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Int. J. Mol. Sci. 2010, 11(1), 79-106; doi:10.3390/ijms11010079

Review
Structural Features and Biological Properties of Ellagitannins in Some Plant Families of the Order Myrtales
Takashi Yoshida *, Yoshiaki Amakura and Morio Yoshimura
College of Pharmaceutical Sciences, Matsuyama University, Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan; E-Mails: amakura@cc.matsuyama-u.ac.jp (Y.A.); myoshimu@cc.matsuyama-u.ac.jp (M.Y.)
*
Author to whom correspondence should be addressed; E-Mail: tyoshida@cc.matsuyama-u.ac.jp; Tel.: +81-89-925-7111; Fax: +81-89-926-7162.
Received: 21 November 2009; in revised form: 25 December 2009 / Accepted: 2 January 2010 /
Published: 6 January 2010

Abstract

: Plant tannins, including hydrolysable and condensed varieties, are well known antioxidants in medicinal plants, foods, and edible fruits. Their diverse biological properties and potential for disease prevention have been demonstrated by various in vitro and in vivo assays. A number of ellagitannins, the largest group of hydrolysable tannins, have been isolated from dicotyledoneous angiosperms and characterized. This diverse class of tannins is sub-grouped into simple ellagitannins, C-glycosidic ellagitannins, complex tannins (condensates of C-glycosidic tannins with flavan-3-ol), and oligomers up to pentamers. This review outlines and describes the chemotaxonomic significance of structural features in various types of ellagitannins found in plants belonging to the Myrtaceae, Onagraceae, and Melastomataceae families, which are all included in the order Myrtales. Any biological activities that have been reported, including antitumor and antibacterial effects as well as enzyme inhibition, are also reviewed.
Keywords:
ellagitannins; C-glycosidic ellagitannins; oligomeric ellagitannins; Myrtales; biological activity

1. Introduction

Plant tannins, one of the major groups of antioxidant polyphenols found in food and beverages, have attracted a lot of attention in recent years because of their multifunctional properties beneficial to human health. These diverse tannins may be divided into two large groups: condensed and hydrolysable. Condensed tannins are formed through the condensation of flavan-3-ols (catechins) and are often referred to as proanthocyanidins. Among the more than 500 hydrolysable tannins hitherto characterized, ellagitannins, which produce ellagic acid upon hydrolysis, constitute the largest group; the remaining group is gallotannins (galloylglucoses). The ellagitannins include: (1) monomeric ellagitannins, (2) C-glycosidic ellagitannins with an open-chain glucose core, (3) condensates of C-glycosidic tannins with flavan-3-ol (complex tannin), and (4) oligomers which are produced through intermolecular C-O or C-C bonds between monomers [1,2]. Unlike the condensed tannins that are widespread throughout the plant kingdom, ellagitannins have been found only in dicotyledoneous angiosperms. Among the plant families rich in ellagitannins are the Myrtaceae, Lythraceae, Onagraceae, Melastomataceae, and Combretaceae [3]. These families belong to the order Myrtales according to the plant classification systems of New Engler, Cronquist, and APGII (angiosperm phylogeny group) [4]. Ellagitannins have also been isolated from plant species of Trapaceae and Punicaceae, which belong to Myrtales in Cronquist’s and the New Engler’s systems. This review outlines and describes the chemotaxonomic significance of structural features found in various types of ellagitannins, focusing on representative examples found in the plants of Myrtales. Any observed antioxidative and antitumor effects of these ellagitannins are also reviewed.

2. Monomeric Ellagitannins

2.1. Simple Ellagitannins

Ellagitannins are characterized by the presence of one or more hexahydroxydiphenoyl (HHDP) unit(s) on a glucopyranose core. The HHDP group is biosynthetically formed through intramolecular, oxidative C-C bond formation between neighboring galloyl groups in galloylglucoses [5]. They are easily hydrolysed, either enzymatically or with acid, to liberate a stable ellagic acid as the dilactone form of hexahydroxydiphenic acid. In addition to the HHDP group, other constituent acyl units in ellagitannins include a galloyl group and HHDP metabolites such as valoneoyl, dehydrohexahydroxydiphenoyl (DHHDP), and chebuloyl groups. Variations in the number and position of these acyl units on the glucose core provide a variety of analogs such as tellimagrandin I (1), and II (2), pedunculagin (6), casuarictin (7) [6], chebulagic acid (14), and chebulinic acid (15) [7] (Figure 1). Note that the chiral HHDP group at O-2/O-3 and O-4/O-6 of the glucose residue has an S-configuration, whereas that at O-3/O-6 has an R-configuration, as indicated by a positive and negative Cotton effect around 230 nm in their respective circular dichroism (CD) spectra [8].

Representative ellagitannin monomers thus far isolated from the Myrtaceae, Melastomataceae, Onagraceae, Trapaceae, Combretaceae, and Punicaceae families are summarized in Figure 1 and Table 1.

Ellagitannins having a 4C1-glucopyranose core, e.g., 18, have been isolated along with gallotannins from various other plant families and show little chemotaxonomic significance. The considerably rare tannins punicalagin (9) and punicalin (10), both of which contain a gallagyl unit and were first isolated from the pericarps of pomegranate (Punica granatum Punicaceae) [40], were a characteristic component in some Terminalia species. This supports the hypothesis that Punicaceae is chemotaxonomically proximate to Combretaceae as classified by Cronquist and Engler. The punicalagin analogs tergallagin (11) and terflavins A (12) and B (13) were also isolated from T. chebula [35] and T. catappa [34].

Some Terminalia species produce ellagitannins with a 1C4-glucopyranose core and a unique chebuloyl group, such as chebulagic acid (14) and chebulinic acid (15). Although 14 and 15 have also been found in plants of the Geranium [41] and Euphorbia genera [42], their co-occurrence with 9 and/or 10 is a chemotaxonomic feature of Terminalia.

2.2. C-Glycosidic Ellagitannins

C-Glycosidic ellagitannins have been found in many plant families, including Lythraceae, Myrtaceae, Combretaceae, Melastomataceae, and Punicaceae, as well as Fagaceae, Betulaceae, Casuarinaceae, Rosaceae, Theaceae, and Elaeagnaceae [1]. They are categorized into two types: castalagin-type, which contain a flavogalloyl unit participating in the C-glucosidic linkage, such as castalagin (16) and its C-1 epimer, vescalagin (18), and casuarinin-type, which contain an HHDP unit, such as casuarinin (20) and stachyurin (21). In addition to these tannins, their metabolites, i.e., grandinin (19), casuariin (22), and 5-desgalloylstachyurin (23), have been isolated from various plants of the Myrtales (Figure 2). Lagerstroemia flos-reginea and L. speciosa (Banaba) belonging to the family Lythraceae are particularly rich in C-glycosidic tannins including 16, 18, and 2023 and casuarinin-type metabolites including punicacortein A (24) and lagerstroemin (29). Punicacortein A (24) and its analogs epi-punicacortein A (25) and punicacorteins B (26)–D (28) were isolated from Punica granatum. Tannins 27 and 28, which both contain a gallagyl unit, were obtained together with punicalagin (9) from Terminalia arborea and T. macroptera, respectively.

The plant sources of C-glycosidic ellagitannins obtained from the order Myrtales are listed in Table 2.

2.3. Complex Tannins

Complex tannins (flavono-ellagitannins) are characterized by a unique C-C condensed structure of C-glycosidic tannins (vescalagin-type or stachyurin-type) with flavan-3-ol (catechin or epicatechin). Unlike the C-glycosidic tannins, these tannins have been found in a rather limited number of plant species belonging to the Combretaceae, Myrtaceae, Melastomataceae, Fagaceae, and Theaceae families [3].

A typical example of a vescalagin-based complex tannin, acutissimin A (30) was first isolated from fagaceous plants and later found in the combretaceous plant, Anogeissus acuminata var. lanceolata [43], and the myrtaceous plant, Syzygium aqueum [21]. Another myrtaceous plant, Psidium guajava, reportedly produces a diversity of complex tannins including 30 and its analogs guajavin B (31), psidinins A (32) and B (34), and mongolicains A (33) and B (35); and the stachyurin-based analogs guajavin A (36), guavins A (38), C (39) and D (40), and psidinin C (41) [54] (Figure 3). Melastoma malabathricum, a member of the Melastomataceae, also produces metabolites from the stachyurin-based complex tannins malabathrins A (43), E (42), and F (44) [55].

A stachyurin-based congener, stenophyllanin A (37), was isolated from Melaleuca squarrosa (Myrtaceae) [52] and Melastoma malabathricum (Melastomataceae) [55].

It is noteworthy that both vescalagin- and stachyurin-based complex tannins hitherto isolated are all characterized by possessing a β-oriented C-C bond at glucose C-1 [1]. The formation of this class of tannins is rationalized by non-enzymatic diastereoselctive nucleophilic substitution reaction at the exo β-position of the benzylic C-1 cation where is less hindered than the α-site. In fact, many examples of hemisynthesis of the complex tannin by simple acid-catalized reaction between C-glycosidic tannin and (+)-catechin or (–)-epicatechin have been reported.

3. Oligomeric Ellagitannins

Oligomeric ellagitannins are common among many plant families, including the Fagaceae, Rosaceae, Coriariaceae, Onagraceae, Melastomataceae, Myrtaceae, and Lythraceae [3]. This class of tannins is divided into three sub-groups based on structural features: (1) oligomers that contain a valoneoyl group or its equivalent, formed by intermolecular C-O bonds between an HHDP group and a galloyl group of a neighboring monomer, (2) macrocyclic oligomers formed by two C-O bonds, and (3) C-glycosidic tannin oligomers produced by intermolecular C-C bond formation between C-1 of one monomer and the aromatic ring of another (see Figure 4). These structural features are chemotaxonomically significant and are often characteristic of the plant genus or family. The following section provides an overview of the oligomers isolated thus far from each of the families within the Myrtales.

3.1. Oligomers from the Combretaceae

Although more than 10 of the combretaceous plant species described above have yielded various ellagitannin monomers, only Anogeissus acuminata was reported to yield C-C linked dimers of C-glycosidic ellagitannin, including castamollinin (45), anogeissusins A (46) and B (47), and anogeissinin (48) [43] (Figure 5). Dimers 4648 are relatively rare tannins in which two equivalents of vescalagin-type monomer are connected to or through the A-ring of a (+)-catechin or (+)-gallocatechin.

3.2. Oligomers from the Lythraceae and Onagraceae

The regio-isomeric dimers, reginins A (49) and D (52) together with reginins B (50) and C (51), which are produced by intermolecular C-O bonds between casuarinin (stachyurin) and pedunculagin, were isolated from Lagerstroemia flos-reginea (Lythraceae) [47] (Figure 6). Reginin A (49) has also been isolated from the leaves of L. speciosa, which are popular as “banaba” in the Philippines [48]. Unique macrocyclic oligomers, woodfordins C (53) and D (58) and their desgalloyl congeners oenotheins B (54) and A (59), were obtained from the leaves of Woodfordia fruticosa, one of the Jamu medicines in Indonesia [56]. Analogous macrocyclic dimers, cuphiins D1 (55) and D2 (56) co-occur with 53 and 54 in Cuphea hyssopifolia, a lythraceous shrub native to Mexico [57]. Oenotheins A (59) and B (54) were first isolated as the main tannins in Oenothera erythrosepala leaves [24] and are widely distributed in the Oenothera and Epilobium species of Onagraceae, i.e., O. laciniata [25], O. biennis [58], O. tetraptera [26], E. angustifolium [23], and many other Epilobium species [59]. The occurrence of oxidized metabolites oenotherins T1 (60) and T2 (61) of 59 in O. tetraptera leaves was recently reported by Taniguchi et al. [26,60]. The chemical conversion of 60 to 59 was achieved by reduction with Na2S2O4.

3.3. Oligomers from Myrtaceae

In addition to the Lythraceae and Onagraceae, oenothein B (54) has been isolated from the myrtaceous plants Eucalyptus alba [15], Eucalyptus cypellocarpa [61], Eucalyptus consideniana [16], Eugenia uniflora [62], Melaleuca leucadendron [63], and Myrtus communis [19]. Of these plants, E. uniflora, E. cypellocarpa, and M. communis also produce eugeniflorin D2 (57) with a dehydrovaloneoyl group isomeric to that in oenotherin T1 (60). It recently has been shown that the leaves of Melaleuca squarrosa, an evergreen shrub indigenous to southeastern Australia, are rich in C-glycosidic ellagitannins including several new oligomers such as melasquanins A (62), B (63), C (64), and D (65), in addition to the previously reported alienanin B (66), and casuglaunins A and B (67) [52] (Figures 79). These oligomers may be biosynthesized through C-C bond formation facilitated by a nucleophillic attack (a–d) of the aromatic acyl ring of casuarinin (20) on β-site of the C-1 benzylic cation from stachyurin (21) (Figure 8) in a similar manner to that described in Sections 2–3.

The plant also yields a unique complex tannin dimer, cowaniin (68), first obtained from Cowania mexicana (Rosaceae) [64]. The chemical structure 68 inferred from spectral data was confirmed by conversion into 67 following an acid treatment.

3.4. Oligomers from Melastomataceae

A series of studies on plant species in six genera (Medinilla, Heterocentron, Tibouchina, Melastoma, Bredia, and Monochaetum) of the Melastomataceae has revealed more than 20 characteristic ellagitannin oligomers up to pentamers, e.g., nobotanins A–C and E–T. These oligomers share two common features: (1) they are essentially composed of two different monomers, casuarictin (7; C) and pterocaryanin C (69; PC), which are coupled alternatively to form the valoneoyl unit; and (2) the galloyl group of 69 can only participate in the formation of the valoneoyl group at O-5, whereas the HHDP groups of both monomers are susceptible to bond formation regardless of their positions [65] (Figure 10).

These characteristics are chemotaxonomically significant relative to oligomers connected through the valoneoyl group, which are mostly constructed from a single monomeric component. The representative oligomers are nobotanins B (70; C-PC) [12], F (71; PC-C), and K (72; PC-C-PC-C), although 70 is the most abundant dimer in most species of this family. Nobotanin B (70) also seems to be a key compound from which trimers and tetramers are producible by further bonding with 7 and 69, as observed in nobotanins E (73; PC-C-PC) and K (72) [66] (Figure 10). The largest pentameric oligomers, melastoflorins A (74) through D (77), were isolated together with several dimers and tetramers from the Colombian shrub Monochaetum multiflorum [65] (Figure 11).

4. Structure Determination of the Oligomeric Ellagitannins

Structure elucidation of the oligomers has generally been achieved by (1) identification of their constituent units by methylation of the tannin followed by methanolysis or direct acid hydrolysis, (2) detailed spectroscopic analyses using MS, UV and NMR spectra including 2-dimensional 1H-1H (or 1H-13C) COSY and 1H-detected multi-bond heteronuclear multiple quantum coherence (HMBC), and (3) chemical confirmation of the structure presumed on the basis of the findings from the above (1) and (2) by the characterization of partial hydrolysates of smaller molecule in hot water as exemplified for nobotanin B (70) in Figure 12. Molecular weights up to 4,000 are nowadays determined with the aid of electrospray mass measurement in the presence of ammonium acetate, or FABMS ([M + H]+ or [M + Na]+). In the NMR analyses, HMBC provides a convenient and reliable way to determine the position of each acyl group on the glucose core by three-bond correlations between the aromatic proton and glucose proton through a common ester carbonyl carbon as illustrated for melasquanin A (62) in Figure 13. The atropisomerism of the chiral biphenyl moiety in the molecule is directly determined without any degradation reaction by circular dicroism (CD) spectrum in which positive or negative Cotton effect at around 230 nm is diagnostic for (S)- or (R)-configuration, respectively [8].

5. Biological Activities of Ellagitannins Found in the Myrtales

Remarkable progress in the structural characterization of the numerous tannins in foods, beverages, and medicinal plants since the 1980s has enabled in vitro and in vivo studies of their biological properties based on structural differences. A wide range of significant biological activities beneficial to human health have been reported for both ellagitannins and proanthocyanidins. The strong affinity of tannins to various biopolymers such as enzymes, and antioxidative effects based on radical scavenging, are key to their diverse biological effects [1]. A survey of the biological activity of the Myrtales tannins using the electronic search engines SciFinder Scholar and Science Direct revealed various antimicrobial, antitumor, enzyme-inhibitory, and immunomodulatory effects of ellagitannins encountered in species of Combretaceae, Lythraceae, Myrtaceae and Onagraceae, as shown in Table 3.

5.1. Casuarinin (20), Castalagin (21), and Related Tannins

Kolodziej et al. [69] evaluated the in vitro antileishmanial activity of various types of tannins using Leishmania donovani. Although none of the tannins showed significant antiparasitic effects against the extracellular promastigote of L. donovani (EC50 > 25 μg/mL), all of the hydrolysable tannins, including oligomers, exhibited potent activity (EC50 < 0.4–12.5 μg/mL) against the intracellular amastigote form which resides within murine macrophage-like RAW 264.7 cells infected with L. donovani. Observed potencies were stronger or comparable to that of the reference compound, Pentosam® (EC50 7.9 μg/mL), which is therapeutically used as antileishmanial drug. Among the hydrolysable tannins, the most potent antileishmanial activity was exhibited by geraniin and related tannins (EC50 < 0.4 μg/mL). The C-glycosidic tannins casuarinin (20) and castalagin (16) also showed pronounced antileishmanial activities with EC50 values of 0.5 and 2.7 μg/mL, respectively. Note that most of these tannins, with the exception of oligomers, exhibited low cytotoxicity against murine host cells (EC50 > 25 μg/mL). Separate functional assays have shown that the amastigote-specific activity of these tannins is likely associated with immunomodulatory effects, such as macrophage activation to release cytokines, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. The degree of these immunomodulatory effects was highly correlated with the degree of intracellular Leishmania death. The search for antiparasitic substances in butanol extracts of Anogeissus leiocarpus and Terminalia avicennoides, which are used to treat some parasitic diseases in Africa, resulted in the characterization of castalagin (16) as a primary antileishmanial component with an EC50 ranging from 55 to greater than 150 μg/mL against the promastigote forms of four Leishmania strains [44].

Casuarinin (20) isolated from Terminalia arjuna also exhibits in vitro antivirus effects against Herpes simplex virus type 2 (HSV-2) with an IC50 of 3.6 and 1.5 μM in XTT and plaque reduction assays, respectively. These effects were associated with the inhibition of viral attachment and cell penetration [67]. Lin et al. [68] also found that 20 induced apoptosis in human breast adenocarcinoma MCF-7 cells and in human non-small cell lung cancer cells A549 by blocking cell cycle progression in the G0/G1 phase.

In the screening of spontaneously hypertensive rats, castalagin (16), chebulinic acid (15), and corilagin were identified as the major antihypertensive substances among the hydrolysable tannins isolated from the leaves of Lumnitzera racemosa (Combretaceae) [45].

Chebulagic acid (14) from Terminalia chebula has been shown to reversibly and non-competitively inhibit α-glucosidase (maltase) activity, suggesting a potential for managing type-2 diabetes [71]. Other tannins that have been identified as α-glucosidase inhibitors are tellimagrandin I (1) and eugeniin (casuarictin) (7) from Syzygium aromaticum (Myrtaceae) [70]. Recently, Reddy et al. reported that 14 also exhibited potent anti-inflammatory effects in mouse macrophage cell line RAW 264.7 that had been stimulated with LPS by inhibition of NF-κ.B activation and MAP kinase phosphorylation [73], and in COLO-205 cells by enzyme inhibition of COX and 5-LOX [72].

5.2. Punicalagin (9) and Related Tannins

Hepatoprotective effects of various tannins based on their ability to scavenge radical reactive oxygen species (ROS) have been demonstrated both in vitro and in vivo. For example, punicalagin (9) and punicalin (10) from Terminalia species exhibited inhibitory effects on hepatotoxicity induced by acetaminophen [75] and CCl4 [38]. Other activities associated with the antioxidative effects of punicalagin (9) include the suppression of bleomycin-induced genotoxicity in cultured Chinese hamster ovary cells [76] and of the proliferation of H-ras-transformed NIH3T3 cells. These effects are due, in part, to decreases in intracellular superoxide levels, which may modulate downstream signaling of Ras protein [77].

5.3. Lagerstroemin (29)

Lagerstroemia speciosa (Lythraceae) has been used as an herbal medicine for the treatment of diabetes in the Philippines. Screening of the plant extract identified lagerstroemin (29), flosin B (C1-epimer of 29), and reginin A (49) as activators of glucose transport using rat fat cells, all of which are characteristic C-glycosidic ellagitannins of the plant [78]. The insulin-like activity of 29 was indicated by increases in glucose uptake by rat adipocytes, and by increased tyrosine-phosphorylation in Chinese hamster ovary cells expressing human insulin receptors [79]. In addition, casuarinin (20), stachyurin (21), and casuariin (22) as well as 29 were identified as active components in the stimulation of insulin-like glucose uptake and in the inhibition of adipocyte differentiation (20 and 29) in 3T3-L1 cells [80].

5.4. Oenothein B (54) and Related Macrocyclic Oligomers

Macrocyclic oenothin B (54) reportedly exhibited remarkable host-mediated antitumor activity with intraperitoneal injection several days before inoculation of sarcoma 180 tumor cells into the abdomen of mice [24]. Evaluation of activity was gauged by the number of survivors and the percent increase in life span (%ILS) 60 days after administration. Treatment with a 10 mg/kg dose of oenothein B (54) resulted in 4 survivors out of 6 mice and 196% ILS, the most potent results of among the approximately 100 polyphenols evaluated. This activity was related to an immunomodulatory effect consisting of macrophage activation and consequent release of cytokine interleukin-1β [87]. Woodfordin C (53) also exhibited a potent activity with 160% ILS and one survivor out of five mice after 60 days [56]. The potent activity of the oligomeric ellagitannins stands in contrast to the negligible activity observed with most of the monomeric hydrolysable tannins, proanthocyanidins, and related low-molecular weight polyphenols.

Woodfruticosin (woodfordin C) (53) was also an effective inhibitor (IC50 2.5 μg/mL) of deoxyribonucleic acid topoisomerase II, the potency of which was 10-fold stronger than that of adriamycin and etoposide in molar concentrations [81].

Eugeniflorin D1 and D2 (57) as well as oenothein B (54) obtained from the extract of Eugenia uniflora (Myrtaceae) were efficient inhibitors of Epstein-Barr virus (EBV) DNA polymerase, a key enzyme for replication of EBV associated with nasopharyngeal carcinoma [82].

Using activity-guided fractionation for bioactive components of Epilobium species, Ducrey et al. [59] showed that oenothein A (59) and B (54) are potent inhibitors of 5α-reductase and aromatase, which are involved in the etiology of benign prostatic hyperplasia.

Biological studies of an oenothein B analog, cuphiin D1 (55), isolated from Cuphea hyssopifolia (Lythraceae) revealed antitumor effects through the induction of apoptosis in human promyelocytic leukemia (HL-60) cells and human cervical carcinoma (HeLa) cells [85]. Cuphiin D1 (55) was also shown to activate human peripheral blood mononuclear cells to release cytokines IL-1β, IL-2 and TNF-α [84].

Many pathogenic bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), have acquired resistance to various clinical antibiotics. This worldwide problem is driving the development of new antibiotic drugs. Observed synergistic effects of certain polyphenols such as oenothein B (54) and tellimagrandin I (1) have been suggested as a means to restore the effectiveness of β-lactam antibiotics against MRSA. When used together with these tannins, the MICs of oxacillin against MRSA strains were markedly lowered to 1/250 or 1/500 [88]. These results may represent one strategy for overcoming emergent bacterial resistance.

5.5. Nobotanins

In a survey for new, natural anticancer chemotherapeutic drugs, some oligomeric ellagitannins showed promise as inhibitors of poly(ADP-ribose) glycohydrolase, which is associated with gene activation upon DNA repair, replication, and transcription [86]. During initiation of gene expression, DNA replication, and cell differentiation, poly(ADP-ribose) from specific chromosomal proteins is degraded primarily by poly(ADP-ribose) glycohydrolase to yield ADP-ribose and mono(ADP-ribosyl) proteins. It has been suggested that this degradation of poly(ADP-ribose) is an important factor in the regulation of gene activation. Ellagitannins showed an appreciable inhibitory effect with an IC50 of 0.3–11.9 μM on poly(ADP-ribose) glycohydrolase purified from human placenta. Procyanidin oligomers and their constituent flavan-3-ols were inactive even at concentrations of 100 μM. Potent activity was exhibited by oligomeric ellagitannins, including dimers such as oenothein B (54) (IC50 4.8 μM) and nobotanin B (70) (IC50 4.4 μM), a trimer (nobotanin E (73), IC50 1.8 μM), and a tetramer (nobotanin K (72), IC50 0.3 μM).

6. Conclusions

A large number of ellagitannins have been isolated and characterized from a wide array of plant sources during the last several decades. The plants from which individual ellagitannins were first isolated belonged largely to the order Myrtales. Most notably, several Terminalia species of Combretaceae produce punicalagin and its congeners, all of which contain a unique gallagyl group, previously found only in Punica granatum (Punicacease). These findings imply a close chemotaxonomic relationship between these plants. Approximately 40% of the oligomeric ellagitannins characterized thus far were initially isolated from species of Onagraceae, Lythraceae, Myrtaceae, Trapaceae, and Melastomataceae, indicating that these plant varieties are good natural sources of these oligomers. In particular, macrocyclic tannins, which include oenothein B and its analogs, are characteristic of the Onagraceae, Lythraceae, and Myrtaceae. Various in vitro and in vivo assays have demonstrated diverse biological activities for these ellagitannins and indicate the potential of these materials as antioxidant food additives [89]. However, although there are several reports that identify ellagitannin metabolites in animal urine and feces, e.g., ellagic acid derivatives (77, 78) [90] and compounds 7984 [91], the bioavailability of these tannins in humans has not been studied extensively.

Further studies in this field will include characterization of immunomodulating effects in the digestive tract that could clarify the role(s) of ellagitannins in human health and help explain their widespread use in traditional medicines.

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Ijms 11 00079f1 1024
Figure 1. Structures of monomeric ellagitannins 115.

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Figure 1. Structures of monomeric ellagitannins 115.
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Figure 2. Structures of C-glycosidic ellagitannins 1629.

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Figure 2. Structures of C-glycosidic ellagitannins 1629.
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Figure 3. (a) Structures of complex tannins 3040. (b) Structures of complex tannins 4144.

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Figure 3. (a) Structures of complex tannins 3040. (b) Structures of complex tannins 4144.
Ijms 11 00079f3a 1024Ijms 11 00079f3b 1024
Ijms 11 00079f4 1024
Figure 4. General oligomerization mode for the types 1 and 2. (1) examples of coupling mode for formation of valeoyl or its equivalent unit by C-O coupling. (2) macrocyclic dimer (double coupling for HHDP and galloyl).

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Figure 4. General oligomerization mode for the types 1 and 2. (1) examples of coupling mode for formation of valeoyl or its equivalent unit by C-O coupling. (2) macrocyclic dimer (double coupling for HHDP and galloyl).
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Ijms 11 00079f5 1024
Figure 5. Structures of C-glycosidic ellagitannin dimers 4548.

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Figure 5. Structures of C-glycosidic ellagitannin dimers 4548.
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Ijms 11 00079f6a 1024
Figure 6. (a) Structures of ellagitannin oligomers 4959. (b) Structures of ellagitannin oligomers 60 and 61.

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Figure 6. (a) Structures of ellagitannin oligomers 4959. (b) Structures of ellagitannin oligomers 60 and 61.
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Ijms 11 00079f7 1024
Figure 7. (a) Structures of ellagitannin oligomers 62 and 66. (b) Structures of ellagitannin oligomers 6365.

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Figure 7. (a) Structures of ellagitannin oligomers 62 and 66. (b) Structures of ellagitannin oligomers 6365.
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Ijms 11 00079f8 1024
Figure 8. Coupling modes (a–d) to melasquanins A (62)–D (65).

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Figure 8. Coupling modes (a–d) to melasquanins A (62)–D (65).
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Ijms 11 00079f9 1024
Figure 9. Structures of ellagitannin oligomers 67 and 68.

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Figure 9. Structures of ellagitannin oligomers 67 and 68.
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Figure 10. Coupling mode of nobotanins.

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Figure 10. Coupling mode of nobotanins.
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Figure 11. (a) Structures of ellagitannin oligomers 72 and 73. (b) Structures of ellagitannin oligomers 7477.

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Figure 11. (a) Structures of ellagitannin oligomers 72 and 73. (b) Structures of ellagitannin oligomers 7477.
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Figure 12. Chemical degradation of nobotanin B (70).

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Figure 12. Chemical degradation of nobotanin B (70).
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Figure 13. HMBC data for melasquanin A (62).

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Figure 13. HMBC data for melasquanin A (62).
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Figure 14. Structures of metabolites from ellagitannins.

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Figure 14. Structures of metabolites from ellagitannins.
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Table Table 1. Ellagitannin monomers found in the Myrtales.

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Table 1. Ellagitannin monomers found in the Myrtales.
Tannin123456789101112131415
Plant source [Ref]
Trapaceae
Trapa japonica [9]++++
Melastomataceae
Bredia tuberculata [10]++
Heterocentron roseum [11]++
Melastoma malabathricum [12]+++
M. normale [10]+++
Tibouchina semidecandra [13]+++
Myrtaceae
Callistemon lanceolatus [14]+++
Eucalyptus alba [15]++++
E. consideniana [16]++++
E. globulus [17]+
E. rostrata [18]+
E. viminalis [16]++++
Myrtus communis [19]++
Pimenta dioica [20]++++
Syzygium aqueum [21]+++
S. aromaticum [22]+++++
Onagraceae
Epilobium angustifolium [23]++++
Oenothera erythrosepala [24]++
O. laciniata [25]+
O. tetraptera [26]+++
Combretaceae
Combretum glutinosum [27]+++
C. molle [28]++
Quisqualis indica [29]++++++
Terminalia arborea [30]+++++
T. arjuna [31]+++
T. brachystemma [32]+
T. calamansanai [33]+++++
T. catappa [34]+++++++++
T. chebula [35]++++++
T. citrina [36]++
T. macroptera [37]++++
T. myriocarpa [38]++
T. triflora [39]+
Punicaceae
Punica granatum [40]++++++
Table Table 2. C-Glycosidic ellagitannins in the order Myrtales.

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Table 2. C-Glycosidic ellagitannins in the order Myrtales.
FamilyPlant speciesC-Glycosidic tanninsRef.
CombretaceaeAnogeissus acuminata16, 17, 18, 19[43]
Anogeissus leiocarpus16[44]
Lumnitzera racemosa16[45]
Terminalia arjuna16, 20, 22[31]
Terminalia macroptera27[37]
Terminalia arborea28[30]
Thiloa glaucocarpa16, 18, 20, 21[46]
LythraceaeLagerstroemia flos-reginea16, 18, 20, 21, 22, 23, 24, 29[47]
Lagerstroemia speciosa16, 18, 19, 29[48]
MelastomataceaeOsbeckia chinensis20, 22, 25[49]
Tibouchina semidecandra16, 18, 20[13]
MyrtaceaeCallistemon lanceolatus20[14]
Eucalyptus alba21, 22[15]
Eugenia grandis16, 18[50]
Kunzea ambigua20[51]
Melaleuca squarrosa20, 21[52]
Pimenta dioica16, 18, 20, 22[20]
Siphoneugena densiflora16, 20[53]
Syzygium aqueum16, 18, 19[21]
Syzygium aromaticum20, 22[22]
PunicaceaePunica granatum20, 22, 25, 26, 27, 28[40]
TrapaceaeTrapa japonica20[9]
Table Table 3. Biological activities of ellagitannins found in the Myrtales.

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Table 3. Biological activities of ellagitannins found in the Myrtales.
Biological activityCompound (source)Ref.
Anti-Herpes simplex virus type 2 activitycasuarinin (20) (Terminalia arjuna)[67]
Apoptosis in human breast adenocarcinoma MCF-7 cellscasuarinin (20)[68]
Antileishmanial activitycasuarinin (20), castalagin (16)[69]
castalagin (16) (Anogeissus leiocarpus)[44]
Antihypertensive activity (rats)castalagin (16) (Lumnitzera racemosa)[45]
corilagin, chebulinic acid (15)
α-Glucosidase inhibitorcasuarictin (7) (Syzygium aromaticum)[70]
chebulagic acid (14) (Terminalia chebula)[71]
Dual inhibitor against COX and 5-LOXchebulagic acid (14) (T. chebula)[72]
Anti-inflammation in LPS-induced RAW 264.7 cellschebulagic acid (14) (T. chebula)[73]
Effect on carageenan-induced inflammationpunicalagin (9), punicalin (10) (T. catappa)[74]
Antioxidant and hepatoprotective effects on acetaminophen-induced liver damage in ratspunicalagin (9), punicalin (10) (T. catappa)[75]
Effect against bleomycin-induced genotoxicity in Chinese hamster ovary cellspunicalagin (9) (T. catappa)[76]
Chemopreventive effect on H-ras-transformed NIH3T3 cellspunicalagin (9) (T. catappa)[77]
Inhibitory effect on HIV-1 reverse transcriptasepunicalin (10), 2-O-galloylpunicalin (T. triflora)[39]
Inhibitory effect on CCl4-induced hepatotoxicitypunicalagin (9) (T. myriocarpa)[38]
Activators of glucose transport in fat cellslagerstroemin (29), reginin A (49) (L. speciosa)[78]
Activation of insulin receptorslagerstroemin (29)[79]
Insulin-like glucose uptake-stimulatory/inhibitory and adiposities differentiation inhibitory activity in 3T3-L1 cellslagerstroemin (29)
casuarinin (20), casuariin (22), stachyurin (21)
[80]
Host-mediated antitumor effectoenothein B (54) (Oenothera erythrosepala)[24]
Host-mediated antitumoroenothein B (54) (Woodfordia fruticosa)[56]
woodfordins A-C (53)
Inhibitor of deoxyribonucleic acid topoisomerase IIwoodfruticosin [= woodfordin C (53)][81]
EBV DNA polymerase inhibitory effectoenothein B (54) (Eugenia uniflora)[82]
eugeniflorins D1, D2 (57)
5α-reductase, aromatase inhibitory effectoenotheins A (59), B (54) (Epilobium sp)[59]
Induction of neutral endopeptidase activity in PC-3 cellsoenothein B (54) (Epilobium angustifolium)[83]
In vitro immunomodulatory effect on human mononuclear cellscuphiin D1 (55) (Cuphea sp)[84]
Induce apoptosis in HL-60 cellscuphiin D1 (55)[85]
Poly (ADP-ribose) glycohydrolase inhibitionnobotanins B (70), K (72) (Tibouchina sp)[86]

L. speciosa: Lagerstroemia speciosa.

Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert