Sphaerophysa salsula (Leguminosae) [4]. Thunalbene 9 was obtained from Thunia alba (Orchidaceae), and the structure was designated as 3,3′-dihydroxy-5-methoxystilbene [5]. The Phragmipedium species produced three new stilbenes including 2,3′-dihydroxy-5′-methoxystilbene 10, 2,3-dihydroxy-3′,5′-dimethoxystilbene 11, and 2,3′-dihydroxy-5,5′-dimethoxystilbene 12 [6]. Phoyunbenes A-D 13–16 were found in Pholidota yunnanensis (Orchidaceae) [7]. 5,4′-Dihydroxy-3-methoxystilbene 17, 3,5-dihydroxy-4′-methoxystilbene 18, and (E)-3,3′-dimethoxy-4,4′-dihydroxystilbene 19 were isolated from Rumex bucephalophorus and Leuzea carthamoides [8, 9], respectively. Two Z-type stilbenes named (Z)-3-methoxy-5-hydroxystilbene 20 and (Z)-3,5-dihydroxystilbene 21, together with a menthane-substituted stilbene (E)-1-(1-terpinen-4-olyl)-3-methoxystilbene 22, were obtained from aerial parts of Alpinia katsumadai (Zingiberaceae) [10, 11].

There are two stilbene representatives isolated from special origins. Bryophytes are characterized by the production of bisbibenzyls, and no stilbene has been obtained before the isolation of 3,4-dihydroxy-3′-methoxystilbene 23 from Marchesina bongardiana (Lejeuneaceae) [12]. Kirkpatrickia variolosa, a kind of Antarctic red sponge of Anchinoidae family, yielded a triacetate derivative 3,4,5-triacetoxystilbene 24 which was the only marine natural stilbene [13].

Two stilbene glycosides, named (E)-3,4′-dimethoxyl-5-rutinosyl stilbene 25 and 3,5-dimethoxy-4′-O-(β-rhamnopyranosyl-(1 → 6)-β-glucopyranoside)stilbene 26, were isolated from Guibourtia tessmanii (Leguminosae) [14, 15]. Acer mono (Aceraceae), a Korean folk medicine for hemostasis, produced two new stilbene glycosides 5-O-methyl-(E)-resveratrol 3-O-β-d-glucopyranoside 27 and 5-O-methyl-(E)-resveratrol 3-O-β-d-apiofuranosyl-(1 → 6)-β-d-glucopyranoside 28 [16].

Prenyl substitution is a conventional derivatization style in stilbenes, exemplified by artoindonesianin N 29 from Artocarpus gomezianus [17]. The prenyl groups in stilbenes cyclize to form new derivatives. 4-Hydroxy-5′-methoxy-6″,6″-dimethylpyran[2″,3″:3′,4′]stilbene 30, 3,5′-dimethoxy-4-hydroxy-6″,6″-dimethylpyran[2″,3″:3′,4′]stilbene 31, and 3,4,5-trimethoxy-6″,6″-dimethylpyran[2″,3″:3′,4′]stilbene 32, with dimethylchromene ring in their structures, have been obtained from Lonchocarpus utilis (Leguminosae) [18]. Furthermore, schweinfurthins A-C 33–35 from the leaves of Macaranga schweinfurthii (Euphorbiaceae) are typical samples of the prenylated stilbenes [19].

Arylbenzofuran derivatives are a group of special stilbenes formed by C7–O–C7 linkage, for instance, gnetofurans B 36 and C 37 from Gnetum klossii [20]. In addition, schoenoside 38, a phenylbenzofuran glucoside discovered from Schoenocaulon officinale (Liliaceae), as well as stemofurans A-C 39–41 from Stemona collinsae belongs to this group [21, 22].

2.2 Oligostilbenes

The structures of oligostilbenes are produced by coupling between homogeneous or heterogeneous monomeric stilbenes, leading to the construction of dimer, trimer, and even the octamer. They do not enjoy a wide distribution in plant kingdom and have been found in the family of Agavaceae, Apiaceae, Arecaceae, Celastraceae, Cyperaceae, Dipterocarpaceae, Gnetaceae, Haemodoraceae, Iridaceae, Leguminosae, Moraceae, Musaceae, Orchidaceae, Pinaceae, Polygonaceae, Ranunculaceae, Vitaceae, and Welwitschiaceae. Thereinto, Vitaceae, Leguminosae, Gnetaceae, and Dipterocarpaceae are particular rich resource of this group.

Oligostilbenes are constructed by C–C or C–O–C linkage of various stilbene units with diverse coupling patterns and producing structures with diverse skeletons, complex configurations, and different degrees of oligomerization. The most common monomeric stilbene units which comprised the oligostilbenes are resveratrol, isorhapontigenin, piceatannol, oxyresveratrol, etc. (Fig. 62.1). Therefore, oligostilbenes are classified into six groups which are resveratrol oligomers, isorhapontigenin oligomers, piceatannol oligomers, oxyresveratrol oligomers, resveratrol and oxyresveratrol oligomers, and finally miscellaneous oligomers [3].

Fig. 62.1
figure 00631

Units comprising oligomeric stilbenes

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2.2.1 Resveratrol Oligomers

The group of resveratrol oligomers comprises the largest number of oligostilbenes and is characterized by the polymerization of two to eight resveratrols. About 180 constituents of this group covering dimer to octamers have been reported, which is produced by diverse polymeric styles.

Vitisinol A 42 isolated from Vitis thunbergii is a dimer linked by four C–C or C–O–C bonds [23]. Two dimeric stilbene glycosides 43 and 44 were reported from Polygonum cuspidatum (Polygonaceae) [24]. Thereinto, 44 is a symmetrical molecule and possesses a novel four-membered ring which is very rare in natural products. Isoampelopsin F 45 linked by three C–C bonds and heimiol A 46 with seven-member ring were isolated from Parthenocissus tricuspidata and Neobalanocarpus heimii [25]. A novel resveratrol dimer with a five-membered lactone ring, namely, shorealactone 47, was obtained from Shorea hemsleyana [26]. Schneide reported the isolation of anigopreissin A 48 from the Anigozanthos preissii (Haemodoraceae) and Musa cavendish (Musaceae), which is the first dimer containing unsaturated benzofuan moiety [27]. Moreover, an aldehyde-substituted derivative, (−)-viniferal 49, was isolated from Vitis vinifera [28].

Two trimers containing rare tribenzobicyclo[3.3.2]decatriene system were isolated from Vatica rassak and V. pauciflora, named vaticanol G 50 and vaticaside D 51 [29, 30]. Caragaphenol A 52, with a nine-membered ring in the molecules, was found in Caragana stenophylla [31]. Three isomers which have bicyclo[5.3.0]decane ring system were obtained including amurensin G 53 from Vitis amurensis [32] and suffruticosols A 54 and B 55 from Paeonia suffruticosa (Ranunculaceae) [33].

Two new resveratrol pentamers, named amurensins E 56 and F 57, have been isolated from Vitis amurensis [34]. The isolation and structural elucidation of a hexamer vaticanol D 58 and a heptamer vaticanol J 59 from Vatica rassak have been reported [29]. An octamer vateriaphenol A 60 from Vateria indica was reported by Ito and coworkers, and it is the largest molecules of stilbenoids [35].

2.2.2 Isorhapontigenin Oligomers

Oligostilbenes of this group mainly occur in the genus of Gnetum. The representatives comprise gnetuhainins P 61 and I 62 from G. hainanense [36, 37], dimeric stilbene epimers gnetifolins M 63 and N 64 from G. montanum [38], gnemonol M 65 from G. gnemon [39], gneafricanin F 66 found in G. africanum [40], as well as bisisorhaphontigenin B 67 obtained from G. africanum [41]. With the exception of Gnetum species, Salacia lehmbachii produced three isorhapontigenin dimers, named lehmbachols A-C 68–70 [42]. The only two isorhapontigenin trimers, gnetuhainins N 71 and O 72, which are stereoisomers have been found in Gnetum hainanense [43]. A tetramer named gnetuhainin R 73 was obtained from the same species (G. hainanense) [44].

2.2.3 Piceatannol Oligomers

Only piceatannol dimers have been discovered from the plant species. Longusol C 74 and gneafricanin C 75 were isolated from Cyperus longus and Gnetum africanum [40, 45]. Tibeticanol 76 was obtained from Caragana tibetica [46]. Two piceatannol dimer glycosides named piceasides A–B 77–78 were isolated from Norway spruce Picea abies as a mixture in a ration of 1:1 [47].

2.2.4 Oxyresveratrol Oligomers

Andalasin A 79 and artogomezianol 80 were isolated from Artocarpus gomezianus (Moraceae) [48]. Structures 79 and 80 are possible intermediates in the biogenesis of oxyresveratrol dimers. Parvifolol C 81 and gnetumontanin A 82 were discovered in two Gnetum species G. parvifolium and G. montanum [49, 50].

2.2.5 Resveratrol and Oxyresveratrol Oligomers

The resveratrol and oxyresveratrol oligomers are only obtained from the genus Gnetum (Gnetaceae) and polymerize by oxidative coupling between resveratrol and oxyresveratrol. About 24 compounds of this group have been elucidated. A dimer containing a benzofuran and a dihydrobenzofuran moiety, named gnemonol G 83, was isolated from G. gnemon [51]. Four stilbene dimers, gnetuhainins A 84, B 85, D 86 and E 87, were obtained from G. hainanense [52]. Gnemonoside J 88, a diglucoside of 84, was isolated from G. africanum [53]. Three stereoisomers including parvifolols A 89 and B 90 and gnetuhainin S 91 have been founded from G. parvifolium and G. hainanense [44, 49, 54]. Gnemonol A 92 and its stereoisomers and gnemonol I 93 composed of two resveratrol units and one oxyresveratrol unit were discovered in G. gnemon [51, 55]. Gnemonol J 94 from G. gnemon possesses the same skeleton of 92 and 93; however, it is coupled by one resveratrol unit and two oxyresveratrol units [51]. Gnemonol C 95 from G. gnemonoides is a stilbene tetramer constructed by three resveratrol and one oxyresveratrol units [55].

2.2.6 Miscellaneous Oligomers

Oligostilbenes polymerize from different stilbene units with the exception of resveratrol and oxyresveratrol oligomers, and containing miscellaneous structural skeleton will be classified into this group. Longusol B 96 from Cyperus longus [45] is a stilbene dimer composed of resveratrol and piceatannol units. Gnetuhainin Q 97, an isorhapontigenin and resveratrol dimer, was found in Gnetum hainanense [36]. The first isorhapontigenin and oxyresveratrol dimer named gnetuhainin J 98 was isolated from G. hainanense [37]. An isorhapontigenin and piceatannol dimer, gneafricanin B 99 was discovered in Gnetum africanum [41]. Two isorhapontigenin and 2-hydroxyisorhapontigenin dimers were obtained from G hainanense and named gnetuhainin G 100. An isorhapontigenin and gnetol dimer gnetuhainin K 101 was isolated from G. hainanense [36].

2.3 Bibenzyls

The bibenzyls are characterized by the presence of one 1,2-diphenylethane structure in their molecules. Similar with the stilbene structures, there are hydroxyls, methyl, methoxy, prenyl, geranyl, etc., located in the structures of bibenzyls. Bibenzyls have been mainly isolated from bryophytes. In addition, a few compounds of this group were reported from the genera of Stemona, Dendrobium, and Polygonum.

According to the suggestion given by Gorm et al. [56], bibenzyl compounds are classified into four groups. However, a few groups of bibenzyls are new addition to the growing list of naturally occurring bibenzyls, such as tyrolobibenzyls. In addition, bibenzyls containing isoprene units, regardless of branched or heterocyclic ring-forming isoprene units, are regarded as the same group. Therefore, the bibenzyls are reclassified into five groups according to their substitute patterns on both the benzene nucleus and ethylidene bridge.

2.3.1 Group A: Simple Bibenzyls

Bibenzyls having halogenated, hydroxylated, methyled, methoxylated, carboxylate, benzoyl, and/or methylenedioxy substitutes constitute the group of simple bibenzyls. The representatives are 2′,6′-bis(p-hydroxybenzyl)-3,3′-dihydroxy-5-methoxybibenzyl 102 from Bletilla formosana [57], bulbophyllum 103 from Bulbophyllum protractum [58], 2-carboxy-4-hydroxy-3,4′-dimethoxybibenzyl 104 from Plagiochila species [59], 2-chloro-3-hydroxybibenzyl 105 from Riccardia marginata [60], 1-(3′,5′-dihydroxyphenyl)-2-(4′-hydroxyphenyl)-ethane-1,2-diol 106 from Polygonum cuspidatum [61], methyl 4-hydroxy-4′-O-methyllunularate 107 from Plagiochila spinulosa [62], tragopogonic acid 108 from Tragopogon porrifolius [63], and 2,4,6-trichloro-3-hydroxybibenzyl 109 from Riccardia marginata [60].

2.3.2 Group B: Isoprene Unit–Substituted Bibenzyls

Bibenzyls of this group are characterized by the presence of prenyl, geranyl, and/or farnesyl substitutes. Isoprene units in the structures may be branched and/or form five- to seven-member rings. The typical compounds of this group are bauhinols A 110 and B 111 from Bauhinia saccocalyx [64], 2-carboxy-3-methoxy-4,6-di-(3-methyl-2-butenyl)-5,4′-dihydroxy-bibenzyl 112 from Lethocolea glossophylla [65], 2-isopropenyl-6-hydro-4-(2-phenylethyl)dihydrobenzoluran 113 from Radula perrottetii [66], and 3,5,4′-trihydroxy-4-(3,7,11-trimethyl-2,6,10-dodecatrienyl)bibenzyl 114 from Radula species [67].

2.3.3 Group C: Glycosylated Bibenzyls

Bibenzyls conjugated with glycosyl substitutes on the aromatic rings or benzylic methylenes (excluding tyrolobibenzyls) belong to this group. The representatives of this group include 2′-carboxy-4,3′-dihydroxybibenzyl-3-O-β-d-glucopyranoside 115 from Ricciocarpus natans [68], 2-carboxyl-3,4′-dihydroxy-5-β-d-xylopyranosyloxybibenzyl 116 and 5,4′-dihydroxy-3-α-l-rhamnopyranosyl-(1 → 3)-β-d-xylopyranosyloxybibenzyl 117 from Tragopogon porrifolius [63], and combretastatin B-1,2′-β-d-glucoside 118 from Combretum erythrophyllum [69].

2.3.4 Group D: Tyrolobibenzyls

Tyrolobibenzyls are a new class of naturally occurring bibenzyl derivatives possessing a unique phenylethyl-benzofuran skeleton. Tyrolobibenzyls A 119, B 120, D 121, and F 122 from Scorzonera humilis L. (Asteraceae) are the typical constituents of this group [70–72].

2.3.5 Group E: Other Bibenzyls

The hydrogenated bibenzyls 123–124 from Plagiochila longispina [73], dihydrocoumarin-type bibenzyl 125 from Vittaria anguste-elongata [74], cannabinoid-type bibenzyl 126 from Radula marginata [75], and dihydrophenanthrene hybrids such as shancilin 127 from Pleione bulbocodioides, and terpenoid hybrid spinuloplagin A from Plagiochila spinulosa 128 are classified into this group.

2.4 Bisbibenzyls

Bisbibenzyls are dimeric bibenzyls and chemically constructed by two lunularin moieties with diarylether and/or biphenyl linkages, and producing cyclic and acyclic four aromatic rings system. They are usually distributed in liverworts and rarely found in other plant species. The first bisbibenzyl not obtained from liverworts is perrottetin H 149, which was isolated from a pteridophyte Hymenophyllum barbatum [2]. It is also believed that the distribution of bisbibenzyls in both pteridophytes and liverwort is an important marker of determining the evolutionary ladder of terrestrial spore-forming plants.

Bisbibenzyls are classified into ten types of cyclic bisbibenzyls and six types of acyclic bisbibenzyls on the basis of basic bisbibenzyls skeletons (see Table 62.1). Over 100 cyclic and acyclic bisbibenzyls have been obtained from plant kingdom to date.

Table 62.1 Cyclic and acyclic bis(bibenzyl) types and their distribution
Full size table

2.4.1 Macrocyclic Bisbibenzyls

According to the constitution of the macrocyclic ring, these bisbibenzyls can be divided into three main groups, those with two diarylether bonds (marchantins, isomarchantins, neomarchantins, and riccardins II), those with two biphenyl bonds (isoplagiochin II), or those with one diarylether bond and one biphenyl bond (riccardin I, isoriccardin C, plagiochins, isoplagiochin I, and planusin A) (see Table 62.1). The range of macrocyclic structures is extended ultimately and derived from additional functions (e.g., carbonyl, hydroxyl, and methoxyl) on both the benzene nucleus and ethylidene bridge and the ways in which aromatic rings are linked.

Asakawa and his coworkers reported the isolation of a marchantin-type macrocyclic bisbibenzyl marchantin P 129 from the liverwort Marchantia chenopoda collected in Venezuela [76]. Three isomarchantin-type macrocyclic bisbibenzyls were isolated from the liverwort Ptychantus striatus, belonging to the Lejeuneaceae, and designated them as ptychantols A-C 130–132 [77]. Neomarchantins A and B 133–134 were obtained from Schistochila glaucescens [78].

Two riccardin I-type compounds, riccardins F 135 and H 136, were isolated from Blasia pusilla [79] and Marchantia polymorpha [80], respectively. Riccardin B 137 from Preissia quadrata belongs to the riccardin II-type bisbibenzyls. Isoriccardin C 138, a compound of isoriccardin group, was obtained from Plagiochila sciophila [81].

Plagiochins A-B 139 and 140 were plagiochin-type constituents from Plagiochila fruticosa [81]. Isoplagiochins E-F 141–142, belonging to the isoplagiochin I-type bisbibenzyls, have been isolated from several Plagiochila species. Isoplagiochins C 143 and D 144 with two biphenyl linkages, which are different from isolagiochin I-type bisbibenzyls, represent isolagiochin II-type of macrocyclic bisbibenzyls. Planusin A 145 with a cis -stilbene moiety was discovered from cultured cells of the liverwort Heteroscyphus planus and classified into planusin-type bisbibenzyls [82].

2.4.2 Acyclic Bisbibenzyls

Compared with cyclic bisbibenzyls, acyclic bisbibenzyls receive less attention due to their small number and poor structural diversity. Some novel acyclic bisbibenzyls, however, have been obtained in the past few years. These bisbibenzyls can be divided into two main groups, those with one diarylether bond (perrottetins and paleatins) or those with one biphenyl bond (isoperrottetin A, plagilins, isoplagilin, plagiolin, artogomezianol, and andalasin). The linkages occurred between two aromatic rings or between one benzene nucleus and ethylidene bridge (see Table 62.1).

Perrottetins and isoperrottetins represent the most frequently encountered skeletal types of acyclic bisbibenzyls. They are of much interest for the investigation of biogenesis of macrocyclic bisbibenzyls, for example, the derivatives of riccardin, plagiochin, ptychantol, and isoplagiochin types. Examples of the perrottetin-type compounds are perrottetins E-H 146–149. They have been found in different liverwort species and a fern Hymenophyllum barbatum [83]. Isoperrottetin A 150 and its chlorinated derivative 151 belong to isoperrottetin-type compounds [66, 84], which contain one biphenyl bond between aromatic rings instead of one diarylether bond for perrottetins.

Plagilin 152, isoplagilin 153, and plagiolin 154 were obtained from a neotropical Plagiochila species [85]. Another plagilin-type bisbibenzyl, vittarin-E 155, has been isolated from the whole plant of Vittaria anguste-elongata [74]. This is one more evidence for the occurrence of acyclic bisbibenzyls in the pteridophytes.

Paleatins A 156 and B 157 were isolated from the methanol extract of Marchantia paleacea var. diptera [86]. These phenolic compounds are of interest because they are the linear analogues of the macrocyclic bisbibenzyl ethers and possible biogenetic precursors of the plagiochins and riccardins.

2.5 Phenanthrenes

The phenanthrenes are a rather uncommon group of aromatic constituents formed by oxidative coupling of the aromatic rings of stilbene precursors and existed in the form of monomers, dimers, and even trimers [87]. A large number of phenanthrenes have been isolated from higher plants (mainly in the Orchidaceae family) and covering 49 species. The genera Dendrobium, Bulbophyllum, Eria, Maxillaria, Bletilla, Coelogyna, Cymbidium, Ephemerantha, and Epidendrum were particularly rich resources of phenanthrenes. In addition, a few phenanthrenes have been discovered in the family of Dioscoreaceae, Combretaceae and Betulaceae, and the Hepaticae class. The greatest number of phenanthrenes has been obtained from the Juncus species.

2.5.1 Monomeric Phenanthrenes

Most of the phenanthrenes are present in the form of monomers, containing about 210 compounds. Hydroxyl and methyloxyl are the most common substitutes located in the phenanthrene skeletons and occupy about 50% of all monomers. For instance, coeloginanthrin 158 from Coelogyne cristata [88], 4-methoxyphenanthrene-2,3,7-triol 159 and 4-methoxyphenanthrene-2,3,6,7-tetrol 160 from Bulbophyllum vaginatum [89], as well as 2-methoxy-3,4,7-trihydroxy-phenanthrene 161 from B. inconsipicum [90] are hydroxyl- and/or methyloxyl-substituted ones.

With the exception of hydroxy and methyloxy groups, methyl-, hydroxymethyl-, carboxy-, formyl-, prenyl-, and vinyl-substituted compounds are observed, with stemanthrenes A-D 162–165, 166, 167, dehydroeffusal 168, and gancaonin U 169 as the representatives [91–94]. Furthermore, glycosides were isolated from the plants of Juncus effusus, Epimedium koreanum, Dendrobium chrysanthum, and Bulbophyllum striata, for example, effuside I 170, epimedoicarisoside A 171, and denchryside A 172 [95–97].

Phenanthraquinones are special phenanthrenes with quinone group in the structures. Ephemeranthoquionone 173 from Dendrobium plicatile, cymbinodin A 174 from C. aloifolium, and moniliformin 175 from D. moniliforme were typical constituents of this group [98–100].

2.5.2 Dimeric Phenanthrenes

The dimeric phenanthrenes are commonly constructed by 1-1′ linkage of monomers, and the dimers with 1-3′, 1-8′, and 3-3′ link patterns also existed. Nearly 40 dimeric phenanthrenes have been found in the plants [87]. The representatives are cirrhopetalanthrin 176 from Cremastra maculosum [101], blestrianol A 177 from Bletilla striata [102], blestriarene B 178 from Bletilla formosana [57], and spiranthesol 179 from Spiranthes sinensis [103].

2.5.3 Triphenanthrene

Hitherto, only one triphenanthrene 180 has been reported from the tubers of an orchidaceous plant Cremastra appendiculata [104].

3 Biosynthesis

3.1 Biosynthesis of Stilbenes

The biosynthesis of simple stilbenes has been found out, and it shared a similar biosynthetic pathway with the flavonoids. Taking resveratrol for example, it starts from a cinnamoyl-CoA unit and extended the chain with three malonyl-CoA molecules (Scheme 62.1) [105]. Then, the resveratrol structure is produced by aldol reaction with the presence of stilbene synthase. Nevertheless, the flavonoids are formed depending on chalcone synthase and Claisen reaction.

scheme 00631

Scheme 62.1

3.2 Biosynthesis of Oligostilbenes

Sotheeswaran has mentioned that the oligostilbenes with dihydrobenzofuran moiety are biosynthesized through an important intermediate trans-ε-viniferin [106]. Combined with the reported work of oligostilbenes, the biosynthesis of oligostilbenes is summarized. For instance, the dimers named (+)-ampelopsin B, (−)-ampelopsin D, and (+)-ampelopsin F are produced by isomerization and/or rearrangement of trans-ε-viniferin (Scheme 62.2). The differences in their structures are caused by the different protonation position at the initial stage of reaction. Furthermore, trans-ε-viniferin is able to transform to the isomers (Scheme 62.3) and then forming the tetramers, (+)-vitisin A, (−)-vitisin B, (+)-hopeaphenol, and (+)-viniferol A, etc., by oxidative coupling (Scheme 62.4) [2, 107].

scheme 00632

Scheme 62.2

scheme 00633

Scheme 62.3

scheme 00634scheme 00634

Scheme 62.4

3.3 Biosynthesis of Bibenzyls and Bisbibenzyls

The biosynthesis of marchantins A and C has been certified by a C-labeled precursor feeding experiment. It shows that rings A and C of the marchantin molecules are derived from the benzene ring of l-phenylalanine. The bibenzyl lunularic acid is biosynthesized through dihydro-p-coumaric acid coupling with three malonyl-CoA units and then coupled in typical ways to form bisbibenzyls marchantins A and C (Scheme 62.5) [108].

scheme 00635

Scheme 62.5

Evidences have confirmed that bisbibenzyls can be produced by the coupling of two phenolic systems by means of free-radical reactions. These reactions can be mediated by oxidase enzymes. C–C bonds involving positions ortho or para to the original phenols, or ether linkages, may be formed in coupling of two of these bibenzyl structures [105]. A previous hypothesis for the biogenesis of marchantins, riccardins, and plagiochins considers cyclization of open-ring precursors, such as perrottetin E 146, through intramolecular phenol oxidation, accompanied by C–O or C–C linkage of the terminal m-hydroxyphenyl units [109]. Likewise, isoplagiochins A-D might be biosynthesized from isoperrottetin A 150 (Scheme 62.6) [110].

scheme 00636

Scheme 62.6

3.4 Biosynthesis of Phenanthrenes

Bibenzyls are regarded as the bicyclic intermediates of 9,10-dihydrophenanthrenes, and the biosynthetic pathway of 9,10-dihydrophenanthrenes was proposed as showed in Scheme 62.7. Oxidative coupling of the bibenzyl intermediate leads to the formation of phenanthrene [2].

scheme 00637

Scheme 62.7

4 Biological Activities

4.1 Antitumor Activity

4.1.1 Stilbenes and Oligostilbenes

Resveratrol, as a representative compound of stilbene, possesses diverse pharmacological activities. The antitumor property has taken the spotlight for its cancer preventive effect on skin cancer in a mice model. Subsequently, plenty of in vivo experiments targeting different tumor model were carried out to evaluate its therapeutic effects on tumors [111]. The results definitely show that resveratrol is able to inhibit or possess chemopreventive functions on different tumors, including breast cancer, liver cancer, gastric cancer, colorectal cancer, prostate cancer, leukemia, lung cancer, neuroblastoma, etc. In these experiments, the incidences, tumor volume, and metastasis are improved. Clinical trials of investigating resveratrol’s effects on colon cancer and melanoma (skin cancer) are intending to launch.

Combretastatins attract a lot of interests for their potent antitumor properties by inhibiting tubulin polymerization and disrupting the formation of tumoral vasculature. Combretastatin A-4 5 was proved to be the most potent candidate of combretastatins with GI50 of 3.20 nM in an antitumor screening project against the NCI-60 human tumor cell lines, followed by combretastatins A-1 2 and A-2 3 [112]. Further studies focused on the antitumor mechanism of combretastatins, and the results suggested that compounds 2, 3, and 5 possessed potent antimitotic effect through binding to the tubulin at colchicine site [113]. Combretastatin A-4, its prodrug combretastatin A-4 phosphate (CA-4-P), and other analogues are currently being investigated in the clinical trials. CA-4-P, being developed as vascular targeting agents, in combination with carboplatin has entered into phase III clinical trial for the treatment of anaplastic thyroid cancer.

The seeds of Iris halophila (Iridaceae) produced halophilol A, which possesses moderate cytotoxicity against KB cells and human mammary epithelial cells (HMECs) with IC50 values of 17.28 and 22.47 μM [114], respectively. The prenyl stilbenes 30–32 with dimethylchromene ring exhibit cytotoxic activity against Hepa-1clc7 cells with IC50 values of 8.5, 13.0, and 7.0 μM [18], respectively. Tested in the NCI-60 cell line human cancer screen, schweinfurthins A 33 and B 34 show significant cytotoxic activity with mean panel GI50 of 0.36 and 0.81 μM. Schweinfurthins E-H were isolated from M. alnifolia [115] and display potent antiproliferative effect against A2780 human ovarian cancer cell line with IC50 values ranging from 0.26 to 5.0 μM, respectively. Lakoochins A and B also possess cytotoxic activity against breast cancer cell line (6.1 and 3.1 μg/mL) and nasopharyngeal carcinoma cell line (20 and 6.1 μg/mL) [116].

4.1.2 Oligostilbenes

Three trimers nepalensinols A, C, and D and three tetramers nepalensinols B, G, and F were obtained from Kobresia nepalensis (Cyperaceae) [117, 118]. The inhibitory effect of the above six oligomers against the decatenation activity of topoisomerase II on kinetoplast DNA is evaluated with IC50 values ranging from 0.02 to 10.8 μg mL−1. Among them, nepalensinol B exhibits the strongest activity with an IC50 of 0.02 μg mL−1, much better than the clinical antitumor drugs daunorubicin (IC50 4.8 μg mL−1) and etoposide (IC50 70.0 μg mL−1). Vaticanol C is a resveratrol tetramer with dibenzobicyclo[3.2.1]octadiene moiety, is widely distributed in Dipterocarpaceae species, and shows potent growth suppressive activity with IC50 values of 5.9 μM against HL60 cells. Upunaphenol A is a hexamer obtained from Upuna borneensis and was found to suppress cell growth in HL60 cells through induction of apoptosis with IC50 at 9.2 μM [119].

4.1.3 Bibenzyls and Bisbibenzyls

Erianin (also named dihydrocombretastatin A-4), a dihydro derivative of combretastatin A-4 which has been initiated phase II clinical trial as antitumor agent, possessed potent cytotoxicity toward diverse cancer cell lines. It was evaluated against A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma cell lines with ED50 ranging from 0.002 to 0.33 μM, respectively [120]. It also showed potent inhibitory activity on the proliferation of HL-60 cells (IC50 38 nM) and was able to alter expression of bcl-2 and bax genes in HL-60 cells [121].

Bauhinols A 110 and B 111 exhibit significant cytotoxicity against NCI-H187 (small-cell lung cancer) and BC (breast cancer) cell lines with IC50 values ranging from 1.1 to 9.7 μg/mL. In addition, bauhinol A 110 is active toward KB cells (IC50 4.5 μg/mL) [64]. 3,5-Dihydroxy-4-methylbibenzyl shows cytotoxic activity, which is able to inhibit the growth rate of P-388 leukemia and hepatoma cell lines by 99.7% and 83.6% at 10 μg/mL, respectively [122].

The bisbibenzyls neomarchantins A 133 and B 134, marchantin C, and Glaucescens Bis Bibenzyl A and B possess moderate cytotoxicity against P-388 leukemia cells with IC50 ranging from 8 to 18 μg/mL [123]. Riccardin C and pusilatins B-C display moderate cytotoxicity against KB cells with ED50 of 7.1 to 16.4 μg/mL [79].

4.1.4 Phenanthrenes

The cytotoxic activities both in vitro and in vivo of lusianthridin and denbinobin isolated from Dendrobium nobile are evaluated. Both of them exhibit potent antitumor effects against A549 human lung carcinoma, SK-OV-3 human ovary adenocarcinoma, and HL-60 human promyelocytic leukemia with EC50 values ranging from 0.11 to 9.8 μg/mL [124].

Dimeric phenanthrenes denthyrsinol, denthyrsinone, and monomer denthirsinin demonstrate potent cytotoxicity against cervix adenocarcinoma HeLa, K-562, and MCF-7 cells with IC50 values from 1.6 to 9.9 μM [125]. A series of phenanthrenes, including 7-hydroxy-2,3,4,8-tetramethoxyphenanthrene, 3-hydroxy-2,4,-dimethoxy-7,8-methylenedioxyphenanthrene, 2-hydroxy-3,5,7-trimethoxyphenanthrene, 2-hydroxy-3,5,7-trimethoxy-9,10-dihydrophenanthrene, and confusarin are evaluated on their antitumor properties against HeLa cell line with IC50 values of 0.97–14.21 μM. [126, 127].

3,6-Dihydroxy-l,7-dimethyl-9-methoxyphenanthrene 181 and 3,6-dihydroxy-l-hydroxymethyl-9-methoxy-7-methylphenanthrene 182 are found to demonstrate significant cytotoxic responses against several tumor cell lines (Table 62.2). Compound 181 is more active against drug-resistant KB cells, while 182 is active against HT (fibrosarcoma) and U373 (glioma) cell lines [128].

Table 62.2 In vitro cytotoxic activity of 181 and 182 with human cancer cell lines (ED50 μg/mL)
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4.2 Antioxidant Activity

4.2.1 Stilbenes and Oligostilbenes

Lespedezavirgatol was obtained from Lespedeza virgata and shows potent antioxidant property. Its oxygen radical absorbance capacity (ORAC) value for Trolox equivalents is 762.96 at 1.5 μM, much better than 164.56 of vitamin C. Inhibitory effects of lespedezavirgatol against lipid peroxidation toward malondialdehyde levels in rat kidney homogenate and plasma are also evaluated with IC50 values of 0.16 and 0.18 mM, better than the control vitamin C, with IC50 values of 5.54 and 3.05 mM. The above results suggest that lespedezavirgatol is a potent candidate for antioxidants [129]. Tibeticanol 76 was obtained from Caragana tibetica and exhibits strong superoxide anion scavenging activity with an IC50 of 1.33 μM [46].

A series of oligostilbenes isolated from Vitis thunbergii are evaluated on their antioxidant properties based on the radical scavenging effect of the stable ABTS•+ free radical. The results are shown in Table 62.3. All of the tested compounds are more active than the positive control Trolox and display free-radical scavenging activity with EC50 values from 2.8 to 13.8 μM. Among them, (+)-ε-viniferin shows the most potent radical scavenging potency with EC50 of 2.8 μM [23].

Table 62.3 Effect of compounds from V. thunbergii on ABTS+ scavenging
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4.2.2 Bibenzyls and Bisbibenzyls

Marchantin H is able to inhibit nonenzymatic iron-induced lipid peroxidation in rat brain homogenates and NADPH-dependent microsomal lipid peroxidation with an IC50 of 0.51 and 0.32 μM [130]. It also possesses inhibitory effects of copper-catalyzed oxidation of human low-density lipoprotein. Marchantinquinone exhibits inhibitory effects of Fe2+-induced lipid peroxidation in rat brain homogenates (IC50 15.3 μM) and displays radical scavenging activity [131]. Schwartner et al. reported the antioxidative potential of three macrocyclic bisbibenzyls [marchantins A, B, and D], one acyclic bisbibenzyl (paleatin B) and a prenylated bibenzyl (perrottetin D) by pulse-radiolytic and EPR-spectroscopic techniques. The results confirm that these compounds are effective antioxidants [132]. Isoamoenylin and 5,4′-dihydroxy-3-α-l-rhamnopyranosyl-(1 → 3)-β-d- xylopyranosyloxybibenzyl showed radical scavenging activity, comparable with the control vitamin C and ascorbic acid [63, 133]. Five prenylated dihydrostilbenes, α,α-dihydro-3,5,3,4-tetrahydroxy-4,5-diisopentenylstilbene, α,α-dihydro-3,5,3,4-tetrahydroxy-5-isopentenylstilbene 183, α,α-dihydro-3,5,4-trihydroxy-4,5-diisopentenylstilbene, α,α-dihydro-3,5,4-trihydroxy-5-isopentenyl stilbene, and α,α-dihydro-3,5,3-trihydroxy-4-methoxy-5-isopentenylstilbene 184, from Glycyrrhiza glabra were tested for antioxidant effects by measuring the absolute inhibition rate constant (k inh) of the oxidation process. Compounds 183 and 184 display potent antioxidant properties with k inh values of 1.1 × 104 and 0.9 × 104 M−1 s−1 [134].

4.3 Antiplatelet Activity

Resveratrol prevents platelet aggregation and thrombus formation in vitro. In a hypercholesterolaemic diet-induced rabbit model, administration of resveratrol inhibited the platelet aggregation. This effect was also verified by reducing the atherosclerotic area and the size of the thrombus generated by laser-induced damage to the endothelium in mice.

Vitis thunbergii (Vitaceae), a folk medicine in Taiwan, produced several resveratrol oligomers, including vitisinol C with a tropilene structure in molecule, vitisinols B and D, and some known compounds (−)-viniferal, (+)-ε-viniferin, and (+)-vitisin C, etc. The isolated compounds were evaluated for antiplatelet aggregation activities induced by arachidonic acid (AA) and 9,11-dideoxy-11α,9α-epoxy-methanoprostaglandin F2α (U46619). Most of the tested oligomers demonstrate potent antiplatelet aggregation property with IC50 < 10 μM, more positive than aspirin (EC50 32.7 μM). In the above bioassay, (−)-viniferal and (+)-vitisin C are most effective against aggregation induced by AA and U46619, with IC50 values of 5.7 and 3.1 μM, respectively [23]. The results are summarized in Table 62.4.

Table 62.4 Effect of compounds isolated from V. thunbergii on the platelet aggregation induced by AA and U46619
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Marchantinquinone displays potent inhibitory activity on the aggregation of washed rabbit platelets induced by thrombin, arachidonic acid (AA), collagen, U46619, and platelet-activating factor (PAF) [135, 136]. It inhibits thromboxane B2 (TxB2) formation induced by thrombin, PAF, and collagen. In addition, marchantinquinone is able to inhibit the rising intracellular Ca2+ concentration stimulated by five inducers mentioned above [136]. Gigantol exhibits antiplatelet aggregation activity on SD-rat platelet aggregation [137]. 3-Methylgigantol possesses significant inhibitory effects against aggregation induced by AA, collagen, and PAF [138]. Among them, 3-methylgigantol is most potent effective against AA-induced aggregation (IC50 30 μM). Moscatilin is able to inhibit AA- and collagen-induced platelet aggregations [139]. Perrottetin E 146 shows inhibitory activity of thrombin (IC50 18 μM) [140].

The phenanthrenes, erianthridin, and denbinobin display potent antiplatelet activity on washed rabbit platelets against aggregation induced by either thrombin, arachidonic acid (AA), collagen, or PAF at a dose of 100 μg/mL. Erianthridin is proved to be the most potent compound with an IC50 of 9 μM against AA-induced aggregation [138].

4.4 Antidiabetic Activity

5,4′-Dihydroxystilbene-3-O-α-arabinopyranoside, named rumexoid, was found in Rumex bucephalophorus (Polygonaceae). This compound and resveratrol display potent α-glucosidase inhibitory activity even better than the commercial antidiabetic agent acarbose [141]. 2′-O-Demethylbidwillol B and addisofurans A-B were prenyl-substituted arylbenzofurans isolated from Erythrina addisoniae. Those compounds are inhibitors of type II diabetes target protein tyrosine phosphatase 1B with IC50 values of 13.6–15.7 μM. The linear prenyl chain was responsible for its inhibitory activity, and the cyclization of prenyl group decreased this effect [142]. In a bioassay-guided fractionation against α-glucosidase, 13-hydroxykompasinol A and scirpusin C were obtained from the seeds of Syagrus romanzoffiana and possess potent inhibitory activity against α-glucosidase type IV from Bacillus stearothermophilus with the IC50 value of 6.5 and 4.9 μM [143].

4.5 Antimicrobial Activity

4.5.1 Stilbenes and Oligostilbenes

Machaeriol B, a compound with hexahydro-6H-benzo[c]chromene system, was obtained from Machaerium multiflorum (Leguminosae), and it demonstrates potent antimalarial activity (IC50 0.12 μg/mL) against Plasmodium falciparum [144]. Preracemosols A and B exhibit moderate antimalarial activity with EC50 of 18.0 and 3.0 mg/mL, respectively [145]. Trans-4-isopentenyl-3,5,2′,4′-tetrahydroxystilbene was discovered in Artocarpus integer (Moraceae) and possesses antimalarial activity against Plasmodium falciparum (EC50 = 1.7 μg mL−1) [146]. This is the first report of antimalarial activity of stilbenes.

A series of arylbenzofuran-type stilbenes, guided by bioautographic assay for antifungal activity against Cladosporium herbarum, have been isolated from the root of Stemona collinsae (Stemonaceae) and tested in microwells against another four microfungi Alternaria citri, Fusarium avenaceum, Pyricularia grisea, and Botrytis cinerea [22]. Among them, stemofuran B shows the highest antifungal potency against above four parasitic fungi with EC50 values of 1.4 μg/mL. Stemofuran E exhibited antifungal property against C. herbarum with EC50 of 0.09 μg/mL.

Stilbene derivatives were obtained from Calligonum leucocladum, and the structures were determined as (E)-resveratrol 3-(6-galloyl)-O-β-d-glucopyranoside. Although ineffective when tested alone, it is able to restore oxacillin’s effectiveness against oxacillin/methicillin-resistant Staphylococcus aureus when used in combination. The galloyl group may play a role in this synergistic activity [147].

Hopeanolin was obtained from the stem bark of Hopea exalata and exhibits potent antifungal properties against six types of pathogenic fungi Alternaria attenata, Alternaria solani, Colletotrichum lagenarium, Fusarium oxysporum f. sp. vasinfectum, Pyricularia oryzae, and Valsa mali with MIC values ranging from 0.10 to 22.5 μg mL−1 [148].

4.5.2 Bibenzyls and Bisbibenzyls

Bryophytes normally grow in humid habitats; however, they are seldom damaged by fungi. It indicates that bryophytes are able to elaborate constitutive and inducible antifungal natural products against adverse effects. A large amount of bibenzyls and bisbibenzyls with antifungal activity have been found in plants, primarily in bryophytes (Table 62.5), which provided important sources for research and development of antifungal agents. The antifungal effects of bibenzyls and bisbibenzyls were summarized in Table 62.5.

Table 62.5 Antifungal bibenzyls and bisbibenzyls
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The bibenzyls 4-hydroxy-3′-methoxybibenzyl, 2,4,6-trichloro-3-hydroxybibenzyl, 2, 4-dichloro-3-hydroxylbibenzyl, 2-chloro-3-hydroxybibenzyl, together with bisbibenzyls neomarchantins A 133 and B 134, and marchantin C show antimicrobial activity against the gram-positive bacterium Bacillus subtilis [60, 123, 150]. In addition, 4-hydroxy-3′-methoxybibenzyl is active toward Escherichia coli [150].

4.6 Anti-inflammatory Activity

Anti-inflammatory properties of resveratrol have been confirmed, which is an effective inhibitor of cyclooxygenase (COX) in vitro. It is also found that resveratrol significantly reduces acute and chronic chemically induced edema, lipopolysaccharide-induced airway inflammation, and osteoarthritis. Resveratrol could also present as an alternative, instead of aspirin, for treatments of chronic inflammation because of the latter’s side effect on the stomach. Resveratrol derivatives displayed similar anti-inflammatory effects. For instance, resveratrol (E)-dehydrodimer 11-O-β-d-glucopyranoside and resveratrol (E)-dehydrodimer from Vitis vinifera show significant inhibitory activity against cyclooxygenase-1 (COX-1) with IC50 of 5.2 and 4.3 μM and against cyclooxygenase-2 (COX-2) with IC50 of 7.5 and 3.7 μM. From the above results, these two compounds seem to be the worthy candidates for further research to find application in anti-inflammatory treatment [151].

(+)-Vitisifuran A and heyneanol A were found in Vitis genus and display potent inhibition on biosynthesis of LTB4 with inhibitory rate of 72% and 76% at a concentration of 10 μM [152]. A tetramer named gnetuhainin R 73 was obtained from the same species (G. hainanense) and shows potent histamine receptor antagonism (IC50 0.1 μM) [44]. Aiphanol exhibited significant inhibitory activities against COX-1 (IC50 1.9 μM) and COX-2 (9.9 μM) [153].

Stemofurans B, D, G, and J and stilbostemin G were reported possessing anti-inflammatory effects with IC50 values ranging from 3.7 to 26.3 μM by inhibiting leukotriene formation [154]. The inhibition of lipopolysaccharide-induced nitric oxide synthase (NOS) by 19 bisbibenzyls in RAW 264.7 macrophages has been reported, and marchantin A is most effective with IC50 values of 1.44 μM. The structure-activity relationship (SAR) is discussed, and the phenolic hydroxyl groups and diarylether bonds play important roles in its inhibitory effect [155]. Pusilatins B-C exhibit selective DNA polymerase-β inhibitory activity with IC50 of 13.0 and 5.16 μM [79]. Bauhinol B 111 and 3,5-dihydroxy-2-(3-methyl-2-butenyl)bibenzyl are potent inhibitors of COX-1 and COX-2 with IC50 ranging from 1.3 to 9.0 μg/mL [134].

Phenanthrenes obtained from the Stemona species were evaluated on their leukotriene biosynthesis inhibition property using human neutrophile granulocytes in vivo. Stemanthrenes A 162 and D 165 display inhibitory activity in a dose-dependent manner, with IC50 values of 8.5 and 4.8 μM. Stemanthrenes B 163 and C 164 possess 100% inhibition against leukotriene biosynthesis at 25 μM. The phenanthrenes might be responsible for the anti-inflammatory and antiasthmatic principles of the Stemona species [154]. Denbinobin, a phenanthraquinone from Dendrobium moniliforme, shows in vitro anti-inflammatory activity. It inhibits the formation of tumor necrosis factor and prostaglandin E2 induced by lipopolysaccharide in RAW 264.7 and N9 cells at a dose of 1 μM [100].

4.7 Neuroprotective Activity

In vivo pharmacological studies have indicated that resveratrol has a neuroprotective effect, including reduced lipid, peroxidation and neurological cell destruction, attenuation of induced lesion areas, induced tolerance to brain injury, reduced frequency of seizures, impairment of motor coordination, and enhancement of learning [111].

Stilbostemin B 3′-β-d-glucopyranoside, stilbostemin H 3′-β-d-glucopyranoside, and stilbostemin I 2″-β-d-glucopyranoside possess significant neuroprotective activity against 6-hydroxydopamine-induced neurotoxicity in human neuroblastoma SH-SY5Y cells [156]. Hopeahainol A from Hopea hainanensis contains an unprecedented carbon skeleton and shows potent acetylcholinesterase inhibitory effect with an IC50 value of 4.33 μM, comparable even to that of huperzine A (IC50 1.6 μM) [157]. The tetramer neohopeaphenol A from the same species also displays significant inhibitory action against AChE with an IC50 value of 7.66 μM [158].

4.8 Hepatoprotective Activity

Acer mono (Aceraceae), a Korean folk medicine for hemostasis, produces two potent hepatoprotective stilbene glycosides, 5-O-methyl-(E)-resveratrol 3-O-β-d-glucopyranoside and 5-O-methyl-(E)-resveratrol 3-O-β-d-apiofuranosyl-(1 → 6)-β-d-glucopyranoside [16]. Those two compounds significantly prevent the depletion of glutathione (GSH) in H2O2-injured primary cultured rat hepatocytes and potently restore the level of GSH depleted by buthionine sulfoximine or diethylmaleate in the presence or absence of H2O2. In addition, they preserve the effects of antioxidant enzymes such as superoxide dismutase, glutathione reductase, and glutathione peroxidase reduced by H2O2 insults. Therefore, it is concluded that both compounds exerted significant hepatoprotective effects against H2O2-induced hepatotoxicity by maintaining the antioxidant defense system [159].

4.9 Cardioprotective Activity

It is well known that drinking wine and grape juices will reduce cardiovascular, cerebrovascular, and peripheral vascular risks due to the presence of resveratrol. As a natural antioxidant, resveratrol is able to prevent LDL oxidation, scavenge intracellular reactive oxygen species, lower the oxidative stress, and induce NO synthesis. Resveratrol modulates various aspects of cardiovascular diseases and is effective against atherosclerosis, hypertension, ischemia reperfusion injury and heart failure, and many other cardiac dysfunctions [111].

4.10 Phytotoxicity

The phenanthrenes, ephemeranthol-A and fimbriol A from Epidendrum rigidum, together with erianthridin from M. densa demonstrated phytotoxicity against Amaranthus hypochondriacus with IC50 values of 0.12, 5.9, and 58.2 μM [160]. The phenanthrenes from the Juncus genus show growth inhibitory effects against the green alga Selenastrum capricornutum with IC50 values ranging from 11.1 to 19.9 μM [161].

Bibenzyls are elaborated to confer the producing plants’ selective advantage against the competition from the other plants and microbial attack. Gigantol, batatasin III, 2,3-dimethoxy-9,10-dihydrophenathrene-4,7-diol, and 3,4,9-trimethoxyphenanthrene-2,5-diol from the orchid Epidendrum rigidum inhibit radicle growth of Amaranthus hypochondriacus with IC50 of 0.65, 0.1, 0.12, and 5.9 μM [160].

5 Conclusion

Stilbenoids represent a group of important natural products in the plant kingdom. The developments of modern analytical methods accelerate the discovery of these compounds, and to this day more than 1,000 stilbenoids have been isolated. For the stilbenes, bibenzyls, and phenanthrenes, these three groups shared the feature of their nucleus with hydroxyls, methyl, methoxy, prenyl, geranyl, glycosyl, etc., substituents. The oligostilbenes and bisbibenzyls are formed by polymerization of stilbene and bibenzyl units, and the diverse polymerized patterns produced their diverse structures. They display diverse biological activities and have the potential to be developed as new drugs, especially in the field of antitumor, anti-inflammation, and cardioprotective drug research. The representative compounds resveratrol and combretastatin A-4 phosphate are currently being evaluated as drugs for the treatment of Alzheimer’s disease and tumors in clinical trials and have shown satisfactory therapeutic effects. Furthermore, resveratrol displays developing prospects as a cardioprotective drug.

There are problems that need to be noted. Concerning the oligostilbenes, they commonly possess large molecules, intricate structures, and complex stereochemistry, and these characteristics cause troubles in structure identification and chemical total synthesis, therefore, limiting the probability to be developed to new drug. The bisbibenzyls are mainly distributed in the bryophytes, which are very small terrestrial spore-forming green plants, and different for collections. Therefore, getting enough plant materials for phytochemical investigation and new drug research is really a Gordian knot and resorts to the chemical synthesis for resolving the resource problems.