Phenanthrenes: A Promising Group of Plant Secondary Metabolites

Review Cite This: J. Nat. Prod. 2018, 81, 661−678

pubs.acs.org/jnp

Phenanthrenes: A Promising Group of Plant Secondary Metabolites Barbara Tóth,† Judit Hohmann,†,‡ and Andrea Vasas*,† †

Department of Pharmacognosy, University of Szeged, 6720 Szeged, Hungary Interdisciplinary Centre of Natural Products, University of Szeged, 6720 Szeged, Hungary

‡

S Supporting Information *

ABSTRACT: Although phenanthrenes are considered to constitute a relatively small group of natural products, discovering new phenanthrene derivatives and evaluating their prospective biological activities have become of great interest to many research groups worldwide. Based on 160 references, this review covers the phytochemistry and pharmacology of 213 naturally occurring phenanthrenes that have been isolated between 2008 and 2016. More than 40% of the 450 currently known naturally occurring phenanthrenes were identified during this period. The family Orchidaceae is the most abundant source of these compounds, although several new plant families and genera have been involved in the search for phenanthrenes. The presence of certain substituent patterns may be restricted to specific families; vinyl-substituted phenanthrenes were reported only from Juncaceae plants, and prenylated derivatives occur mainly in Euphorbiaceae species. Therefore, these compounds also can serve as chemotaxonomic markers. Almost all of the newly isolated compounds have been studied for their biological activities (e.g., potential cytotoxic, antimicrobial, anti-inflammatory, and antioxidant effects), and many of them showed multiple activities. According to the accumulated data, denbinobin, with a novel mechanism of action, has great potential as a lead compound for the development of a new anticancer agent.

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rather distinct families taxonomically.4 To date, this list has been enlarged by five other families, as phenanthrene derivatives were reported recently also in the Annonaceae, Brassicaceae, Cannabinaceae, Lauraceae, and Malpighiaceae (Table S1, Supporting Information). Most of the newly identified phenanthrenes were reported from Orchidaceae and Juncaceae species. These compounds have been isolated from different parts of the plants, but mainly from the tubers, roots, rhizomes, and stems. In some cases, the chemical constituents of the leaves or the whole plant were investigated.

INTRODUCTION In the past few years more than 200 novel phenanthrene derivatives have been isolated from plants belonging to the Annonaceae, Aristolochiaceae, Cannabaceae, Combretaceae, Dioscoreaceae, Euphorbiaceae, Juncaceae, Lauraceae, Malpighiaceae, Orchidaceae, and Stemonaceae families. These relatively rare secondary metabolites have drawn the considerable attention of phytochemists and pharmacologists all over the world. Although many phenanthrene-containing plants have been used in traditional medicine for hundreds of years in order to treat several diseases, the chemical composition and the mechanism of action of many of these species have not been studied thoroughly yet and are worthy of further investigation. The aims of this review are to summarize the novel phenanthrenes and 9,10-dihydrophenanthrenes, along with dimeric and trimeric derivatives reported in the period 2008− 2016, as well as to provide an overview of their biological activities. Synthetic or semisynthetic approaches to the phenanthrenes are not included into this review, since there are other reviews covering this topic.1−3 Phenanthrenes are relatively rare secondary metabolites in the plant kingdom. Until now, only a relatively few phenanthrene-containing families have been identified. Most of these aromatic secondary metabolites were described from Combretaceae, Dioscoreaceae, Juncaceae, and Orchidaceae species. Until 2008, phenanthrenes were identified from 12 © 2017 American Chemical Society and American Society of Pharmacognosy

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TRADITIONAL USES OF PHENANTHRENE-CONTAINING PLANT SPECIES Phenanthrene-containing plants are widely used for the treatment of several diseases in Africa, Asia, and South America. Most of the naturally occurring phenanthrenes were isolated from the species of the Orchidaceae family.4 Several phenanthrene-containing epiphytic representatives of this family have been used traditionally; for example, pseudobulbs of Bletilla striata and Monomeria barbata are used in the People’s Republic of China in cases of pulmonary disorders.5−7 Special Issue: Special Issue in Honor of Susan Horwitz Received: July 18, 2017 Published: December 27, 2017 661

DOI: 10.1021/acs.jnatprod.7b00619 J. Nat. Prod. 2018, 81, 661−678

Journal of Natural Products

Review

of the stilbene skeleton, is very limited. Stilbene synthaserelated enzymes catalyze several biosynthetic transformations in plants. The transformation of dihydro-m-coumaroyl-CoA into dihydrostilbenes (bibenzyls) is catalyzed by bibenzyl synthase (Figure 1).39

The popular traditional Chinese medicine (TCM) product “Shan-Ci-Gu” contains the tubers of Cremastra appendiculata and has been used for the treatment of different types of cancer in Asia.8 A traditional medicine, the so-called “Xiao Huang Cao Shi-Hu”, is derived mainly from the stems of Dendrobium nobile and D. of f icinale, but other Dendrobium species (D. aphyllum, D. chrysotoxum, D. denneanum, D. nobile, D. off icinale) are also used in order to treat stomach disorders and fever.9−12 The long-term traditional use of Dendrobium plants are well justified by pharmacological studies.13 Several Eulophia species were used in Bengal and elsewhere in eastern India and for many indications, for example, as aphrodisiac, anticancer, immunomodulatory, and anthelminthic agents.14−16 In TCM, Pholidota chinensis (also known as “Shi-Xian-To”) has been consumed in order to alleviate various diseases, such as headache and high blood pressure.17 Traditionally, the whole plant or the pseudobulbs of Pholidota yunnanensis are consumed for the treatment of trauma, stomachache, and cough.18 Spiranthes sinensis is also used in TCM in order to treat cancer and inflammatory diseases.19 In Korean phytotherapy, the roots of Brassica rapa ssp. campestris are consumed for hangovers, constipation, jaundice, liver, and kidney diseases.20 In Western Uganda, a decoction of Neoboutina macrocalyx (Euphorbiaceae) is used for the treatment of malaria and in cases of headache and fever.21,22 Certain plants belonging to the family Combretaceae are consumed in Tanzania in order to treat different types of cancer.23 Several species in the family Dioscoreaceae are widely used in folk medicine.4,24,25 Dioscorea nipponica is a wellappreciated plant in aura medicine, which helps to ameliorate the symptoms of undernourishment, diarrhea, and chronic fatigue.26 Dioscorea zingiberensis has been used in TCM for the therapy of cardiovascular diseases and gastrointestinal disorders.27 Recently, a series of newly identified phenanthrenes were isolated from Juncaceae species.4,28−33 “Dengxincao” (Juncus ef fusus) is commonly consumed in TCM for its sedativehypnotic and anxiolytic effects.34 Other Juncus species are used for the treatment of colds, fevers, and inflammation.35 Malpighiaceae species are commonly cultivated for their savory fruits [e.g., acerola (Malpighia emarginata)], but species from this family are also used for medical purposes, e.g., in the treatment of asthma, fever, and skin infections (Banisteriopsis anisandra is used externally as a fungicide agent).36 Although recently four phenanthrene derivatives were isolated from industrial hemp, a variety of Cannabis sativa, certain cannabinoid constituents from this species have greater potential therapeutic significance.37,38

Figure 1. Biosynthesis of phenanthrenes and 9,10-dihydrophenanthrenes in plants.

The phenanthrene core could be generated from stilbenes by UV irradiation in the presence of oxidants.41,42 Hence, hydroxy or methyl substitutions that occur in most of the phenanthrenes correspond with the 3,5-disubstitution pattern of stilbenes.43 The biosynthesis of phenanthrenes can also be induced by oxidative stress or fungal infection in higher plants. These cyclized metabolites are more potent antioxidant and antifungal agents than their stilbenoid precursors.44 Fungal infections can also contribute to the high content of dihydrophenanthrenes in Juncaceae species.45 Besides a stilbenoid origin, phenanthrenes also could have other biosynthetic precursors. In 1974, Szendrei et al. hypothesized the production of phenanthrene derivatives from morphine alkaloids. Their proposal was proved to be correct, since thebaol, isolated from opium, shares the same core structural elements as thebaine.46 Two new phenanthrene alkaloids (143 and 144) were isolated from Cryptocarya crassinervia.47 These compounds are probably not derived from the polyketide pathway, because very similar aporphine alkaloids were isolated from the same plant.48 A carboxamide-substituted phenanthrene (146) was isolated from Aristolochia manshuriensis, which is presumably derived from aristolochic acid.49 Aristolochic acids form an unusual group of secondary metabolites, and, according to their structure, these compounds are alkaloid-like phenanthrenes. During their biosynthesis from aromatic amino acids (e.g., tyrosine) two phenylethane units are formed.50 The coupling of the phenylethane units results in norlaudanosoline, as an intermediate, from which aristolochic acid and 3,4-methyIenedioxy-8-methoxy-10-nitro-phenanthrene-1-carboxylic acid are derived.51 Therefore, nitrogen-containing phenanthrenes do not have a stilbenoid origin. The family Euphorbiaceae is well-known as a source of diterpenes, but the occurrence of phenanthrenes is rather sporadic within the family.4,52 Ethylated, oxymethylated, and thiomethylated phenanthrenes reported from the family are not unequivocally derived from stilbenes.53 Although the highly aromatized norditerpene trigonochinene E (76) possesses a phenanthrene skeleton, it seems very likely that biogenetically this compound is a norditerpenoid.54

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BIOSYNTHESIS OF PHENANTHRENES Phenanthrenes are considered to be important taxonomic markers because of their limited occurrence. These rare secondary metabolites are derived through a specific biosynthetic pathway. According to the most widely accepted hypothesis, the phenanthrene skeleton can be formed by oxidative coupling of the aromatic rings of stilbene precursors.39 In 1983, Fritzemeier and Kindl proved that Lphenylalanine is the key precursor for the biosynthesis of dihydrostilbenes and dihydrophenanthrenes.40 From L-phenylalanine, almost all higher plants are able to synthesize malonylCoA and CoA-esters of cinnamic acid derivatives. These compounds are the precursors of stilbenoids, but the occurrence of stilbene synthase, which catalyzes the formation 662



Review

Figure 2. Purification of phenanthrenes and phenanthrene glycosides (PE: petroleum ether; EtOAc: ethyl acetate; VLC: vacuum-liquid chromatography; CC: column chromatography; RPC: rotation planar chromatography; prep. TLC: preparative thin-layer chromatography).

by electronic circular dichroism (ECD) measurements.33,58,85,102

Vinylated phenanthrenes occur only in the Juncaceae family. Therefore, it is suspected that these compounds share their own biosynthetic origin, which is slightly different from other pathways.4 It is assumed that phenanthroquinones are oxidative derivatives of phenanthrenes or dihydrophenanthrenes, but details of the biosynthesis of these compounds are not fully understood. Oxygenated phenanthrenes and abietane-type diterpenoids can provide the analogous phenanthrenequinones and alkylated 1,4-phenanthrenequinones, respectively.55,56

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COMPOUND STRUCTURAL DIVERSITY AND BIOLOGICAL ACTIVITY Monophenanthrenes. Around 80% of the naturally occurring phenanthrenes that have been reported are monophenanthrenes.4 The inclusion of an array of substituents and the saturation of the bond between C-9 and C-10 have resulted in the wide diversity of monomers. The 9,10-dehydro derivatives are called phenanthrenes, and compounds with a saturated C-9−C-10 bond are dihydrophenanthrenes. Among the monophenanthrenes, their 9,10-dehydro and dihydro derivatives are distributed almost equally, with around 60% of the compounds being dihydrophenanthrenes (Table S2, Supporting Information).4 It has been established that all of the naturally occurring phenanthrenes are substituted. Most of the substitutents are linked at C-2 and C-7, and further substituents can occur at C10, C-9, C-3, C-6, and C-4, respectively. None of the recently discovered naturally occurring dihydrophenanthrenes were found to be substituted at C-10. Substitution at position C-9 is also quite rare. Five dihydrophenanthrenes isolated from Dendrobium denneanum contain hydroxy (44−48) groups at C9.11 Loddigesiinol A (97) identified from Dendrobium loddigesii is also substituted with a hydroxy group at C-9.12 Some compounds isolated from Trigonostemon species [76, 81,54,59 stemophenanthrene B (105),60 and brassicaphenanthrene A (107)]20 have methoxy group substitution at C-9. Compound 165 is derived presumably from the condensation of a pentasubstituted phenanthrene with methyl acetate, forming a lactone ring involving C-9 and C-10.61 In the case of crystalltone (163), the phenanthrene skeleton is enlarged with a lactone ring at positions C-4, C-4a, C-5, and C-5a.62 There are only two examples [plicatol A and thrigonosomone B (81)] of 9,10-disubstituted phenanthrenes.54 Almost all of the monophenanthrenes have hydroxy group substitution, with compounds (e.g., 38) that do not bear this substituent usually being O-glycosides, suggesting that biogenetically they were also hydroxylated.63 The hydroxy

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ISOLATION AND STRUCTURE ELUCIDATION OF PHENANTHRENES All types of phenanthrenes have been isolated from different plant organs by the use of very similar procedures (Figure 2). The amount of the raw material required for this purpose may vary between 1 kg21 and 77 kg,20 but usually 5−15 kg of dried plant materials has been used for preparative phytochemical investigations. The plant materials (stems, leaves, medullae, tubers, roots, rhizomes, or whole plants) have been extracted usually with EtOAc, Me2CO, MeOH, EtOH, and aqueous EtOH at room temperature. After filtration and concentration, the extracts were dissolved in water or aqueous MeOH and subjected to solvent−solvent partition with n-hexane or petroleum ether, CHCl3 or CH2Cl2, EtOAc, and butanol. Mono- and diphenanthrenes are then typically concentrated in the nonpolar fractions, but glycosides and triphenanthrenes occur in the polar fractions.57 Phenanthrenes can be detected at 254 and 366 nm when using UV light. Phenanthrene-rich fractions may then be subjected to a series of separation steps, usually starting with vacuum-liquid chromatography on silica gel. Reversed-phase silica gel and Sephadex LH-20 may also be used as stationary phases for separation. Preparative HPLC and TLC are commonly applied for the final purification of these compounds.33 The structure determination of the compounds usually has been carried out by spectroscopic data analysis, 1D and 2D NMR (1H−1H COSY, HSQC, HMBC, NOESY) spectroscopy, and HRESIMS experiments. In some cases, the absolute configurations of the chiral compounds were also determined 663



Review

7)25−27,78 also serve as good sources of methoxy-groupsubstituted phenanthrenes.

Chart 1

Chart 2

Most of the phenanthrenes from species in the family Juncaceae are substituted with methyl groups. Methyl substitutions generally have been found at C-1 or C-7. Only phenanthrenes isolated from the members of Juncaceae have vinyl substitution, particularly at C-5. Therefore, vinylated phenanthrenes can be considered as chemotaxonomic markers for Juncaceae species.4 A monosaccharide moiety (e.g., glucose) can also be linked to the phenanthrene skeleton, but disaccharide-substituted phenanthrenes, such as phenanthrene-glucoapioside (95) and phenanthrene-glucorhamnoside (96), were also reported from higher plants.11 Most of the glycosides were isolated from Orchidaceae species [Bletilla striata, Cremastra appendiculata (36−38, 91, 92, 114−117),8,63,79 Cymbidium Great Flower Marie Laurencin (39),68 Dendrobium denneanum (44, 45, 94− 96),11 Dendrobium primulinum (55),80 and Liparis regnieri (103, 104)].81 Two glycosides were identified from Dioscoreaceae species (6, 79),26,54 with phenanthrene glycosides reported from the families Juncaceae and Berberidaceae previously.4 Prenyl-substituted phenanthrenes are relatively uncommon. However, Ilmiawati et al. reported five prenylated compounds, including three new prenyl-substituted phenanthrenes (62, 63, 161) from Macaranga javanica (Euphorbiaceae).82 Recently, hydroxymethyl-substituted phenanthrenes (14, 16, 20, 25, 82) were isolated from plants belonging to the genus Juncus (J. ef f usus, J. inf lexus, J. setchuensis, and J. subulatus).32,33,35,83,84 Carboxylic acid substitution (86) occurs occasionally among monophenanthrenes.34 A formyl group when present occurs at C-1 in the case of compounds isolated from Banisteriopsis anisandra (27−29)36 and at C-5 in components of Juncus ef f usus (10, 13).29,34

group is usually linked at C-2 or C-7. The presence of the hydroxy group at C-9 is more frequent among dihydrophenanthrenes (e.g., 43−49)64 compared with the phenanthrenes (97). The second most common substituent is a methoxy group, mainly at positions C-2, C-4, C-5, and C-6. Most of the phenanthrenes from Orchidaceae species are methoxylated, e.g., calanphenanthrene A (30), calanhydroquinones A−C (31−33), and calanquinones A−C (131, 138, 139) from Calanthe arisanensis,65,66 cephanthrenes A (34) and B (35) from Cephalantheropsis gracilis,67 marylaurencinols A−C (40− 42) and ephemeranthoquinone C (141) from Cymbidium Great Flower Marie Laurencin,68,69 51, 100, and 101 from Dendrobium moniliforme and D. nobile,70−72 and 102 from Liparis nakaharai.73 Moreover, Stemona (S. japonica, S. tuberosa, and S. sessiflora) (58−61)74−77 and Dioscorea species (D. membranaceae, D. nipponica, and D. zingiberensis) (4− 664



Review

Chart 3

Since almost all of the phenanthrenes are of stilbene origin, it is not unexpected that stilbene-substituted phenanthrenes have been isolated from several plants. In the case of phochinenins I (68), J (69), and K (70),85 batatasin III (dihydrostilbene) is connected with lusianthridin, and in phochinenin L (71) thunalbene (stilbene) is linked to a dihydrophenanthrene, which was previously isolated from a liverwort (Plagiochila spinulosa).86 Pholidota phenanthrenes are also derived from lusianthridin, substituted with either batatasin III (72) or thunalbene (73).87 The 9,10-dihydrophenanthrene skeleton of monbarbatain E (67) is also linked to a dihydrostilbene moiety (stilbostemin E), but in this case through an O atom, in contrast with the above-mentioned phenanthrenes, where the two parts of the compounds are connected via C−C coupling.88 Hydroxybenzyl-substituted monophenantheres were isolated from genera of the Orchidaceae family, including Bletilla (e.g., 108−110),89 Cremastra (e.g., 64, 111, 112),90 Cyrtopodium (118),91 Monomeria (119),6 and Pholidota (162)18 and Dioscoreaceae species (D. bulbifera; diobulbinone A, 66).92 Symmetrical naturally occurring phenanthrene derivatives are rather uncommon, but recently a symmetrical tetracyclic molecule, juncutol (74), was obtained from Juncus acutus.93

The compound may be derived from effusol, which was previously reported from the same plant,94 through coupling between C-4 and the methine carbon of the vinyl group. During the past nine years, a number of phenanthroquinones, especially from Orchidaceae species [Calanthe arisanensis (131, 138, 139),65,66 Cymbidium Great Flower Marie Laurencin (132, 141),68,69 Dendrobium aphyllum (121),9 D. draconis (133),95 D. longicornu (134),96 D. sinense (135),97 Bletilla striata (126),98 Oncidium isthmi (136),99 and Odontioda Marie Noel ”Velano” (140)]100 have been reported. These compounds have been found with several substituents, with mainly methyl, methoxy, and hydroxy groups being attached to the skeleton. Phenanthrene-1,4-quinones are the most commonly occurring phenanthrenequinones; hence phenanthrenes usually bear hydroxy substitution at C-1 and C-4. A carbonyl group can also occur at C-2 and C-3 (e.g., 128).60 The saturation level of these compounds can vary depending on the type of the phenanthrene unit. Phenanthrenes with carbonyl-group substitution are also quite common; such compounds were isolated from several species belonging to the Orchidaceae, Juncaceae [Juncus inf lexus (120), J. setchuensis (124), and Luzula luzuloides (luzulin A, 125)],33,101,102 Stemonaceae [S. japonica (japonin D, 127) and 665



Review

Some monophenanthrenes have additional different substituents. Compound 167 is most likely derived from compound 147 substituted with batatasin III, and the cyclization of the stilbene moiety resulted in compound 192.63 A phenanthrene substituted with a lactam ring (145) was isolated from Fissistigma bracteolatum.110 Previously several aristolochic acids were isolated from other species of the Fissistigma genus; therefore it is suspected that this phenanthrene could also be characterized as an alkaloid.106 A novel phenanthrene, a denitroaristolochic acid derivative, named aristolamide II (146), was isolated from Aristolochia manshuriensis, substituted with a methylenedioxy functionality.49 Of the relatively few Euphorbiaceae species containing phenanthrenes, recently the first naturally occurring sevenmembered O-heterocyclic phenanthrene (142) was isolated from Trigonostemon lii.59 The authors also provided a biogenetic scheme for this compound, according to which it is a ring-enlarged phenanthrene derivative. Di- and Triphenanthrenes. More than 40 dimers and a new trimer have been described since 2008 (Tables S2 and S3, Supporting Information). It is worth noting that almost all of the novel diphenanthrenes were reported from Juncaceae and Orchidaceae species. Monophenanthrenes can connect through their functional groups or directly via C−C coupling to form di- or triphenanthrenes. The monomers can be linked together at many different positions; usually C-1 is involved in the connection. The linking monomers have usually been isolated previously from the same plant, the same genus, or the same family. Almost all of the monomeric parts of the dimers have been isolated earlier, with probably only a few examples being yet undiscovered. These secondary metabolites are even more sporadic and rare than monophenanthrenes. The single novel example of a Dioscoreaceae diphenanthrene (201) is an 8,8′-linked homodimer of a known tetrasubstituted phenanthrene, which was previously isolated from other species of the family.4,25 Among the isolated Juncaceae diphenanthrenes, the occurrence of symmetrical compounds is quite high. The dihydrophenanthrene dimers effususin A (168) and effususin D (169) are homodimers of effusol.30 According to their proposed biosynthetic pathway, these two effusols lose their hydroxy groups from position C-7 to form effususin D (169). The other newly identified dimers of the genus Juncus have at least one unsaturated phenanthrene ring in their structure. In effususin B (183), dehydroeffusol and effusol are linked at the C-8 and C-3′ positions.30 Presumably effususin C (203) is a dimer of 7,7′-dehydroxylated dehydroeffusols linked through the former hydroxy groups.30 In the case of 8,8′-bidehydrojuncusol (202), two dehydrojuncusol units form a symmetrical homodimer through an 8,8′ coupling.28 Vinyl groups, characteristic functional groups of phenanthrenes from species in the family Juncaceae, can also take part in the dimerization (184, 204).111 The novel heptacyclic compound jinflexin D (185) may be derived by the coupling of dehydrojuncuenin A (87) with 2,7-dihydroxy-1,8-dimethyl-5vinyl-9,10-dihydrophenanthrene through their vinyl groups.33 Most of the dimers isolated from the family Orchidaceae are considered to be formed by the coupling of the commonly occurring monomers of Orchidaceae species,4 e.g., lusianthridin (172, 175, 176, 179, 181, 190, 196−199),6,17,85,87,91,112,113 lusianthrin (198, 199, 212),112 coelonin (171, 172, 178, 189, 191, 193−195),6,63,112,114 6-methoxycoelonin (186, 188),5,6

Chart 4

S. tuberosa (128, 137)],60,103,104 Dioscoreaceae [Dioscorea zingiberensis (130)],27 Trigonostemon chinensis (122), T. lii (123)], and Cannabaceae [Cannabis sativa (129)]38 families.105,106 In some cases, the oxidation of phenanthrenes results in the hydroxy group substitution of C-4a or C-8a (121, 124).9,101 Phenanthrofurans and phenanthropyrans form another group of monophenanthrenes. These rings are usually attached to the phenanthrene core at C-1 and C-2 (147, 148, 150−154, 158−160),10,12,17,63,91,107,108 C-2 and C-3 (149, 155− 157),91,109 or C-4 and C-5 (162).18 Interestingly, all of the novel furan-condensated derivatives are saturated between C-9 and C-10, and among the phenanthropyrans, only loddigesiinol B (160)12 has an unsaturated phenanthrene skeleton, while the others are dihydrophenanthrenes. In macajavanicin C (161),82 a pyran ring is formed from the prenyl group at C-6 with the hydroxy group at C-7. Two phenanthrenes were isolated from Combretum adenogonium, which were derived from the condensation of a dihydrophenanthrene (164) and a phenanthrene (165) with esters.61 In the case of these derivatives, the furan ring involves C-1, C-1a, and C-10, and a lactone ring has also been elaborated. Phenanthrenelactones were reported also from Dendrobium crystallinum (163)62 and Juncus setchuensis (166).101 666



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Chart 5

flavanthrinin (191, 192, 206−208),63,114,115 orchinol (182),19 nudol (186, 196, 197, 205, 209, 210),5,91,116,117 and 2hydroxy-4,7-dimethoxyphenathrene (187−190, 193−195, 209, 211).6,114,117 Monbarbatains B (198) and C (199) are both derived by the coupling of lusianthridin with lusianthrin and differ only in the positions of their linkages.112 In the case of compound 207, the recently isolated aerosanthrene (89) serves as a monomer.114,118 Symmetrical dimers can also be found among the isolated compounds of Orchidaceae species, for example, in a diphenanthrene (170) obtained from Bletilla yunnanensis, in which two O-methylorchinol monomers are linked at C-1 and C-1′.119 8,8′-Biflavidin (174) is derived from two flavidins through a direct C−C coupling.120 Homodimers of lusianthridin, named phochinenin G (176) and phoyunnanin C (181), have also been reported.85,87 Monbarbatain A (212) is a 1,1′-linked dimer of lusianthrin and its unsaturated

form, lusianthridin.112 Compound 182 is a symmetrical 3,3′linked homodimer of orchinol.19 Compound 206 is the only naturally occurring glycosylated phenanthrene dimer that have been reported thus far.115 This diphenanthrene, isolated from Cremastra appendiculata, could be formed by the coupling of flavanthrinin and flavanthrinindiglucoside. 2,5-Dihydroxy-6-methoxy-9,10-dihydrophenanthrene was reported from Plagiochila spinulosa, a liverwort species, yet several Orchidaceae diphenanthrenes are formed by the coupling of this monomer with other, more common monomers previously described from Orchidaceae species, e.g., coelonin (178) and three lusianthridin derivatives (175, 177, 179).17,85 Phochinenin B (200) is formed by the coupling of 2,5-dihydroxy-6-methoxy-9,10-dihydrophenanthrene and its unsaturated form, which has not been described previously.17 Compound 173 obtained from Dendrobium nobile121 is a homodimer of two 2-hydroxy-3,4,7-trimethoxy-9,10-dihydro667



Review

Chart 6

and in other cases the whole plant material has been investigated (e.g., 171, 175, 181, 182).17,19,87,112 Biological Activities. Phenanthrenes show a wide range of biological activities, including antiproliferative, antimicrobial (antiviral, antibacterial, fungicidal), anti-inflammatory, antioxidant, antiallergic, spasmolytic, and anxiolytic effects. Biological evaluations of phenanthrenes performed in the past nine years are summarized in the following sections, which will focus on only the most active compounds and their activities. The results of all investigations are summarized in Table S4 (Supporting Information).

phenanthrene monomers, which was reported previously from Plagiochila spinulosa.86 The single novel triphenanthrene described recently, monbarbatain D (213), is presumably derived from the coupling of three lusianthridin units.112 Phenanthrene dimers have been obtained from different anatomical parts of the plants investigated. Dimers were reported from the roots (185),33 rhizomes (202),28 and medulla (168, 169, 183, 203)30 of species of the Juncaceae. Several diphenanthrenes were isolated from the tubers (e.g., 170, 191, 198)63,112,119 of plants in the family Orchidaceae, 668



Review

Chart 7

Antiproliferative Activity. Many previously isolated phenanthrenes possessed quite potent cytotoxic activities against cancer cell lines.4 Among them, denbinobin, one of the most widely investigated phenanthrene derivatives (Figure 3), has shown noteworthy activities in this regard. The cytotoxic activity of denbinobin apparently involves several different mechanisms of actions. The apoptosis induction of this substance includes caspase-dependent and caspase-independent [translocation of cytochrome c and apoptosis-inducing factor (AIF)] effects on colon cancer (COLO 205) cells, but Bcl-2 proteins and the Akt pathway

do not appear to be involved in the apoptotic mechanism observed in COLO 205 cells.122 By targeting TAK1 kinase, the compound inhibits the phosphorylation and degradation of the NF-κB inhibitory protein (IκBα), and it blocks NF-κB activation on Jurkat leukemia cells.123 Moreover, it induces apoptosis by enhancing the synthesis of reactive oxygen species (ROS) in human lung adenocarcinoma (A549) and in Jurkat leukemia cells.123,124 Denbinobin increased ROS generation, leading to activation of the ASK1/JNK/AP-1/Bim cascade, with increasing levels of the pro-apoptotic Bcl-2 protein (Bim) causing mitochondrial dysfunction and initiating the cell death 669



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Chart 8

of A549 cells.124 A structure−activity relationship study revealed that the quinone substructure of this compound is crucial for enhancement of MAPK-independent ROS production activity.123 Denbinobin decreased the phosphorylation of protein kinase B (Akt kinase) by reducing the phosphorylation of NF-κB inhibitory protein in the A549 and human glioblastoma multiforme (GBM8401) cell lines.125,126 The compound activated the pro-apoptotic regulator Bad protein on A549 cells, which induces mitochondrial dysfunction, and the activation of both caspase-dependent (caspase-3, cytochrome c, Smac) and caspase-independent apoptotic mediators (AIF) led to programmed cell death.126 Denbinobin enhanced caspase-3 protein activation and PARP cleavage on both the A549 and GBM8401 cell lines.125,126 However, apoptosis caused by denbinobin on human colorectal cancer (HCT-116) cells did not involve either caspase cascade or PARP cleavage.127 The compound induced p53 protein-caused

DNA damage in HCT-116 cells and elevated the level of Bcl-2 proteins (Bax, PUMA, NOXA), which help to release AIF from the mitochondria. Programmed cell death in GBM8401 cells by denbinobin was independent from Bcl-2 family proteins.125 Denbinobin-caused apoptosis in SNU-484 cells was induced by the inactivation of the antiapoptotic Bcl-2 and by the activation of proapoptotic Bax protein.128 The compound decreased the level of antiapoptotic decoy receptor 3 (DcR3) in human pancreatic adenocarcinoma cells (BxPC3) and increased the translocation of AIF from the mitochondria.129 Through the downregulation of DcR3, denbinobin enhanced synergistically the proapoptotic effects of FasL and sensitized the cells toward programmed cell death. After 24 h of treatment, denbinobin arrested the cell cycle of human chronic myelogenous leukemia (K562) and prostate cancer (PC3) cells at the G2/M phase, with IC50 values of 1.8 and 7.5 μM, respectively.130,131 Denbinobin may cause G2/M 670



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Chart 9

further mechanism of action of antimigration activity was discovered.131 At a 5 μM concentration, the compound inhibited CXCL12-induced migration by inhibiting Rac1 protein; therefore the functions of cortactin were blocked. On the other hand, denbinobin did not affect the caspase cascade mechanism in PC3 cells, and it did not influence CXCL12-induced Src phosphorylation. The effects of denbinobin against human colon cancer (COLO 205) xenografts were shown in vivo in athymic nude mice.122 The intraperitoneally administered compound (20 mg/kg/day) proved to be inhibitory against subcutaneously implanted HCT-116 cells in SCID mice, with relatively low toxicity.127 In another in vivo murine xenograft experiment, denbinobin suppressed insulin-like growth factor-1 (IGF-1)induced angiogenesis using human umbilical vascular endothelial cells (HUVECs), and thus the compound may influence tumor metastatic mechanisms.133 These results reveal that denbinobin can be regarded as a promising lead compound in the search for new anticancer agents.134 Compound 90 and 3,4,6-trimethoxyphenanthrene-2,7-diol, identified from Appendicula reflexa, were found to possess

Figure 3. Structure of denbinobin.

phase arrest due to enhancing polymerized tubulin levels and stabilizing microtubules.130 The antimigratory effects of denbinobin are also very promising, as the compound inhibited the invasion of human gastric cancer (SNU-484) cells dose-dependently, which involved the downregulation of matrix metalloproteinases (MMP-2 and MMP-9) and the inhibition of calcium-binding cell migration protein (S100A8).128 In human (MDA-MB231) and mouse (4T1-Luc) breast cancer cell lines, 10 μM of denbinobin affected the migration and the invasion of the EGF-treated cells by reducing Src kinase activity. Moreover, denbinobin inhibited the metastasis in vivo. In mice treated with 10 mg/kg denbinobin no metastasis was observed in the lung tissue.132 In the case of prostate cancer (PC3) cells, a 671



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inhibitory activity (IC 50 values of 0.07 and 0.2 μM, respectively) in a CDK1/cyclin B kinase assay.5 A dihydrophenanthrene (27) isolated from Banisteriopsis anisandra proved to be active against the MeWo (5.0 μg/mL), CT26.WT (4.0 μg/mL), B16-F10 (8.0 μg/mL), and CHO (6.0 μg/mL) cell lines when compared to 5-fluorouracil [8.0 μg/mL (MeWo), 5.0 μg/mL (CT26.WT), 4.0 μg/mL (B16F10), and 12 μg/mL (CHO)] as positive control.36 A phytochemical investigation of Bulbophyllum odoratissimum led to the isolation of two new dimeric phenanthrenes, bulbophythrins A (171) and B (172). Both compounds exerted potent cytotoxic activities against the K562 (IC50 values of 6.1 and 2.8 nM/mL), HL-60 (IC50 values of 1.3 and 4.0 nM/mL), A549 (IC50 values of 9.2 and 1.2 nM/mL), and SGC-7901 (IC50 6.1 nM/mL for 172) cell lines, which were comparable to that of cisplatin [IC50 0.27 nM/mL (K562), IC50 2.3 nM/mL (HL-60), IC50 1.5 nM/mL (A549), and IC50 0.7 nM/mL (SGC-7901)].112 The cytotoxic potential of calanquinone A (138) was tested against several cancer cell lines. This quinone inhibited the activity of the growth of A549 (IC50 0.19 μg/mL), PC-3 (IC50 0.16 μg/mL), DU145 (IC50 0.34 μg/mL), HCT-8 (IC50 0.20 μg/mL), MCF-7 (IC50 0.03 μg/mL), KB (IC50 0.32 μg/mL), and vincristine-resistant KB (IC50 0.45 μg/mL) cell lines. It was equally effective for both the vincristine-resistant (KBVIN) cell line and the normal nasopharyngeal (KB) cancer cell line.65 Ephemeranthoquinone B (132), obtained from Cymbidium Great Flower Marie Laurencin, was shown to possess cytotoxic activity (IC50 2.8 μM) in a WST-8 assay when compared to mitomycin C (IC50 0.1 μM).68 4,9-Dimethoxyphenanthrene2,5-diol from Dendrobium chrysotoxum exerted cytotoxic activity against human hepatoma (BEL-7402) (IC50 1.8 μg/ mL) and gastric cancer (SGC-7901) (IC50 2.9 μg/mL) cell lines.135 Monomeria barbata is an abundant source of biologically active phenanthrenes. Monbarbatain B (198) showed inhibitory activity for a HL-60 cell line (IC50 7.3 μg/mL), and monbarbatain D (213) inhibited the growth of Skov-3 cells (IC50 = 41.5 μg/mL), and both were compared to cisplatin (IC50 values of 7.7 μg/mL, HL-60, and 37.9 μg/mL, Skov3).112 Bioactivity-guided fractionation and isolation of Odontioda Marie Noel “Velano” led to the isolation of two phenanthrenes. 5-Hydroxy-2,3-dimethoxy-1,4-phenanthrenequinone (140) and ephemeranthoquinone B (132) showed specific cytotoxic activity against the HL-60 cell line (IC50 values of 4.7 μM for 140 and 3.0 μM for 132) using the MTT assay. According to a DNA fragmentation assay, none of the compounds caused apoptosis.100 A new phenanthrenequinone (136) obtained from Oncidium isthmi showed cytotoxic activity against the NCI-H460 (IC50 5.0 μM) and M14 (IC50 1.5 μM) cell lines. Further to followup caspase 3/7 activation and LDH release assays, this compound was found to induce apoptosis.99 Antimicrobial Activity. Several phenanthrenes were tested against different (resistant and nonresistant) bacterial and fungal strains, and many of them showed promising growth inhibitory activities, which can be explained by the phytoalexin characteristics of these compounds. An ethanol extract of Combretum adenogonium showed antimicrobial activity against nine bacterial strains (B. anthracis, B. cereus, E. coli, K. pneumoniae, P. aeruginosa, S. typhi, S.

f lexneri, S. aureus, and S. faecalis).23 A mixture of compounds 3, 77, 164, and 165 isolated from the plant proved to be active against P. aeruginosa (MIC 0.16 mg/mL).61 Trigonochinene E (76) was found to possess antimicrobial activities against S. aureus (ATCC 25923) (IC50 6.25 μg/mL), S. epidermidis (ATCC 12228) (IC50 6.25 μg/mL), M. luteus (ATCC 9341) (IC50 12.5 μg/mL), C. albicans (ACTT 1600) (IC50 12.5 μg/mL), and M. gypseum (IC50 6.25 μg/mL).54 The antibacterial properties of several phenanthrene dimers [187−190, 4,8,4′,8′-tetramethoxy(1,1′-biphenanthrene)2,7,2′,7′-tetrol, and blestriarene C] isolated from the roots of B. striata were evaluated against Gram-positive and Gramnegative bacteria [S. aureus (ATCC 25923, ATCC 29213, and ATCC 43300), S. epidermidis (CMCC 26069), E. faecalis (ATCC2 9212), and B. subtilis (CGMCC 1.1470)]. Except for compound 187, all these dimers exhibited antibacterial activities against Gram-positive strains comparable in potency to the positive control ampicillin.6 The antimicrobial properties of blestriarenes B and C, isolated from B. yunnanensis tubers, were tested against Gram-positive and Gram-negative bacteria, and both compounds proved to be active against S. aureus (IC50 values of 6.25 and 25 μg/mL).119 The antibacterial effects of phenanthrenes isolated from the EtOAc-soluble fraction of Cymbidium Great Flower Marie Laurencin were determined against B. subtilis and K. pneumoniae. Ephemeranthoquinone B (132) was the most active substance against B. subtilis, with an MIC value of 4.9 μg/mL.100 Marylaurencinol C (42) showed antimycotic activity by inhibiting the growth of T. rubrum (inhibition zone of 12.7 mm at 10 μg/disk), comparable to ketoconazole (inhibition zone of 15.7 mm at 5 μg/disk).69 Stemanthrene F (58) displayed inhibitory activity against S. aureus (IC50 25 μg/mL) and S. epidermidis (IC50 12.5−25 μg/ mL).74 The acetone extract of Cannabis sativa (variety “carma”) exhibited anti-HIV-1 activity, so compounds isolated from this extract were tested. Among them, denbinobin at the tested concentration did not inhibit HIV-1 reverse transcription and integration into Jurkat-LAT-GFP cells, but it inhibited effectively HIV-1 reactivation, induced by TNFα (IC50 < 1 μM), PMA, or α-CD3/α-CD28 mAbs (IC50 values = 1.5 and 2.5 μM, respectively), in a concentration-dependent manner. Denbinobin inhibited the HIV-1-LTR transactivation through modifying the NF-κB pathway, and, presumably, its major target is the NF-κB inhibitory (IκBα) protein.136 The antifungal activity of a novel dihydrophenanthrene (27) isolated from Banisteriopsis anisandra was tested against four Candida strains by the use of the microdilution method, and it showed activity against C. krusei (IC50 31.3 μg/mL) and was compared to fluconazole (IC50 32.0 μg/mL).36 Neonthrene (8) showed antiplasmodial activity against chloroquine-resistant P. falciparum (FcB1) at a concentration of 9.8 μg/mL.21 Anti-inflammatory Activity. Several phenanthrene-containing plants have been used traditionally as antiphlogistics. A new, amide-substituted phenanthrene (146), along with several known analogues, were obtained from the stems of Aristolochia manshuriensis by the use of bioassay-guided isolation. Aristolamide II (146) inhibited elastase release (ER), with an IC50 value of 4.1 μg/mL, but had no effect on superoxide anion generation (SG) using fMLP-induced human neutrophils. Among the known phenanthrenes, aristolochic acid IVa (IC50 values of 8.5 μg/mL for ER and 5.8 μg/mL for 672



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SG) and aristolactam IIIa (IC50 values of 0.20 μg/mL for ER and 0.12 μg/mL for SG) possessed activities in both assays. Aristolactam IIIa proved to be more effective than the positive control genistein (IC50 values of 7.0 μg/mL for ER and 0.54 μg/mL for SG).49 Batatasin I and 6-hydroxy-2,7-dimethoxy-1,4-phenanthraquinone, obtained from Dioscorea batatas roots, were tested for their potential anti-inflammatory activity. Batatasin I inhibited PGD2 generation in a dose-dependent manner (IC50 1.8 μM) by reducing the COX-2 protein level, while 6-hydroxy-2,7dimethoxy-1,4-phenanthraquinone inhibited both COX-1- and COX-2-induced PGD2 secretion, with IC50 values of 0.27 and 0.08 μM, respectively. Both compounds inhibited mast cell degranulation and exhibited dose-dependent inhibition of 5LOX-dependent LTC4 generation, suggesting that batatasin I and 6-hydroxy-2,7-dimethoxy-1,4-phenanthraquinone may have antiallergic potential. Therefore, these compounds should be considered for the development of new COX-2/5-LOX inhibitors.137,138 Dioscorea nipponica is traditionally used in the prevention of neurodegenerative diseases. An ethanol extract of this plant acted as an NGF agonist using the C6 rat glioma cell line. Among the compounds isolated, diosniposide B (6) and 4,7dihydro-2,6-dimethoxy-9,10-dihydrophenanthrene were found to enhance NGF secretion (140.9% and 147.9%, respectively) in C6 cells without apparent cytotoxicity. 3,7-Dihydroxy-2,4,6trimethoxyphenanthrene displayed neuroprotective activity, due to its neurotrophic and antineuroinflammatory effects, involving three different mechanisms of action. The compound induced NGF production (162.4%) in C6 glia cells and diminished the NO secretion of LPS-induced BV2 microglial cells (IC50 19.6 μM). Moreover, it enhanced neurite outgrowth at 5 and 20 μM concentrations in N2a cells.139 6Methoxycoelonin, another phenanthrene isolated from D. nipponica, inhibited the LPS-induced NO production in BV2 cells; its IC50 value (19.4 μM) was comparable to that of the positive control NMMA (IC50 16.3 μM).26 These results support the traditional uses of D. nipponica. Dioscopposides A (78) and B (79), isolated from Dioscorea opposita, exerted inhibitory activity on LPS-induced NO production on murine macrophage RAW 264.7 cells. Their IC50 values (5.8 and 7.2 μM) were both greater than that of the positive control aminoguanidine (IC50 15.3 μM).57 Moreover, 9,10-dihydro-7-methoxy-2,5-phenanthrenediol, from D. opposita, inhibited the COX-2 enzyme (IC50 10.6 μg/mL) selectively.140 The anti-inflammatory properties of juncutol (74) were evaluated by an assay involving the inhibition of iNOS protein expression in LPS-stimulated RAW 264.7 cells. Compound 74 at 10 μM showed pro-anti-inflammatory activity (protein expression 11.2%).93 Dehydrojuncusol and its dimer (202) were also assayed by the same procedure. According to an immunoblot analysis, the effect of dehydrojuncusol (59.0%) on iNOS protein expression decreased dramatically (>88.0%) using this dimeric compound.28 Effususin B (183) inhibited the LPS-induced NO production on RAW 264.7 cells (7.4 μM).30 The potential anti-inflammatory activity of phenanthrenes, isolated from the medulla of Juncus ef f usus, was determined using RAW 264.7 cells by the inhibition of LPS-induced NO production. Among these, 8-hydroxymethyl-2-hydroxy-1-methyl-5-vinyl-9,10-dihydrophenanthrene (14) (IC50 14.4 μM), 5-(1-methoxyethyl)-1methylphenanthrene-2,7-diol (85) (IC50 11.1 μM), effusol

(IC50 15.1 μM), dehydroeffusol (IC50 12.7 μM), dehydroeffusal (IC50 10.5 μM), 2,7-dihydroxy-5-hydroxymethyl-1methyl-9,10-dihydrophenathrene (IC50 16.0 μM), 5-hydroxymethyl-1-methylphenanthrene-2,7-diol (82) (IC50 16.3 μM), dehydrojuncusol (IC50 15.6 μM), and a mixture of 2,7dihydroxy-1,8-dimethyl-5-vinyl-9,10-dihydrophenanthrene and juncusol (IC50 15.6 μM) showed inhibitory activities comparable to the positive control quercetin (IC50 6.6 μM).32 The anti-inflammatory effects of juncusol (IC50 3.1 μM), juncuenin B (18) (IC50 4.9 μM), and dehydrojuncuenin B (88) (IC50 3.2 μM) were observed in a superoxide anion generation assay. Juncuenin B (18) also inhibited elastase release, with an IC50 of 5.5 μM, which was comparable to that of the positive control [LY294002 (4.8 μM)].102 Compounds isolated from Dendrobium denneanum were evaluated for their anti-inflammatory activity on LPS-induced NO production in RAW 264.7 cells. Curcumin was used as positive control. None of the compounds showed growth inhibitory effects on RAW 264.7 cells in the concentration range of 0.7−41.5 μM. Follow-up mechanism of action work indicated that compounds 48 and 94 inhibit both MAPK- and NF-κB-mediated inflammation, by inhibiting the phosphorylation of these factors.11 The newly identified loddigesiinols A (97) and B (160) (IC50 values of 2.6 and 10.9 μM, respectively) and the known moscatin (IC50 6.4 μM), 5-hydroxy-2,4-dimethoxyphenanthrene (IC50 5.3 μM), and lusianthridin (IC50 4.6 μM), isolated from Dendrobium loddigesii, inhibited LPS-induced NO production in RAW 264.7 macrophage cells, while rotundatin and hircinol were less active compared to the positive control aminoguanidine (17.5 μM).12 A newly identified compound 100 (IC50 20.4 μM) and nine known compounds [hircinol (IC50 26.4 μM), erianthridin (IC50 19.5 μM), ephemeranthol A (IC50 12.0 μM), 5,7dimethoxyphenanthrene-2,6-diol (IC50 35.7 μM), coelonin (IC50 10.2 μM), flavanthridin (IC50 34.1 μM), ephemeranthol C (IC50 17.6 μM), lusianthridin (IC50 9.6 μM), and fimbriol B (IC50 28.9 μM)] from Dendrobium nobile exerted antiinflammatory activity. Aminoguanidine was used as positive control (IC50 17.5 μM).71 Ephemeranthol A exerted antiinflammatory acivity (IC50 12.0 μM) by inhibiting LPSinduced NO production in RAW 264.7 cells; its mechanism of action involved NF-κB and MAPK pathways. The compound, along with the new phenanthrene 101, reduced the production of some proinflammatory cytokines (TNF-α, IL-1β, IL-6) at a concentration of 25 μg/mL.72 Eulophia ochreata has been used as an anti-inflammatory agent in Indian folk medicine, which was supported by the findings of Datla et al. According to their results, 9,10-dihydro2,5-dimethoxyphenanthrene-1,7-diol (56), isolated from this plant, exhibited anti-inflammatory activity through toll-like receptor-4.16 2,5-Dihydroxy-4,9-dimethoxyphenanthrene, obtained from Odontoglossum harvengtense “Tutu”, showed activity (IC50 24.1 μM) in LPS-induced RAW 264.7 cells by inhibiting the production of NO. This activity might be due to its inhibitory effects on the iNOS protein expression. 141 1-(4′Hydroxybenzyl)imbricatin (162) (Pholidota yunnanensis) also inhibited the LPS-induced NO production of RAW 264.7 cells (IC50 20.8 μM).18 Imbricatin and methoxycoelonin isolated from Vanda coerulea dose-dependently suppressed the PGE2 production (IC50 values of 12.2 and 19.3 μM, respectively) in HaCaT cells 673



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eulophiol (27.7 μM), and 2,4,7-trihydroxy-9,10-dihydrophenanthrene (10.0 μM) were comparable to that of the positive control resveratrol (21.2 μM). Phoyunnanins A (72) and B (73) had lower activities with EC50 values of 55.9 and 47.3 μM, respectively.87 The antioxidant activity of imbricatin, methoxycoelonin, flavidin, and coelonin was confirmed by two in vitro free radical-scavenging (DPPH, •OH) assays (IC50 values of 8.4, 9.0, 6.6, and 8.5 μM, DPPH assay; IC50 values of 0.03, 0.04, 0.08, and 0.08 μM, •OH assay). Moreover, imbricatin and methoxycoelonin neutralized dose-dependently the ROS production in H2O2-induced HaCaT cells (IC50 values of 8.8 and 9.4 μM, respectively).142 CNS Activities. Juncus species are found in traditional Asian medicines used for sedative and anxiolytic agents. The ethnopharmacological use of the plants was confirmed by the isolation of their CNS-depressant constituents. Dehydroeffusol at 5 mg/kg reduced anxiety in animal studies [elevated plusmaze test [time mice stayed in open arms (OT) = 56.54 s, entries into open arms (OE) > 6) and hole-board test (head dips >80)], but its sedative activity was not linked with decreased motor function.146 Wang et al. proved the anxiolytic properties of effusol and juncusol on mice by using an elevated plus-maze test (OT = 58.8 s, OE = 6.6 for effusol, and OT = 75.5 s, OE = 7.8 for juncusol). Their sedative activity was also confirmed by the decreased locomotion (516.1 for juncusol, 498.1 for effusol, and 365.6 for diazepam) in the open field test. In all cases, diazepam was used as positive control (OT = 111.9 s, OE = 13.6).34 A mechanism of action study revealed that effusol and dehydroeffusol dose-dependently inhibited the α1β2γ2s subtype of GABAA receptor. Flumazenil, a benzodiazepine antagonist, did not inhibit the action of these phenanthrenes. Therefore, it was assumed that effusol and dehydroeffusol were not attached to the benzodiazepine binding site of the GABAA receptor.147 Coelonin isolated from P. chinensis enhanced dose-dependently the IGABA value, but at 300 μM the receptors were not saturated.148 Other Activities. Brassicaphenanthrene A (107) exhibited LDL-oxidation inhibitory activity in the TBARS assay at a 2.9 μM concentration, which supports in part the beneficial effects of the consumption of Brassica rapa ssp. campestris.20 Bioactivity-guided fractionation of the 20% aqueous ethanol extract of Combretum adenogonium roots led to the isolation of four phenanthrenes (3, 77, 164, 165), and a mixture of these compounds possessed activity (LC50 12.1 μg/mL) in the brine shrimp lethality bioassay. Cyclophosphamide was used as positive control (LC50 16.4 μg/mL).61 Several isolated phenanthrenes from Dendrobium nobile were studied for their antifibrotic activities in a hepatic stellate (HSC-T6) cell line using the MTT assay. Compounds 99 (9.0 μM), denbinobin (15.2 μM), coelonin (13.4 μM), and fimbriol B (11.0 μM) possessed inhibitory activity and were compared to (−)-epigallocatechin-3-gallate (9.9 μM).121 The mechanism of action of denbinobin, fimbriol B, and 2,3,5-trihydroxy-4,9dimethoxyphenanthrene (99) was further investigated. It was found that these compounds decreased selectively, dose- and time-dependently the viability of HSC-T6 cells. At a 10 μM concentration, the tested compounds induced apoptotic cell transformations, and at a concentration of 30 μM necrotic changes of the cells were observed. According to the caspase3/7 activity assay, fimbriol B and compound 99 caused caspase-dependent apoptosis.149

due to their COX-2 inhibitory (IC50 values of 12.0 and 5.8 μM, respectively) activities. Methoxycoelonin diminished the UVBinduced COX-2 expression as well.142 Antioxidant Activity. Du et al. studied the antioxidant activity of dihydrophenanthrenes isolated from Dioscorea zingiberensis. At the lowest concentration used (20 μM) only 5,6-dihydroxy-2,4-dimethoxy-9,10-dihydrophenanthrene exhibited DPPH radical-scavenging activity (scavenging % = 2.5), which was comparable to the positive control ascorbic acid (scavenging % = 2.9).27 The antioxidant capacity of 8,8′-bidehydrojuncusol (202) was measured by an ABTS radical cation decolorization assay, and it was observed that the biphenanthrene possessed free radical scavenging activity (85.2%). In case of the positive control ascorbic acid, the inhibition was proved to be 88.7%.28 7-Methoxy-9,10-dihydrophenanthrene-2,4,5-triol (50), isolated from Dendrobium draconis, proved to be as active (IC50 10.2 μM) as the positive control Trolox (IC50 11.7 μM) using the DPPH radical-scavenging assay.95 Loddigesiinol A (97), moscatin (IC50 59.8 μM), and lusianthridin (IC50 62.2 μM) showed activity (IC50 26.1 μM) compared to resveratrol (IC50 28.7 μM) and aminoguanidine (IC50 21.7 μM), using the DPPH-scavenging assay.12 Five phenanthrenes (fimbriatone, confusarin, flavanthrinine, 2,5-dihydroxy-4,9-dimethoxyphenanthrene, and 3,7-dihydroxy2,4-dimethoxyphenanthrene) isolated from Dendrobium nobile were tested by the DPPH assay in order to determine their antioxidant activity. Confusarin displayed comparable activity to ascorbic acid (IC50 18.0 μM), with an IC50 value of 12.9 μM. According to structure−activity relationship studies, methoxy and hydroxy groups present in an ortho position resulted in more pronounced antioxidant activity.143 Among the isolated compounds of Dendrobium chrysanthum, 2,5-dihydroxy-4,9-dimethoxyphenanthrene (IC50 6.8 μM) and moscatin (IC50 9.2 μM) showed antioxidant activity of similar potencies to vitamin C (IC50 8.3 μM) when using a DPPH radical-scavenging assay.144 Monbarbatains A−D (198, 199, 212, 213) (IC50 values of 15.1, 12.9, 9.4, and 4.8 μg/mL, respectively), 4,7,4′,7′-tetrahydroxy-2,2′-dimethoxy-1,1′-bis(9,10-dihydrophenanthrene) (IC50 7.7 μg/mL), and 4,7dihydroxy-1-(4-hydroxybenzyl)-2-methoxy-9,10-dihydrophenanthrene (IC50 12.2 μg/mL), from Monomeria barbata, demonstrated antioxidant activity in a DPPH radicalscavenging assay. The IC50 values of the positive controls BHA and rutin were determined as 9.3 and 5.2 μg/mL, respectively.88,113 2,5-Dihydroxy-4,9-dimethoxyphenanthrene and flavanthrinin, isolated from Odontoglossum harvengtense “Tutu”, showed NO scavenging activity (IC50 values of 19 and 2 μM).141 Several dihydrophenanthrenes (lusianthridin, cannabidihydrophenanthrene, coelonin, hircinol, erianthridin, 4,5-dihydroxy-2-methoxy-9,10-dihydrophenanthrene, eulophiol, and 2,4,7-trihydroxy-9,10-dihydrophenanthrene) from Pholidota chinensis showed antioxidant activity in the DPPH radicalscavenging assay, with IC50 values of 22.3, 24.7, 16.7, 28.9, 14.9, 21.4, 27.7, and 16.2 μM, respectively.145 Phenanthrene derivatives, as isolated from Pholidota yunnanensis, were also assayed for their antioxidant capacity using DPPH radical-scavenging assay. Among the isolated compounds, imbricatin was the most potent (EC50 8.8 μM). The EC50 values of phoyunnanin C (181) (26.7 μM), 4,7,4′,7′-tetrahydroxy-2,2′-dimethoxy-9,10,9′,10′-tetrahydro1,1′-biphenanthrene (15.6 μM), lusianthridin (22.3 μM), 674



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The dose-dependent cellular protective effect of dehydroeffusol was proven by the use of a reactive oxygen induced photohemolysis assay (τ50/control τ50 = 5.3 at 10 μM) on human neutrophils. The compound showed 11.3% penetration rate into the erythrocyte membrane, and it had a high antioxidant effect because of its strong ROS-scavenging activity (the OSC50 of dehydroeffusol and L-ascorbic acid was 1.7 and 0.41 μM, respectively).150 Dehydroeffusol inhibited KCl-, Bay-K8644-, pilocarpine-, and histamine-induced smooth muscle spasms, but at high doses (30−90 μM), it provoked contractions on the isolated rat jejunum. Therefore, it is suspected that dehydroeffusol may have antagonist activity on L-type Ca2+ channels, with agonistic properties at high concentrations.151 The smoothmuscle-relaxant activity of gymnopusin, fimbriol A, and erianthridin, isolated from Maxillaria densa, was studied on noradrenaline- and KCl-pretreated rat aorta rings. The results indicated that gymnopusin might effectively block L-type voltage-gated Ca2+ channels, whereas it enhanced the opening of K+ channels, but did not affect the cGMP signaling pathway.152 Confusarin displayed neuroprotective activity on PC12 cells. The cells were treated with 10 μM phenanthrene, and after 72 h of incubation increased neurite outgrowth (7.1%) was observed. In the case of the positive control NGF, this value was 11.9% at a 50 ng/mL concentration.153 The bone-healing folk medicinal use of Pholidota articulata was supported by pharmacological studies. Oxoflavidine showed significant osteogenic activity on mice calvarial osteoblasts by the use of an osteoblast ALP assay at concentrations of 1 pM, 100 pM, and 1 nM. Cell mineralization was the most pronounced after using 100 pM oxoflavidin. According to real-time quantitative PCR measurements, 100 pM oxoflavidin enhanced the transcription of osteogenic proteins (e.g., BMP-2, OCN) after 24 and 48 h.154 Synthesis of Denbinobin. Owing to the promising pharmacological activities of denbinobin, several total synthesis research groups have initiated efforts to prepare this compound. The first synthesis of denbinobin was reported by Krohn et al. in 2001. They applied two methods to afford a series of 1,4-phenanthrenequinones. The direct method was a Diels−Alder reaction of styrenes and benzoquinones that led to the substituted phenanthrenequinones or the corresponding dihydro compounds. In the second method, oxygenated phenanthrenes were oxidized to the corresponding quinones.155 Later, the Kraus group synthesized denbinobin in seven steps from a quinone, substituted with methoxy groups with the correct regiochemistry.156 Soon after, Wang et al. used 3,5-dimethoxybenzyl bromide and 2-bromoisovanillin as starting materials, and in this seven-step synthetic route, the key reactions were intramolecular free radical cyclization of a stilbene intermediate and Fremy’s salt-mediated oxidation.157 In 2011, Thangaraj et al. described the total synthesis of four natural compounds, among them denbinobin from commercially available trimethoxybenzaldehyde.158 Lee’s group modified the procedure of the Kraus group, as they prepared 3,2-aldehyde-1,4-quinone by DDQ oxidation of 2,5-dihydroxybenzaldehyde, and 23 compounds were synthesized.159 Very recently, Lee and co-workers published the total synthesis of denbinobin with an 10% overall yield. A FeCl3-assisted cyclization of stilbene was used to form a phenanthrene.160

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CONCLUSIONS

Phenanthrenes are considered to form a relatively small group of natural products. Since the 1970s, more than 450 compounds of this type have been isolated from different sources. The discovery of new phenanthrene derivatives with the evaluation of their prospective biological activities has become of great interest to many research groups worldwide. During the last nine years, more than 210 novel phenanthrenes were identified. The family Orchidaceae is still the most abundant source of these compounds. However, several new families and genera have been recorded as biosynthesizing phenanthrenes. In most cases, related phenanthrene derivatives have been obtained from the same species. The limited occurrence of phenanthrenes attests to their importance as chemotaxonomic markers. It is suspected that the occurrence of the enzymes required for the biosynthesis of these compounds is plant-specific. The presence of certain phenanthrene substituents may be restricted to specific families. For example, vinyl-substituted phenanthrenes have been reported only from Juncaceae species, and prenylated derivatives occur mainly in Euphorbiaceae species. Phenanthrenes connected to a stilbene or dihydrostilbene moiety have been described exclusively from Orchidaceae species, mainly from the genus Pholidota. Methoxybenzyl-substituted phenanthrenes were isolated only from Cremastra species. The occurrence of glycosylated compounds seems to be characteristic to the family Orchidaceae. Interestingly, phenanthrenequinones have been described from many different families, but it seems that these compounds originate from phenanthrenes. During the last nine years, 36 newly identified dimers were reported from Orchidaceae species, eight from the family Juncaceae, and one from Dioscoreaceae. To date, only two trimeric phenanthrenes are known, and these were reported from Orchidaceae species. Phenanthrenes have been found to occur in very different vegetative plant parts, although organ-specific screening studies have not been carried out yet. It would be worth investigating whether there are any plant organs that are predominantly responsible for phenanthrene synthesis. It can be assumed that the close coexistence of different species led to the accumulation of dimers from plants in the Orchidaceae, containing a monophenanthrene moiety that has been isolated previously from liverwort species, but not from higher plants. It is worth noting that almost all of the newly isolated phenanthrenes have been studied for their potential biological activities, and several have shown multiple activities. During the past 10 years, numerous previously identified phenanthrene derivatives also were screened for their biological effects. Detailed mechanism of action studies have been carried out on several promising compounds. According to the accumulated data, denbinobin has potential as a lead anticancer compound, with a novel mechanism of action. However, for many compounds, despite promising in vitro results, their in vivo activities are seldom determined. In some cases, considerable amounts of phenanthrenes were isolated from natural sources (e.g., juncuenin B and juncusol from Juncus inflexus and effusol from J. ef f usus), but synthetic approaches to phenanthrenes are also well studied. Although the isolated compounds do not possess very great chemical diversity, the relative simplicity of their semisynthetic modifications could contribute to their ultimate pharmacological use in drug therapy. 675



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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00619.

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Sturctures of novel phenanthrenes, their plant sources, and their pharmacological activities (PDF)

AUTHOR INFORMATION

Corresponding Author

*Tel: +36-62-546451. Fax: +36-62-545704. E-mail: vasasa@ pharmacognosy.hu. ORCID

Andrea Vasas: 0000-0002-1818-7702 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from GINOP-2.3.2-15-2016-00012 is gratefully acknowledged. A.V. acknowledges the award of a János Bolyai scholarship of the Hungarian Academy of Sciences.

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DEDICATION Dedicated to Dr. Susan Band Horwitz, of Albert Einstein College of Medicine, Bronx, NY, for her pioneering work on bioactive natural products.

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