The Diversity of Stemona

Review pubs.acs.org/jnp

The Diversity of Stemona Stilbenoids As a Result of Storage and Fungal Infection Harald Greger* Chemodiversity Research Group, Faculty Center of Biodiversity, University of Vienna, Rennweg 14, A-1030 Wien, Austria ABSTRACT: In relation to their biogenetic origin, 68 Stemona stilbenoids have been grouped into four structural types and are listed in order of increasing substitution pattern. Besides different hydroxylations and methoxylations, the rare C-methylations of the aromatic rings represent a typical chemical feature of these compounds. The formation of phenylbenzofurans constitutes another important chemical character separating Stemona species into two groups consistent with morphological and DNA data. Fungal infection leads to an increasing accumulation of stilbenes, dihydrostilbenes, and phenylbenzofurans with unsubstituted A-rings, suggesting the ecological role of these compounds as phytoalexins. Further oxygenations and methylations of both rings are interpreted as a result of aging or the drying processes. Bioautographic tests on TLC plates and germ-tube inhibition assays in microwells against four different fungi exhibited antifungal activities for almost all stilbenoids tested. Some derivatives also showed effects against yeasts and bacteria. Further activities may also be seen as dormancy-inducing factors of Stemona species occurring in periodically dry habitats. A leucotriene biosynthesis inhibition assay using 15 stilbenoids showed interesting structure−activity relationships, with more potent effects of some compounds than the commercial 5-lipoxygenase inhibitor zileuton being observed. Potential neuroprotective activities have been reported for three dihydrostilbene glucosides against 6-hydroxydopamine-induced neurotoxicity in human neuroblastoma SH-SY5Y cells.

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INTRODUCTION The stilbenoids are characterized by a 1,2-diphenylethane backbone and are closely related biosynthetically to the flavonoids. The key enzyme stilbene synthase shows 75−90% amino acid sequence identity with the chalcone synthase catalyzing flavonoid biosynthesis. Despite this close relationship, stilbenoids are not as widespread in plants as flavonoids.1−3 Phylogenetic analysis of the corresponding gene families showed that the stilbene synthase genes have evolved independently from chalcone synthase genes several times in the course of evolution.4,5 Owing to their wide range of bioactivities, stilbenoids have become of great interest to many research groups in biomedicine as well as those in agricultural and food chemistry.2,6 In the course of our comprehensive investigation of bioactive compounds of the family Stemonaceae a large number of stilbenoids have been isolated and identified.7,8 In addition to Stemona alkaloids9−11 and dehydrotocopherols12 these compounds mainly accumulate in the underground parts of Stemona species that consist of tuberous roots and rhizomes. In particular, S. collinsiae Craib was shown to be a rich source of different stilbenoid structural types. In addition to the more widespread stilbenes, dihydrostilbenes, and dihydrophenanthrenes, the formation of phenylbenzofurans represents a rare and characteristic chemical feature.7 Only three dihydrostilbenes known from S. tuberosa Lour. have been reported previously as bibenzyl derivatives.13 In contrast to Stemona alkaloids, the stilbenoids do not show toxic properties against insects, but they do possess pronounced antifungal activity.7 To © 2012 American Chemical Society and American Society of Pharmacognosy

gain more insight into their structural diversity and antifungal properties, different Stemona species have been analyzed subsequently in our laboratory as part of diploma and doctoral theses.14,15,33 Following our first publication,7 newly described dihydrostilbene, phenylbenzofuran, and dihydrophenanthrene derivatives have been designated by common basic names, such as stilbostemins, stemofurans, and stemanthrenes, respectively, combined with capital letters in alphabetical order. However, in the interim, further derivatives have been described independently by other authors who adopted our approach to compound designation.16−23 Lack of awareness of the already existing names in our diploma and doctoral theses14,15 has led to a number of duplications in the trivial names used for these compounds. Moreover, some other derivatives were reported twice in the literature and have been designated with different names. To provide a basis for further correct naming and to show the distribution of Stemona stilbenoids, in the present review all relevant investigations have been considered and valid names are listed, giving priority to those published in peer-reviewed journals. Since some compounds have had to be renamed, new trivial names are introduced (Figures 2−6). The cultivation of some Stemona species in the greenhouse of the Botanical Garden of the University of Vienna has provided insight into chemical differences between freshly harvested young, old, or dried underground parts of the same individual. Moreover, an accumulation of additional stilbenoids has been Received: October 4, 2012 Published: December 17, 2012 2261

dx.doi.org/10.1021/np300690c | J. Nat. Prod. 2012, 75, 2261−2268

Journal of Natural Products

Review

position 2, a second O-substitution occurs at either position 3 (17−20, 57−60) or 4 (21−25, 52−56). An alternative second oxygenation at position 5 is restricted to the dihydrostilbenes 26−33, isolated so far only from Chinese collections of S. tuberosa,20 S. japonica (Bl.) Miq.,16,19 and S. sessilifolia (Miq.) Miq.17 All phenolic OH groups in rings A and B are subject to a different degree of methylation most likely catalyzed by Sadenosyl-L-methionine-dependent O-methyltransferases.5 As a result, a number of closely related stilbenoids are formed ranging from mono- to polymethoxylated derivatives. However, of special chemotaxonomic significance for Stemona stilbenoids is the frequent occurrence of C-methylation. This has been found in all four structural types7 and is indicated by bold letters in Figures 2−6. This chemical trend has only rarely been detected in other plant stilbenoids.2 C-Methylation occurs mainly in ring B, and here preferably at the activated position 4′, but was also detected in ring A of four phenylbenzofurans (49−51, 56) and five phenanthrene derivatives (61−65). As reported previously, stilbene synthase enzymes may accept different cinnamic acid derivatives as substrates and a single enzyme might be responsible for the formation of different A-ring oxygenations, depending on the preferred starter molecule.5 Cinnamoyl precursors with hydroxylations at the para- or meta-positions are already known, but corresponding derivatives with ortho-hydroxylation, explaining the preferred C-2 oxygenation of Stemona stilbenoids, have not been found so far. Further experiments will be needed to show whether an alternative specific cytochrome P450 enzyme is responsible for hydroxylation at C-2 or the corresponding position at C-6, giving rise to the formation of the oxygen bridge between C-6 and C-2″ in the phenylbenzofurans. The conversion from dihydrostilbenes into dihydrophenanthrenes shown in Figure 1 has been reported for these compounds when they occur in the plant families Dioscoreaceae26 and Orchidaceae.27−29 With respect to the same substitution patterns of rings A and B, this biosynthetic sequence was also suggested to convert stilbostemin F (20) into stemanthrene D (59), co-occurring in S. collinsiae,7 or stilbostemin G (19) into stemanthrene A (57) in S. pierrei Gagnep.8 The mechanism of biosynthesis of phenylbenzofurans, also classified as 2-arylbenzofurans, is still unknown. Owing to the co-occurrence of the stilbene oxyveratrol and the moracin phenylbenzofurans in the genus Morus of the family Moraceae, these compounds have been suggested to be derived from stilbenes.30 Regarding the oxygen bridge between C-6 and C-2″ in phenylbenzofurans, the occurrence of the preferred oxygenation at C-2 or C-6 in the stilbenes of Artocarpus integer Merr. of the family Moraceae31 and the predominating phenylbenzofurans in the related A. f retessi Hassk.32 again confirm this hypothesis. In the case of Stemona stilbenoids, the co-occurrence of the two stilbenes pinosylvin (1) and 4′methylpinosylvin (2) with the two structurally corresponding phenylbenzofurans stemofuran A (38) and stemofuran C (39) in S. collinsiae7,15 also supports the biosynthetic pathway shown in Figure 1.

Figure 1. Proposed biosynthetic pathways of Stemona stilbenoids.

observed after infection with an aqueous spore suspension of the fungus Botrytis cinerea.15 Hence, at least four different stilbenoid patterns are to be expected from a single Stemona species depending on the relative condition of the plant material. The purpose of this review is to present an overview on the considerable structural diversity of Stemona stilbenoids and to focus on characteristic accumulation trends toward specific structural types and substitution patterns as well as their biological activities.

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STRUCTURAL RELATIONSHIPS As shown in Figure 1, the stilbenoids are formed by three malonyl-CoA groups and one CoA-ester of a cinnamic acid derivative.5 Thus, the resulting two aromatic rings A and B are of different biogenetic origin and mostly show different substitution patterns. As a cyclization product of three malonyl-CoA units, ring B is usually characterized by a 3′,5′dioxygenation pattern. With the exception of stilbostemin L (33) and stemanthraquinone (64), this substitution pattern was found for all Stemona stilbenoids. So far, 68 derivatives of this type were reported among Stemona species, falling into four structural types (Figure 1): the two larger groups are formed by dihydrostilbenes, also classified as bibenzyls, containing 31 derivatives (Figure 2), and phenylbenzofurans, with 18 derivatives (Figure 4). The two smaller groups are represented by dihydrophenanthrenes (Figure 5) and stilbenes (Figure 2), comprising eight and two derivatives, respectively. Glycosylation was reported so far only for three dihydrostilbenes isolated from S. tuberosa (Figure 6).25 Whereas all these compounds have been isolated from underground parts, four dimeric dihydrostilbenes were reported for the aerial parts of S. parvif lora C. H. Wright (Figure 3).24 The oxygenation patterns of ring A are simple but show more variable arrangements than those of ring B, possibly still reflecting the different substitution patterns of the cinnamoyl precursors.5 Therefore, all derivatives shown in Figures 2, 4, and 5 are listed in order of increasing A-ring oxygenation. Stilbenoids with a monosubstituted A-ring preferably have oxygenation at position 2, with only a few oxygenated at positions 3 (61−65) or 4 (15, 16, 48, 67). For almost all derivatives with a disubstituted A-ring with oxygenation at

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STILBENES With the exception of the Australian S. lucida (R.Br.) Duyfjes, pinosylvin (1) and/or 4′-methylpinosylvin (2) have been detected in all Stemona species so far (Table 1). In contrast to other stilbenoids, the stilbenes of Stemona apparently do not undergo further substitutions in ring A. A broad-based HPLCUV comparison of different Stemona species has shown that the 2262



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Figure 2. Stilbenes 1 and 2 and dihydrostilbenes 3−33 from Stemona species, listed in order of increasing A-ring substitution. *Newly introduced trivial names.

suspension of the fungus Botrytis cinerea or irradiation with UV light.15 This supports their assumed protective role as

stilbenes 1 and 2 were not detected in freshly harvested intact roots, but greatly accumulated after infection with a spore 2263



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Figure 3. Dimeric dihydrostilbenes from aerial parts of Stemona parviflora.24

phytoalexins already reported previously35−37 and explains the divergent reports on their occurrence.

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DIHYDROSTILBENES (= BIBENZYLS) Like the stilbenes 1 and 2, the two structurally corresponding dihydrostilbenes dihydropinosylvin (3) and stilbostemin B (4) have been shown to be distributed widely in Stemona species (Table 1), and their accumulation also increased substantially after fungal infection. From comparative studies, it became apparent that the two pairs 1 and 2 and 3 and 4 constitute the characteristic stilbenoid profile of S. kerrii Craib and the S. tuberosa group in Thailand, showing a clear prevalence of the latter pair. However, all four compounds could not be detected in freshly harvested healthy roots. Slow drying of the roots of various species at room temperature resulted in an oxygenation of dihydrostilbenes at position C-2 of ring A, leading to stilbostemin A (7) and especially the widespread C-4′methylated derivative stilbostemin D (9).15 To what extent the other closely related O- or C-methylated derivatives (6, 8, 10−14), mainly reported for the Chinese collections of S. sessilifolia and S. tuberosa, may also be regarded as products of drying or aging processes of living roots cannot be deduced from the publications available. An additional oxygenation at C3 leads to the derivatives 17−20, from which stilbostemin F (20) was observed to accumulate in living, old, brown-coated tuberous roots of S. collinsiae, but was not detected in young, white ones.15 It should be pointed out that the two stilbostemins 19 and 20 are regarded as precursors of the dihydrophenanthrenes stemanthrenes A (57) and D (59), showing the same substitution patterns in the two aromatic rings, and co-occur in S. collinsiae, S. pierrei, and S. lucida7,8,33 (Table 1). The 2,4-dioxygenated derivatives 21−25 have a restricted distribution and are reported mainly for a single Chinese collection of S. tuberosa.20 One member of this series, stilbostemin S (23), has been isolated previously from S. japonica, where it was named originally stilbostemin P.21 With respect to its limited occurrence, C-4-oxygenation apparently reflects a specific enzymatic activity probably also responsible for the formation of the two C-4-monosubstituted derivatives stemostilbenes A (15) and B (16). Both have also been found in the same collections of S. tuberosa20 and S. japonica21

Figure 4. Phenylbenzofurans from Stemona species, listed in order of increasing A-ring substitution. 2264



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same extract afforded stilbostemin L (33), which deviated from all other Stemona stilbenoids by an unusual oxygenation at positions C-2′ and C-4′16 instead of biogenetically derived 3′,5′-dioxygenations. The formation of phenylethylbenzoquinone structures by an additional oxygenation at C-2′ of ring B was also reported for the dimeric dihydrostilbenes parvistemins A−D (34−37) isolated from the aerial parts of S. parvif lora (Figure 3).24

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PHENYLBENZOFURANS (= 2-ARYLBENZOFURANS)

As shown in Table 1, the majority of phenylbenzofurans (Figure 4) have been isolated from the six species, S. collinsiae, S. curtisii Hook.f., S. burkillii Prain, S. aphylla Craib, S. involuta Inthachub, and S. cochinchinensis Gagnep., collected in Thailand. Recently, they were also detected in the Australian S. lucida.33 However, it is apparent from the results available that phenylbenzofurans have not been found either in the S. tuberosa group or in collections of S. kerrii. Moreover, they were not described so far from the Chinese species S. japonica, S. sessilifolia, and S. parvif lora (Table 1).16−21,24,38 On the basis of a preliminary HPLC-UV analysis of a small sample of S. sessilifolia, received from the Chinese University at Hong Kong, stemofurans A (38) and B (42) were also detected recently in our laboratory by comparison with authentic samples together with two unknown derivatives.33 The greatest structural diversity was found in S. collinsiae,7,15 S. curtisii,15,22 and S. aphylla.23 Comparative analyses exhibited clear differences in the substitution patterns between freshly harvested, infected, or dried roots; for example, the stemofurans A (38) and C (39) accumulated only in infected roots of S. collinsiae, where, however, no stilbenoids could be detected in the HPLC-UV profiles of intact, freshly harvested roots. Both stemofurans have the same substitution patterns as the co-occurring stilbenes 1 and 2 and the dihydrostilbenes 3 and 4, characterized by an unsubstituted A-ring. In contrast, the profile of the dried roots clearly deviated by the occurrence of higher substituted stemofurans B (42), D (43), and E (44).15 Like the dihydrostilbenes, phenylbenzofurans with a monosubstituted A-ring preferably show oxygenation at position C-2 (42−47), sometimes accompanied by a C-methylation at position 3 (49−51).7 A second oxygenation at C-4 was reported mainly for compounds 52−56 of S. aphylla,23 but stemofurans N (52) and M (53) of this series were isolated originally from S. curtisii and S. burkillii in the course of work for a diploma thesis, where they were named stemofurans O and R, respectively.14 The C-4 monooxygenated derivative racemofuran (48) was described for Asparagus racemosus Willd.39 However, in this case, the co-occurrence with stemanthrene D (= racemosol) (59) and the characteristic Stemona alkaloid didehydrostemofoline (= asparagamine A)11 suggests a confusion with S. collinsiae.7 Increasing Cmethylation in 41, 46, 47, and 51 leads to unusual fully substituted B-rings. In this case the UV absorption maxima showed a strong hypsochromic shift indicating nonplanarity and interruption of the conjugation between the two aromatic rings.7 The fully substituted aromatic rings in stemanthrene C (60) and the four quinoid systems of dimeric dihydrostrilbenes (Figure 3) are generated in a different way, linking two C atoms of different rings.

Figure 5. Dihydrophenanthrenes 57−64 and phenanthrene 65 from Stemona species.

Figure 6. Dihydrostilbene glucosides from S. tuberosa.25 *Newly introduced trivial names.

mentioned above, but were named originally stilbostemins O and R, respectively. Similar to the 2,4-dioxygenated dihydrostilbenes, the 2,5-dioxygenated derivatives 28−33 are also known only from Chinese collections of S. tuberosa,20 S. japonica,16,19,21 and S. sessilifolia.17,38 From the petroleum ether fraction of the EtOH extract of S. japonica, the rare japonin C (32) was isolated in trace amounts. It shows an additional oxygenation at C-2′, leading to the formation of a phenylethylbenzoquinone structure.19 The CHCl3 fraction of the 2265



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Table 1. Distribution of Different Types of Stilbenoids in Stemona Species Stemona species

phenylbenzofurans

S. collinsiae

3, 4, 6, 7, 9, 18, 20

S. curtisii

4, 9

S. burkillii S. aphylla

4, 7, 9 4, 9, 11, 20

S. S. S. S. S. S. S. S. S.

3, 4, 6, 9, 20 3, 4, 9 3, 4, 9, 18, 19 3, 4, 9, 20 y,a za 3, 4, 7, 8, 9, 10, 14, 17, 19, 27 38, 42 3, 4, 5, 6, 7, 9, 16, 18, 23, 26, 28, 29, 32, 33 9,bdimeric: 34, 35, 36, 37 3, 4, 7, 9 3, 4, 7, 8, 9, 11, 12, 13, 15, 18, 20, 21, 22, 23, 24, 25, 29, 30, 31, glycosides: 66, 67, 68 3, 4, 7, 9

involuta cochinchinensis pierrei lucida sessilifolia japonica parvif lora kerrii tuberosa agg.

S. phyllantha a

dihydrostilbenes

38, 39, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51 38, 40, 41, 42, 43, 44, 45, 46, 52 42, 44, 45, 53, wa 38, 42, 44, 45, 46, 47, 52, 53, 54, 55, 56 38, 39, 42, xa 38, 42, 44, 45, 49

dihydrophenanthrenes

stilbenes

refs

59

1, 2

7,15,39

59

2

15,22

59 59

1, 2 1, 2

14,15 14,15,23

1, 2 1, 2 1, 2 2 1, 2 1, 2 1, 2 1

33 15 8 33 15,17,18,33,38 15,16,19,21 15,24 15 13,15,20,25

1, 2

15

57, 57, 57, 57, 62,

64

58, 58, 58, 60, 63,

60 60 59, 60 61 65

w−z: unidentified phenylbenzofurans based on preliminary NMR analyses. bIsolated from aerial parts.24

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DIHYDROPHENANTHRENES In contrast to dihydrophenanthrenes found in plants of the families Orchidaceae and Dioscoreaceae, only a restricted distribution of these compounds occurs in Stemona species. Although stemanthrene D (59) was detected in small amounts in several species, an accumulation of this type of stilbenoid as a major compound type was reported so far for only S. pierrei8 and S. lucida (Table 1).33 A substantial amount of stemanthrene E (61) was isolated from S. sessilifolia together with small quantities of stemanthrenes A (57) and C (60).17 Two different A-ring substitutions appear to be of some chemotaxonomic significance: while the more widespread stemanthrenes A−D (57−60) show 2,3-dioxygenation, already known from the dihydrostilbenes 17−20, the stemanthrenes E−G (61−63), stemanthraquinone (64), and japonin D (65) of the Chinese representatives S. sessilifolia,17 S. japonica,16,19,21 and S. tuberosa20 share a rare monooxygenation at C-3 accompanied by C-4 methylation. A further common trend of S. japonica19 and S. tuberosa20 is the oxygenation at C-2′ of ring B, leading to the quinoid structures of stemanthraquinone (64) and japonin D (65), respectively. The latter represents the only Stemona stilbenoid with a phenanthrene structure. Similar to stilbostemin L (33), stemanthraquinone (64) deviates from all other Stemona stilbenoids by an unusual oxygenation at C-4′ in ring B. Regarding the clear morphological differences between S. japonica and S. tuberosa, the common chemical trend generating this rare dihydrostilbene and dihydrophenanthrene derivatives is surprising. Hence, with respect to the frequent confusions of Stemona species in the chemical and pharmaceutical literature, a re-examination of the plant identities would be desirable.

occurs not only between different geographical collections but also between individuals of the same population.11 Following up on the present survey, Stemona species can be separated into two different groups due to the presence or absence of phenylbenzofurans (Figure 4, Table 1). This separation is also supported by morphological characters41 and DNA sequencing.42 Infection of living roots leads to an increasing formation of the stilbenes 1 and 2 and dihydrostilbenes 3 and 4 in almost all species, suggesting that they play an ecological role as phytoalexins.15,35,36 In this case, the phenylbenzofuran-producing species were characterized additionally by the structurally corresponding stemofurans A and C (38, 39) (Table 1), confirming the supposed biosynthetic connection between stilbenes and phenylbenzofurans shown in Figure 1. Additional oxygenations and methylations were shown to be clearly independent from phytoalexin reactions and might be interpreted as a result of aging or drying processes of the tuberous roots.15

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BIOLOGICAL ACTIVITIES Antifungal and Antibacterial Activity. On the basis of broad-based bioautographic tests on TLC plates using conidiospore suspensions of the fungus Cladosporium herbarum (Pers.: Fr.) Link, antifungal activities were detected in methanolic crude extracts of all species listed in Table 1. They were attributed to the presence of various stilbenoids. Isolated pure compounds have shown that derivatives of all four structural types (Figure 1) possessed antifungal activities. Particularly the derivatives 1−4, 9, 43, and 44 displayed clear inhibition zones, while 19, 49, 51, 57, 58, and 60 were partly overgrown by the fungus, suggesting either weaker activity or degradation, e.g., as found for stemanthrene B (58).7,8,15 To get more detailed and reliable data, a selection of stilbenoids was tested in microwells against four fungi with potential parasitic activity and against one with saprophytic activity. Stemofuran B (42) showed the highest germ-tube inhibition effect against the parasitic fungi, but only weak activity against the saprophytic Cladosporium herbarum. The two other highly active derivatives, stilbostemin B (4) and stemofuran E (44), were also very effective against C. herbarum when evaluated using TLC

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DISTRIBUTION On the basis of literature data and our own investigations, the accumulation of stilbenoids in the family Stemonaceae is restricted to the genus Stemona, and these compounds are located mainly in the tuberous roots and rhizomes. In surveying the alkaloid composition of different Stemona species and geographical provenances, a vicarious accumulation between alkaloids and stilbenoids has been detected.10,11 In S. aphylla it could be demonstrated clearly that this chemical variability 2266



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bioautographic testing.7 Regarding species-specific reactions, it is interesting to note that Pyricularia grisea (Cooke) Sacc., the causative agent of rice blast disease, was shown to be most susceptible to all Stemona stilbenoids tested.7 Potent activity against the yeast Candida albicans was reported for the two stilbostemins A (7) and E (18) isolated from S. japonica.21 The stemofurans P (54) and R (55) from S. aphylla showed the same potency against C. albicans as the positive control amphotericin B, but were less active against Cryptococcus neoformans.23 Moderate activities against the latter pathogen were reported for stilbostemins U (24), X (25), and Y (31) isolated from S. tuberosa.20 Regarding antibacterial activities, the three stilbostemins B (4), D (9), and L (33) and the dihydrophenanthrene stemanthrene F (62) from S. japonica were shown to be active against the hospital pathogenic Grampositive bacteria Staphylococcus aureus and S. epidermidis, but were less effective against Gram-negative Escherichia coli.16 Stilbostemin U (24) from S. tuberosa exhibited potent activity against Bacillus pumilus.20 With respect to the generally weak effects of stemofurans E (44), J (45), M (53), P (54), and R (55) against E. coli, Klebsiella pneumoniae, S. aureus, and S. pyogenes, the pronounced activities of 44, 45, and 55 against a methicillin-resistant strain of S. aureus deserve special attention. These three derivatives show similar substitution patterns that are characterized by a 2′,3′,4′,5′-tetrasubstituted B-ring.23 The formation of a distinctive set of stilbenoid-derived phytoalexins has already become of great interest, and these were investigated intensively, e.g., in the pine tree Pinus sylvestris35,36 and peanut Arachis hypogaea.6 On the basis of comparative experiments with living Stemona species, cultivated in the greenhouse of the Botanical Institute of the University of Vienna, the former doctoral candidate Thomas Pacher has shown that the two stilbenes pinosylvin (1) and 4′methylpinosylvin (2) as well as the two dihydrostilbenes dihydropinosylvin (3) and stilbostemin B (4) clearly accumulate in response to fungal attack. Moreover, the two phenylbenzofurans stemofurans A (38) and C (39), possibly derived from compounds 1 and 2, may also be concluded as being phytoalexins.15 Apart from playing an important role in plant defense mechanisms against microorganisms, stilbenoids may also be seen as factors affecting the dormancy of Stemona species often occurring in periodically very dry habitats. Several dormancy-inducing stilbenoids, the batatasins, have been detected in bulbils of the yam Dioscorea batatas.26 Leukotriene Biosynthesis Inhibition and Potential Neuroprotective Activity. In an ex vivo leukotriene biosynthesis inhibition assay, 15 Stemona stilbenoids, representing all four structural types, were tested for inhibitory effects using human neutrophilic granulocytes.40 They showed clear structure−activity relationships in a dose-dependent manner. The IC50 values ranged from 3.7 μM for stemofuran G (49), 4.8 μM for stemanthrene D (59), and 8.5 μM for stemanthrene A (57) to compounds with less than 10% inhibition at 50 μM, as exemplified by dihydropinosylvin (3) and stilbostemins A (7), D (9), and F (20). The inhibitory effects of 49, 57, and 59 were notably higher than the commercial specific 5-lipoxygenase inhibitor zileuton, which showed an IC50 value of 10.4 μM.40 It should be pointed out that stemanthrenes B (58) and C (60), initially showing potent activity with 100% inhibition at 25 μM, lost activity during storage due to degradation. The instability of these compounds has been described previously in antifungal testing.8 Two other similar compounds, stemanthrenes A (57) and D (59), retained

activity. It is notable that the stilbene pinosylvin (1) (IC50 22.7 μM) was significantly more active than the C-1″−C-2″ saturated dihydrostilbene dihydropinosylvin (3) (IC50 >50 μM). With the exception of stilbostemin G (19), all other dihydrostilbenes (4, 7, 9, 20) showed only minimal inhibition at 50 μM.40 The roots of S. tuberosa were reported to exhibit activity against 6-hydroxydopamine-induced neurotoxic effects. From the n-BuOH fraction of the MeOH extract of this species the three dihydrostilbene glucosides 66−68 (Figure 6) were shown to exert significant activity when tested against human neuroblastoma SH-SY5Y cells.25

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AUTHOR INFORMATION

Corresponding Author

*Tel: +43 1 4277 54072. Fax: +43 1 4277 9541. E-mail: harald. [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The author would like to thank the staff of the Botanical Garden of the University of Vienna, particularly Mr. F. Tod, for the valuable assistance in cultivating plants for bioassays.

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REFERENCES

(1) Gorham, J. The Biochemistry of the Stilbenoids; Chapman & Hall: London, 1995. (2) Xiao, K.; Zhang, H. J.; Xuan, L. J.; Zhang, J.; Xu, Y. M.; Bai, D. L. In Studies in Natural Products Chemistry, Vol. 34; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 2008; pp 453−646. (3) Schröder, J. Trends Plant Sci. 1997, 2, 373−378. (4) Tropf, S.; Lanz, T.; Rensing, S. A.; Schröder, J.; Schröder, G. J. Mol. Evol. 1994, 38, 610−618. (5) Chong, J.; Poutaraud, A.; Hugueney, P. Plant Sci. 2009, 177, 143−155. (6) Sobolev, V. S.; Khan, S. I.; Tabanca, N.; Wedge, D. E.; Manly, S. P.; Cutler, S. J.; Coy, M. R.; Becnel, J. J.; Neff, S. A.; Gloer, J. B. J. Agric. Food Chem. 2011, 59, 1673−1682. (7) Pacher, T.; Seger, C.; Engelmeier, D.; Vajrodaya, S.; Hofer, O.; Greger, H. J. Nat. Prod. 2002, 65, 820−827. (8) Kostecki, K.; Engelmeier, D.; Pacher, T.; Hofer, O.; Vajrodaya, S.; Greger, H. Phytochemistry 2004, 65, 99−106. (9) Greger, H. Planta Med. 2006, 72, 99−113. (10) Schinnerl, J.; Brem, B.; But, P. P. H.; Vajrodaya, S.; Hofer, O.; Greger, H. Phytochemistry 2007, 68, 1417−1427. (11) Kongkiatpaiboon, S.; Schinnerl, J.; Felsinger, S.; Keeratinijakal, V.; Vajrodaya, S.; Gritsanapan, W.; Brecker, L.; Greger, H. J. Nat. Prod. 2011, 74, 1931−1938. (12) Brem, B.; Seger, C.; Pacher, T.; Hartl, M.; Hadacek, F.; Hofer, O.; Vajrodaya, S.; Greger, H. Phytochemistry 2004, 65, 2719−2729. (13) Zhao, W. M.; Qin, G. W.; Ye, Y.; Xu, R. S.; Le, X. F. Phytochemistry 1995, 38, 711−713. (14) Hartl, M. Antifungale Stilbenoide der Gattung Stemona − unter besonderer Berücksichtigung der stressinduzierten Derivate. Diploma thesis, University of Vienna, Austria, 2003. (15) Pacher, T. Phytochemical Analyses within the Two Tropical Plant Genera Glycosmis (Rutaceae) and Stemona (Stemonaceae) in Special Consideration of the Formation of Phytoalexins and Artifacts. Ph.D. dissertation, University of Vienna, Austria, 2005. (16) Yang, X. Z.; Tang, C. P.; Ye, Y. J. Asian Nat. Prod. Res. 2006, 8, 47−53. (17) Yang, X. Z.; Tang, C. P.; Ke, C. Q.; Ye, Y. J. Asian Nat. Prod. Res. 2007, 9, 261−266. (18) Zhang, T.; Zhang, Y. Z.; Tao, J. S. J. Asian Nat. Prod. Res. 2007, 9, 479−485. 2267



Review

(19) Yang, X. Z.; Lin, L. G.; Tang, C. P.; Liu, Y. Q.; Ye, Y. Helv. Chim. Acta 2007, 90, 318−324. (20) Lin, L. G.; Yang, X. Z.; Tang, C. P.; Ke, C. Q.; Zhang, J. B.; Ye, Y. Phytochemistry 2008, 69, 457−463. (21) Zhang, Y. Z.; Xu, G. B.; Zhang, T. J. Asian Nat. Prod. Res. 2008, 10, 634−639. (22) Chaiyong, S.; Jatisatienr, A.; Mungkornasawakul, P.; Sastraruji, T.; Pyne, S. G.; Ung, A. T.; Urathamakul, T.; Lie, W. J. Nat. Prod. 2010, 73, 1833−1838. (23) Sastraruji, T.; Chaiyong, S.; Jatisatienr, A.; Pyne, S. G.; Ung, A. T.; Lie, W. J. Nat. Prod. 2011, 74, 60−64. (24) Yang, X. Z.; Gulder, T. A. M.; Reichert, M.; Tang, C. P.; Ke, C. Q.; Ye, Y.; Bringmann, G. Tetrahedron 2007, 63, 4688−4694. (25) Lee, K. Y.; Sung, S. H.; Kim, Y. C. J. Nat. Prod. 2006, 69, 679− 681. (26) Fritzemeier, K. H.; Kindl, H.; Schlösser, E. Z. Naturforsch. 1984, 39c, 217−221. (27) Fritzemeier, K. H.; Kindl, H. Eur. J. Biochem. 1983, 133, 545− 550. (28) Gehlert, R.; Kindl, H. Phytochemistry 1991, 30, 457−460. (29) Reinecke, T.; Kindl, H. Phytochemistry 1994, 35, 63−66. (30) von Reuß, S. H.; König, W. A. Phytochemistry 2004, 65, 3113− 3118. (31) Boonlaksiri, C.; Oonanant, W.; Kongsaeree, P.; Kittakoop, P.; Tanticharoen, M.; Thebtaranonth, Y. Phytochemistry 2000, 54, 415− 417. (32) Soekamto, N. H.; Achmad, S. A.; Ghisalberti, E. L.; Hakim, E. H.; Syah, Y. M. Phytochemistry 2003, 64, 831−834. (33) Zraunig, A. Isolierung und Identifizierung Charakteristischer Stemona Stilbenoide aus S. involuta und S. lucida. Diploma thesis, University of Vienna, Austria, 2012. (34) Sekine, T.; Fukasawa, N.; Murakoshi, I.; Ruangrungsi, N. Phytochemistry 1997, 44, 763−764. (35) Gehlert, R.; Schöppner, A.; Kindl, H. Mol. Plant-Microbe Interact. 1990, 3, 444−449. (36) Preisig-Müller, R.; Schwekendiek, A.; Brehm, I.; Reif, H. J.; Kindl, H. Plant Mol. Biol. 1999, 39, 221−229. (37) Celimene, C. C.; Smith, D. R.; Young, R. A.; Stanosz, G. R. Phytochemistry 2001, 56, 161−165. (38) Yang, X. Z.; Yang, Y. P.; Tang, C. P.; Ke, C. Q.; Ye, Y. Chem. Res. Chin. Univ. 2007, 23, 48−51. (39) Wiboonpun, N.; Phuwapraisirisan, P.; Tip-pyang, S. Phytother. Res. 2004, 18, 771−773. (40) Adams, M.; Pacher, T.; Greger, H.; Bauer, R. J. Nat. Prod. 2005, 68, 83−85. (41) Kongkiatpaiboon, S.; Keeratinijakal, V.; Gritsanapan, W. Pharmacog. J. 2010, 2, 1−4. (42) Vongsak, B.; Kengtong, S.; Vajrodaya, S.; Sukrong, S. Planta Med. 2008, 74, 1764−1766.

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The Diversity of Stemona

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