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Phytochemistry Reviews

, Volume 17, Issue 4, pp 833–851 | Cite as

Family Juncaceae: promising source of biologically active natural phenanthrenes

  • Csaba Bús
  • Barbara Tóth
  • Dóra Stefkó
  • Judit Hohmann
  • Andrea Vasas
Article

Abstract

Phenanthrenes represent a relatively small group of aromatic secondary metabolites, which can be divided into three main subgroups (mono-, di-, and triphenanthrenes). Phenanthrenes are reported as an intensively researched field in phytochemistry according to their structural diversity and promising biological activities. Because of their limited occurrence phenanthrenes are considered to be as important taxonomic markers. Juncaceae is a relatively large plant family divided into seven genera of which Juncus and Luzula are the most important ones from phytochemical and pharmacological points of view. To date, almost one hundred natural phenanthrenes have been isolated but only from eight (Juncus acutus, J. effusus, J. inflexus, J. maritimus, J. roemerianus, J. setchuensis, J. subulatus, and Luzula luzuloides) Juncaceae species, including mono-, and diphenanthrenes, and phenanthrene glucosides. Great deal of the isolated compounds are substituted with a vinyl group. This substitution is characteristic exclusively to Juncaceae species. Juncusol (2) was isolated from every investigated species. The richest source of phenanthrenes, as well as the most extensively investigated species is J. effusus. Several isolated compounds possessed different biological activities, e.g. antiproliferative, antimicrobial, anti-inflammatory, antioxidant, spasmolytic, anxiolytic, and antialgal effects. Among them, dehydroeffusol (60) is the most promising one, as it showed antimicrobial, anxiolytic, sedative, spasmolytic, cellular protective and antiproliferative activities. The aim of this review is to summarize the occurrence of phenanthrenes in the family Juncaceae, and give a comprehensive overview of their isolation, structural characteristics and biological activities.

Keywords

Phenanthrenes Juncaceae Juncus Luzula Biological activities 

Introduction

Juncaceae is a relatively large family with approximately 500 plant species worldwide; it holds a rather unique position among angiosperms. Juncaceae consists of seven genera (Distichia, Juncus, Luzula, Marsippospermum, Oxychloe, Patosia, Rostkovia) of which Juncus L. is by far the most important (Tackholm 1974). The monocotyledonous Juncaceae plants are usually perennial herbs, but some representatives are annual. From the creeping rhizomes of the plants, short lived leafy shoots (culms) grow that end in an inflorescence, but the rhizome is sometimes reduced or lost. Juncus species are widespread and present in several parts of both hemispheres, either in coastal marsh lands or inland. Species of this genus usually grow in the salty marshes or badly-drained soils under different climatic conditions. Juncus species comprises marsh herbs usually with sympodial rhizomes developing leafy shoots (culms) which are typically slender, unbranched and nodeless. The long, narrow leaves have sheathing base, but in certain cases, the leaves are reduced to scale-like structures on the rhizome (Fig. 1) (Snogerup 1978; Tutin et al. 1980; Flora of China 2000; Simon 1992).
Fig. 1

Juncaceae species (J. atratus and L. sylvatica)

The genus Luzula has a cosmopolitan distribution with species occurring throughout the world, especially in temperate regions, and higher elevation areas in the tropics. Plants of the genus are known commonly as wood rush. These rushes are usually perennials with rhizomes and sometimes stolons. Luzula species can be recognised by the existence of closed-leaf sheaths and multicellular hairs on the leaves. The inflorescence is often a dense cluster of flowers with two leaf-like bracts at the base, or sometimes a solitary flower or a few flowers borne together. The number of ovules and type of placentation is also characteristic to Luzula species, because they have three basal ovules, whereas all of the other genera have numerous axile or parietal ovules. Luzula species have six brownish tepals (Fig. 1) (Tutin et al. 1980; Simon 1992).

Various Juncus species are used in the traditional Chinese medicine for the treatment of numerous disorders. Medulla Junci (“Deng Xin Cao”), the dried stem pith of J. effusus L., is official in the Pharmacopoeia of the People’s Republic of China (2005). The stem is collected from late summer to autumn and dried under the sun. After removing the outer part of the stem, the pith so obtained is then straightened out or ligated into a small bundle to obtain Medulla Junci. It is recommended for the treatment of fidgetiness and insomnia with oliguria and painful difficult urination or with ulceration in the mouth or on the tongue. The whole herb of J. effusus and its medulla (Medulla Junci TCM) are also used for treatment of diseases including pharyngitis, aphtha, and traumatic bleeding (Ma et al. 2016). This drug was recorded to be used in traditional medicine as an antipyretic, antiphlogistic and as a sedative agent in Japan and China (Miles et al. 1977; Shima et al.1991; Hanawa et al. 2002). The seeds of J. rigidus are consumed in Egypt in order to treat diarrhoea and diuretic disorders (Mahmoud and Gairola 2013). In Basque regions, the stems of J. conglomeratus, J. effusus and J. inflexus were used in rituals against warts and other skin diseases (Menendez-Baceta et al. 2014, 2015). The aerial parts of J. balticus and J. effusus and the roots of J. ensifolius were consumed as healthy foods by indigenous people in Canada (Kuhnlein and Turner 1991). The traditional usage of plants belonging to other genera of the family has not been reported yet.

Several Juncaceae species have economic significance. Juncus plants (e.g. J. acutus, J. arabicus, J. rigidus) have been used to make mats, mattresses, sandals and baskets throughout Africa since 895 B.C (Sen and Rajpurohit 1982; Lu et al. 2014; Kubitzki 1998). J. kraussii is a valuable source of fibre among Zulus; bridal sleeping mats and baskets are weaved from the culms of the plant (Traynor 2008). Great deals of Juncus species are native to South-America; therefore, these plants (e.g. J. arcticus var. andicola, J. effusus, J. ramboi subsp. colombianus) are commonly used in that region in order to prepare traditional craftworks (Macía 2001). Some species, such as J. acutus, J. rigidus, and few Luzula species were used in the paper industry (Sharma 2009).

Juncaceae species accumulate different secondary metabolites, e.g. phenanthrenes (Kovács et al. 2008), flavonoids (Mansour et al. 1986), triterpenes (DellaGreca et al. 1994), steroids (Dong-Zhe et al. 1996), phenolic acid derivatives (Shan et al. 2008), coumarins and coumarinic acid esters (Awaad 2006; Dong-Zhe et al. 1996; Shima et al. 1991). According to the literature data, the major bioactive components of Juncaceae species are phenanthrenes. Phenanthrenes form a small group of aromatic secondary metabolites, which are proved to be derived from stilbene precursors (Chong et al. 2009). Phenanthrenes are divided into three major groups: mono-, di-, and triphenanthrenes. Monophenanthrenes can be classified, according to the saturation of the bond between C-9 and C-10 atoms, to phenanthrenes and dihydrophenanthrenes. Based on the type and number of the connecting substituents these compounds can be further categorized. Di- and triphenanthrenes are subdivided according to the type of connection of the phenanthrene units (Fig. 2).
Fig. 2

Common structures of monophenanthrenes

Phenanthrenes have drawn considerable interest from the aspect of natural product drug discovery because of the wide range of their potentially valuable biological activities (e.g. antiproliferative, antibacterial, anti-inflammatory, antioxidant, anxiolytic, cell-protective, sedative, spasmolytic, and antialgal effects) and their structural diversity.

Phenanthrenes of Juncaceae species

To date, almost one hundred novel phenanthrenes have been isolated from the family, but only from seven Juncus and one Luzula species (J. acutus, J. effusus, J. maritimus, J. roemerianus, J. setchuensis, J. subulatus, J. inflexus and L. luzuloides). Almost 20% of the currently known (approx. n = 450) natural phenanthrenes were described from Juncaceae species.

The richest source of phenanthrenes is J. effusus, to date 58 compounds have been isolated from this plant. These compounds were identified from different plant parts (medulla, root and whole plant), among them dihydrophenanthrenes (14, 6, 8, 9, 1115, 18, 2123, 25, 2734, 3638, 4042, 4851, 56), phenanthrenes (57, 60, 62, 63, 65, 6771), phenanthrene glycosides (4347) and diphenanthrenes (8184, 8789). A high number of compounds (n = 41) were isolated from J. acutus too. The most common phenanthrenes in Juncaceae species are juncunol (1), juncusol (2), effusol (4), juncuenin B (23) and dehydrojuncusol (57). Juncusol (2) has been isolated from all mentioned species. Most of the described compounds are dihydrophenanthrenes, majority of them are substituted with vinyl group.

The majority of phenanthrenes were isolated exclusively from Juncus species, but recently four compounds (2, 23, 65 and 66) were identified from L. luzuloides (Tóth et al. 2017). The isolation of vinylated phenanthrenes from L. luzuloides confirmed that besides flavonoids, phenanthrenes are also characteristic constituents of this plant. The secondary metabolite profile of L. luzuloides showed great similarity to that of species belong to genus Juncus. Therefore, Luzula species can also be promising sources of phenanthrenes.

The structures of the isolated Juncaceae phenanthrenes with the corresponding plants are listed in Tables 1, 2, 3, 4, 5.
Table 1

Vinyl-substituted dihydrophenanthrenes

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R1

R2

R3

R4

R5

R6

Trivial name

Species

Reference

1

Me

OH

H

H

Me

H

Juncunol

J. acutus

J. effusus

J. roemerianus

J. subulatus

DellaGreca et al. (1992, 2001, 2002a, 2004), Behery et al. (2013), Sarkar et al. (1988), Abdel-Razik et al. (2009)

2

Me

OH

H

Me

OH

H

Juncusol

J. acutus

J. effusus

J. inflexus

J. roemerianus

J. setchuensis

J. subulatus

L. luzuloides

DellaGreca et al. (1992, 2001, 2002a, b, 2004), Behery et al. (2007), Mody et al. (1982), Wang et al. (2010, 2012, 2014), Ishiuchi et al. (2015), Ma et al. (2016), Tóth et al. (2016a, 2017), Miles et al. (1977), Chapatwala et al. (1981), Sarkar et al. (1988), Li et al. (2015), Abdel-Razik et al. (2009)

3

Me

OH

H

OH

Me

H

 

J. acutus

J. effusus

DellaGreca et al. (1992, 2001, 2004)

4

Me

OH

H

H

OH

H

Effusol

J. acutus

J. effusus

J. maritimus

J. setchuensis

J. subulatus

DellaGreca et al. (1992, 2001, 2004), Mody et al. (1982), Wang et al. (2010, 2012, 2014), Ishiuchi et al. (2015), Ma et al. (2016), Sahli et al. (2017), Li et al. (2015), Abdel-Razik et al. (2009)

5

Me

OH

H

Me

H

H

 

J. acutus

DellaGreca et al. (2004)

6

Me

OH

H

Me

H

OH

 

J. acutus

J. effusus

DellaGreca et al. (1992, 2001, 2004)

7

Me

OH

H

CH2OH

OH

H

 

J. acutus

DellaGreca et al. (2004)

8

Me

OH

H

H

CH2OH

H

 

J. acutus

J. effusus

J. subulatus

DellaGreca et al. (1997, 2004), Abdel-Razik et al. (2009)

9

Me

OH

H

CH2OH

H

H

 

J. acutus

J. effusus

DellaGreca et al. (1997, 2004), Behery et al. (2007)

10

Me

OH

OH

Me

H

OH

 

J. acutus

DellaGreca et al. (2004)

11

Me

OH

OH

H

Me

H

 

J. effusus

DellaGreca et al. (1993)

12

Me

OH

H

H

OH

Me

 

J. acutus

J. effusus

DellaGreca et al. (1992, 2002a, 2004), Ma et al. (2016)

13

Me

OH

H

H

OMe

Me

 

J. acutus

J. effusus

DellaGreca et al. (1992, 2002a, 2004)

14

Me

OMe

H

H

CONH2

H

Juncuenin E

J. effusus

Su et al. (2013)

15

Me

OH

H

H

H

CH2OH

 

J. effusus

J. setchuensis

Ma et al. (2016)

Li et al. (2015)

16

CH2OH

OMe

H

Me

OH

H

Jinflexin B

J. inflexus

Tóth et al. (2016aa)

17

Me

OMe

H

H

OH

H

 

J. acutus

J. subulatus

DellaGreca et al. (2004), Abdel-Razik et al. (2009)

18

Me

OMe

H

Me

H

OH

 

J. acutus

J. effusus

DellaGreca et al. (1992, 2002a, 2004)

19

Me

OMe

H

H

Me

H

 

J. acutus

DellaGreca et al. (2004)

20

Me

OH

H

COOH

H

H

 

J. acutus

DellaGreca et al. (2004)

21

Me

OH

H

H

COOH

H

 

J. acutus

J. effusus

DellaGreca et al. (1992, 2004), Wang et al. (2012)

22

Me

OH

H

H

H

COOH

 

J. acutus

J. effusus

DellaGreca et al. (1993, 2004), Wang et al. (2012)

Open image in new window

 

R1

R2

R3

R4

Trivial name

Species

Reference

23

OH

H

OH

Me

Juncuenin B

J. effusus

J. inflexus

J. setchuensis

L. luzuloides

Ishiuchi et al. (2015), Tóth et al. (2016a, 2017), Wang et al. (2009, 2010)

24

OH

H

OH

COOH

Juncuenin C

J. setchuensis

Wang et al. (2009)

25

Open image in new window

Juncuenin D

J. effusus

J. inflexus

J. setchuensis

Ishiuchi et al. (2015), Tóth et al. (2016a), Wang et al. (2009, 2010)

26

Open image in new window

Juncuenin A

J. inflexus

J.setchuensis

Tóth et al. (2016a), Wang et al. (2009)

Table 2

Dihydrophenanthrenes without vinyl group

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R1

R2

R3

R4

R5

Name

Species

Reference

27

OH

Ac

OH

Me

H

Juncunone

J. effusus

J. roemerianus

DellaGreca et al. (2001), Miles and Randle (1981)

28

OH

H

OH

Me

H

Micrandol B

J. effusus

DellaGreca et al. (1993)

29

OH

CH(CH3)OH

OH

Me

H

 

J. acutus

J. effusus

DellaGreca et al. (1993, 2002a, 2004)

30

OH

CH(CH3)OMe

OH

Me

H

 

J. acutus

J. effusus

DellaGreca et al. (1993, 2004)

31

OH

CH(CH3)OH

H

Me

OH

 

J. acutus

J. effusus

DellaGreca et al. (1993, 2001, 2002a, 2004)

32

OH

CH(CH3)OH

H

OH

Me

 

J. effusus

DellaGreca et al. (1997)

33

OH

CH2OH

H

OH

H

 

J. acutus

J. effusus

DellaGreca et al. (2004), Ma et al. (2016)

34

OH

CH2OH

H

OH

Me

 

J. acutus

J. effusus

DellaGreca et al. (1997, 2004)

35

OH

CH(CH3)OEt

H

OMe

Me

 

J. acutus

DellaGreca et al. (2002a, 2004)

36

OH

Ac

OH

Me

H

 

J. effusus

DellaGreca et al. (1993)

37

OH

CHO

H

OMe

Me

 

J. effusus

DellaGreca et al. (1993)

38

OH

CHO

OH

Me

H

 

J. effusus

DellaGreca et al. (1993)

39

OH

CH2OH

H

OH

OH

 

J. roemerianus

Sarkar et al. (1988)

40

OH

CH2OH

H

OMe

Me

 

J. effusus

DellaGreca et al. (1997)

41

OH

CH2OH

H

Me

H

 

J. effusus

DellaGreca et al. (1997)

42

OH

CH2OH

H

OH

Me

 

J. effusus

DellaGreca et al. (1997)

43

OH

CH2–O–Glc

H

OMe

Me

Effuside I

J. effusus

DellaGreca et al. (1995)

44

OH

CH2–O–Glc

H

OH

Me

Effuside II

J. effusus

DellaGreca et al. (1995)

45

OH

CH2OH

H

O–Glc

Me

Effuside III

J. effusus

DellaGreca et al. (1995)

46

GlcO

CH2OH

H

OH

Me

Effuside IV

J. effusus

DellaGreca et al. (1995)

47

GlcO

CH2–O–Glc

H

OMe

Me

Effuside V

J. effusus

DellaGreca et al. (1995)

48

OH

CHO

H

OH

Me

Juncuenin F

J. effusus

Su et al. (2013), Ma et al. (2016)

49

OH

CH(CH3)OEt

H

OH

H

Juncuenin G

J. effusus

Su et al. (2013), Ma et al. (2016)

 

R1

R2

R3

R4

R5

Name

Species

Reference

50

OH

CH(CH3)OMe

H

OH

H

Effususol A

J. effusus

Ishiuchi et al. (2015), Ma et al. (2016)

51

OH

CHO

H

OH

H

 

J. effusus

Su et al. (2013), Wang et al. (2012), Ma et al. (2016)

52

OH

CH(CH3)OMe

H

OH

Me

Jinflexin A

J. inflexus

Tóth et al. (2016a)

53

Open image in new window

Juncutol

J. acutus

Behery et al. (2007)

54

Open image in new window

Jinflexin C

J. inflexus

Tóth et al. (2016a)

55

Open image in new window

 

J. acutus

DellaGreca et al. (2002a, 2004)

56

Open image in new window

 

J. effusus

DellaGreca et al. (1997)

Table 3

Vinyl-substituted monophenanthr**enes

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R1

R2

R3

R4

Name

Species

Reference

57

OH

Me

OH

H

Dehydrojuncusol

J. acutus

J. effusus

J. inflexus

J. roemerianus

DellaGreca et al. (2002a, 2004), Behery et al. (2007), Ishiuchi et al. (2015) Shima et al. (1991), Wang et al. (2012), Ma et al. (2016), Tóth et al. (2016a), Sarkar et al. (1988)

58

OH

Me

H

H

 

J. acutus

DellaGreca et al. (2002a, 2004)

59

OMe

Me

OMe

H

 

J. acutus

DellaGreca et al. (2002a, 2004)

60

OH

H

OH

H

Dehydroeffusol

J. acutus

J. effusus

J. setchuensis

DellaGreca et al. (2002a), Shima et al. (1991), Ishiuchi et al. (2015), Wang et al. (2012, 2014), Ma et al. (2016), Li et al. (2015)

61

OH

CH2OH

H

H

 

J. acutus

DellaGreca et al. (2004)

62

OH

H

COOH

H

 

J. effusus

Wang et al. (2012)

63

OMe

H

OH

H

 

J. effusus

Wang et al. (2014)

64

Open image in new window

Dehydrojuncuenin A

J. inflexus

J. setchuensis

Tóth et al. (2016a), Wang et al. (2009)

65

Open image in new window

Dehydrojuncuenin B

J. effusus

J. inflexus

J. setchuensis

L. luzuloides

Ishiuchi et al. (2015), Tóth et al. (2016a, 2017), Wang et al. (2009, 2010)

66

Open image in new window

Luzulin A

L. luzuloides

Tóth et al. (2017)

Table 4

Monophenanthrenes without vinyl group

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R

Name

Species

Reference

67

CHO

Dehydroeffusal

J. acutus

J. effusus

DellaGreca et al. (2002a), Shima et al. (1991), Wang et al. (2014), Ma et al. (2016)

68

CH2OH

 

J. effusus

Ma et al. (2016), Yang et al. (2007)

69

CH(CH3)OEt

Dehydrojuncuenin D

J. effusus

Su et al. (2013), Ma et al. (2016)

70

CH(OH)CH3

Dehydrojuncuenin E

J. effusus

Su et al. (2013), Ma et al. (2016)

71

CH(CH3)OMe

 

J. effusus

Ma et al. (2016)

72

Open image in new window

Dehydrojuncuenin C

J. setchuensis

Wang et al. (2009)

The most common substituents of monophenanthrenes are methyl, methoxy and hydroxy groups. Almost all of the monophenanthrenes are substituted with a methyl group at C-1, with the exception of jinflexin B (16); this compound contains an oxymethylene group at this position (Tóth et al. 2016a). Methyl-substitution is also common at C-6, C-7 and C-8. Methoxy and hydroxy groups are located mainly at C-2 and C-7. It can be observed that only a few compounds are substituted at C-3, but exclusively with a hydroxy group (9, 10). The structural particularity of Juncaceae phenanthrenes is the vinyl-substitution which is characteristic only for phenanthrenes of this family, and it was described to be connected exclusively on ring C, at positions C-5, C-6 or C-8. The position of the methoxyethyl, ethoxyethyl, hydroxyethyl, oxymethylene and aldehyde groups suggests that biogenetically these components are originated from a vinylated compound.

From Juncaceae family, compounds containing only one kind of substituent, and C-9 and C-10 substituted phenanthrenes are not known. Five compounds (2022, 24, 62) are substituted with carboxyl group. Besides carboxyl group, these compounds are substituted only with methyl and hydroxy groups. All of the formyl group-containing phenanthrenes (37, 38, 48, 51, 67) were isolated from J. effusus. Only one compound, juncuenin E (14) is substituted with an amide group.

In case of J. acutus, J. effusus and J. inflexus, several of the isolated phenanthrenes can be paired, based on the saturation of the C-9–C-10 bond, as the substitution patterns of the pairs [e.g. dehydrojuncuenin A (64) and juncuenin A (25); dehydrojuncuenin B (65) and juncuenin B (23); dehydrojuncusol (57) and juncusol (2)] are the same, the first member of the pairs are phenanthrenes, and the second ones are their 9,10-dihydro analogues.

In some cases, the absolute configuration of phenanthrenes (25, 52, 54, 66, 85), containing an asymmetric carbon atom were determined by NOE correlations, chiral HPLC analysis and calculations based on their ECD spectra. Jinflexin A (52) was determined to be a racemic mixture. The absolute configuration of jinflexin C (54), juncuenin D (25) and luzulin A (66) was described to be (S), the chiral HPLC analysis showed 80, 4, and 25% enantiomeric excess respectively, derived from the S-enantiomers. Jinflexin D (85) is the only chiral dimeric compound, 9% enantiomeric excess was described, derived from the (R) enantiomer (Tóth et al. 2016a, 2017).

Some phenanthrenes have unique structure, e.g. compound 55 has a hydrocarbon chain connected through an oxygen atom. Phenanthrenes 53 and 56 are substituted with a saturated five-membered ring, in the case of 56 it is a heterocyclic ring substituted with hydroxy groups. Luzulin A (66) and dehydrojuncuenin C (72) are substituted with carbonyl groups. In case of dehydrojuncuenin C (72), the carbonyl group comprises a six-membered lactone ring. Jinflexin C (54) is also a carbonyl (C-1) substituted, partly saturated phenanthrene, not only its core is unusual, but also the presence of a methyl and a vinyl group at the same carbon (C-7) is unique (Tóth et al. 2016a).

Phenanthrene glycosides are rare in the family Juncaceae. From J. effusus five glycosides have been isolated (effusides I–V, 4347) (DellaGreca et al. 1995).

Phenanthrenoid dimers have been reported rarely from Juncaceae species so far. The dimerization pattern between two monomers could be classified into two types. One features a cage-like carbon framework with complicated stereochemistry, and the other is characteristic by a single C–C’ linkage between two monomers, such as the reported 3–3′, 7–7′, 8–3′, 8–8′, and 8–11′ linkages. In case of dijuncuenins A (84) and B (88), linkages occur between a C2 substituent and 3′ or 8′, respectively. The isolated diphenanthrenes are substituted with vinyl, methyl, carbonyl and hydroxy groups. Diphenanthrenes 7480, isolated from J. acutus, have unusual hepta-and octacyclic structures (DellaGreca et al. 2002b, 2003, 2005). Jinflexin D (85) is a dimer with an unprecedented heptacyclic ring system, which may be considered to derive by the coupling of dehydrojuncuenin A (64), with 2,7-dihydroxy-1,8-dimethyl-5-vinyl-9,10-dihydrophenanthrene (12) through their vinyl groups, forming a unique structure (Tóth et al. 2016a). There are a variety of possible linkage patterns between two monomers, therefore, additional novel dimeric phenanthrenoids are to be expected.

The oxidative transformation of juncuenin B (23) afforded its possible biometabolites, juncuenin D (25), dehydrojuncuenin B (65) and luzulin A (66). These findings confirmed that the phenanthrenequinones, luzulin A (66) and juncuenin D (25), and the phenanthrene, dehydrojuncuenin B (65) can be formed by oxidation of juncuenin B (23), and most probably similar process may happen during their biosynthesis (Tóth et al. 2017).

Isolation of phenanthrenes from Juncaceae species

Phenanthrenes have a great structural diversity; this implies that separation methods are also changing in wide range. There are many examples for both normal and reverse phase column- and high performance liquid chromatographic processes. The polarity of the applied solvent systems is quite variable: some separation steps needed polar solvents including MeOH or EtOAc in high amounts (Behery et al. 2007), while in other cases application of non-polar solvents (e.g. petroleum ether) was sufficient (Wang et al. 2012).

The first step of the isolation is the extraction of the plant materials. The most frequently used solvents are MeOH and EtOH (Yang et al. 2007), in some cases EtOAc (DellaGreca et al. 2003) or even less polar solvents (light petrol) (DellaGreca et al. 2002a) were used. The extracts are usually partitioned with solvents with increasing polarity, the most frequently used ones are CHCl3, EtOAc (Su et al. 2013), and n-BuOH (Abdel-Razik et al. 2009). In most of the cases, the next step is a column chromatographic separation using normal- or reversed-phase silica gel, the elution is performed in gradient conditions. Polyamide (Tóth et al. 2016a), Sephadex LH-20 gel (Su et al. 2013) and MCI resin (Xiao et al. 2016) are also used as stationary phases. The separation of the crude extracts is easy to follow by using TLC. Phenanthrenes can be detected in the layer, under UV-light at 366 nm. After spraying the TLC plate with vanillin-sulfuric acid reagent and heating it, phenanthrenes have unique color patterns (blue, yellow, or in current cases brown or orange). Besides the above mentioned column chromatography techniques, medium pressure liquid chromatography (MPLC) (DellaGreca et al. 2004) was also applied for crude separations.

In order to retrieve pure compounds, preparative thin-layer chromatography (PTLC) and high-performance liquid chromatography (HPLC) are also commonly applied. In case of HPLC purifications, reversed-phase columns are used more often than normal phase ones. Certain compounds were separated by using a column modified by –NH2 groups (e.g. 1, 9 and 61, DellaGreca et al. 2004). For normal phase HPLC, the most frequently used eluents were n-hexane and EtOAc, mostly with isocratic conditions, e.g. dehydrojuncusol (57) was separated from a pyrene having a very similar structure by DellaGreca et al. (2002a). In case of reversed-phase separations, MeOH–H2O, and acetonitrile–H2O systems were found to be used frequently, e.g. juncusol (2), dehydrojuncusol (57) and dehydroeffusol (60) have been separated by using RP-HPLC with MeOH–H2O–TFA 55:45:0.1 solvent system as eluent (Ishiuchi et al. 2015).

Monophenanthrenes were separated in a relatively simple way; some compounds were isolated by using column chromatographic methods. Nevertheless, separation of several compounds by using PTLC is also presented (DellaGreca et al. 2004; Abdel-Razik et al. 2009).

All of the phenanthrene glycosides (4347) have been isolated from J. effusus. The plant was extracted with MeOH, and solvent–solvent partition was performed with EtOAc. The fractionation was carried out by using Sephadex LH-20 column and droplet countercurrent chromatography. After fractionation, HPLC separations led to the isolation of glycosides (DellaGreca et al. 1995).

Diphenanthrenes have been isolated from J. acutus, J. inflexus and J. effusus. The roots of J. inflexus was percolated with MeOH, the extract was partitioned with n-hexane, CH2Cl2 and EtOAc. The CH2Cl2 phase contained phenanthrenes. This extract was subjected to a polyamide column, eluting with MeOH–H2O gradient system, and then silica gel column chromatography and Sephadex LH-20 gel chromatography were applied to yield compound 85 (Tóth et al. 2016a).

In case of J. effusus the roots, the medulla and the whole plant were also processed. The medulla was extracted with EtOH, and thereafter it was separated by using a silica gel column. Effususins A–D (8183, 87) were isolated from subfractions after further purification by column chromatography on silica gel, gel-filtration and PTLC (Ma et al. 2015). In case of the whole plant, the EtOH extract was partitioned with petroleum ether and CH2Cl2. The CH2Cl2 fraction was separated by using MCI resin and silica gel column chromatography, eluted with EtOH–H2O and petroleum ether–acetone gradient systems, respectively. The corresponding subfraction provided dijuncuenins A (84) and B (88) after purifying by gel filtration (EtOH) and RP-HPLC (acetonitrile–H2O gradient) (Xiao et al. 2016).

Numerous diphenanthrenes have been described from J. acutus. The rhizomes of the plant were extracted with EtOAc, and the extract was subjected to MPLC, using n-hexane–EtOAc (9:1) under isocratic conditions. The corresponding subfraction was rechromatographed by MPLC, and the yielded subfractions were separated by using normal- and reversed-phase HPLC to obtain five diphenanthrenes (7377) (DellaGreca et al. 2002b, 2003). Another dimer [8,8′-bidehydrojuncusol (86)], was described from the ethyl acetate fraction of the plant after column chromatographic separations (Behery et al. 2013).

Considering the described isolation methods for phenanthrenes, it is difficult to determine general conclusions; in certain cases, numerous compounds were separated by PTLC or column chromatography; while in other cases, compounds with very similar structures were described to be separated by using gel filtration.

Biological activities

Phenanthrenes possess a wide range of pharmacological activities, including antiproliferative, antimicrobial (antibacterial, antiviral, antifungal), antioxidant, anti-inflammatory, and anxiolytic effects.

Antiproliferative activity

In the past few years several phenanthrenes, isolated from the members of the genus Juncus, were tested for their in vitro cytotoxicity against various cancer cell lines in different test systems. The effect of effusol (4), dehydroeffusol (60), juncusol (2), dehydrojuncusol (57), juncuenin B (23), dehydrojuncuenin B (65), and juncuenin D (25) on cell survival in HT22 cells were investigated in a mouse hippocampal neuroblastoma cell line at 10, 30 and 100 μM for 24 h, by the MTT assay. Among them, effusol (4), juncusol (2), juncuenin B (23), dehydrojuncuenin B (65) and juncuenin D (25) resulted in a decrease of MTT reduction (9.9, 25.4, 13.6, 8.4 and 23.7%, respectively) at 100 μM, and caused a destruction of neuronal integrity (Ishiuchi et al. 2015). Juncuenins E–G (14, 48, 49), dehydrojuncuenin D (69) and compound 51 were tested on different human cancer (A549, MCF-7, BEL-7402, HeLa, COLO205, BGC-823, and SK-OV-3) cell lines. Among them only juncuenin E (14) and compound 51 exhibited cytotoxic activity (21.3 and 9.17 μM against MCF-7 cells, and 60.5 and 19.6 μM against HeLa cells, respectively) compared to adriamycin [0.406 µM (MCF-7) and 0.539 µM (HeLa)] (Su et al. 2013). Fifteen phenanthrene derivatives (2 and 12, 4, 15, 33, 4851, 57, 60, 6771), isolated from J. effusus were screened on five cancer cell lines (SHSY-5Y, SMMC-7721, HepG2, HeLa and MCF-7) in order to evaluate their cytotoxic activities. Several showed promising activities compared to paclitaxel. Compound 71 possessed selective inhibitory activity (IC50 10.9 µM) on MCF-7 cells. Dehydroeffusal (67) inhibited the growth of HepG2 and HeLa cells with similar IC50 values (12.4 and 13.1 µM, respectively). All of the investigated compounds, but compound 33, exerted some activity. These results indicated that the presence of a hydroxy group at C-7 is necessary for cytotoxic activity. In addition, vinyl substitution at C-5, and an unsaturated C-9–C-10 bond increased this type of activity (Ma et al. 2016).

The cell growth inhibitory properties of dimeric phenanthrenes (8183, 87) were investigated. Among them effususin B (83) possessed pronounced cytotoxic activity against SHSY-5Y (IC50 32.6 μM), HepG2 (IC50 12.9 μM), HeLa (IC50 25.1 μM), MCF-7 (IC50 12.5 μM) and SMMC-7721 (IC50 13.6 μM) cell lines compared to paclitaxel [> 100 μM (SHSY-5Y), 0.09 μM (SMMC-7721), 36.8 μM (HepG2), 25.9 μM (HeLa), 28.6 μM (MCF-7), and 0.09 μM (SMMC-7721)] as positive control in the CCK-8 assay. Effususin A (81) displayed moderate activity on all tested cell lines, whereas effususins C (87) and D (82) proved to be inactive (Ma et al. 2015).

Dehydroeffusol (60) showed activity against two metastatic cancer cell lines [SGC-7901 (human gastric carcinoma) and AGS (human caucasian gastric adenocarcinoma)] in a dose-dependent manner according to the Alamar blue assay. The compound dose-dependently (12–48 μM) inhibited the gastric cancer cell mediated vasculogenic mimicry on SGC-7901 cells by the use of tube formation assay. It decreased the VE-cadherin expression and exposure, and it suppressed the MMP2 protease expression and activity too. Dehydroeffusol (60) inhibited the gastric cancer cell adhesion, migration and invasion effectively without significant acute toxicity (Liu et al. 2015). Later, it was observed that this compound (60) inhibited effectively the gastric cell growth and the tumorigenicity through inducing tumor suppressive ER stress responses and concurrently diminishing tumor adaptive ER responses (Zhang et al. 2016).

In an investigation, juncusol (2) showed cytotoxicity on Hela cells. The cell-cycle of Hela cells were analyzed by using the flow cytometry and it was found that juncusol (2) treatment for 24 h increased the cell population in the G2/M and sub-G1 phases. Compound 2 shown to have pro-apoptotic property through the presence of active caspase-3, 8, and 9 in Hela cells, suggesting that juncusol (2) cause cell death by apoptosis induction. Moreover, the compound (2) inhibited the tubulin polymerization in vitro (Kuo et al. 2016).

The cytotoxic activity of 18 phenanthrenes (14, 6, 1113, 18, 21, 22, 2831, 3638) were evaluated through the brine shrimp (Artemia salina) lethality assay. All compounds were found to be toxic [LC50 25.3 (1), 4.6 (2), 3.0 (3), 5.6 (4), 4.0 (6), 16.5 (11), 3.0 (12), 11.2 (13), 3.0 (18), 14.1 (21), 15.7 (22), 6.5 (28), 8.0 (29), 16.1 (30), 5.0 (31), 84.9 (36), 81.5 (37), 83.0 (38) µg/mL], and the most active compounds were those with a hydroxyl function in the ring C and the vinyl group at C-5 (DellaGreca et al. 1993).

Antimicrobial activity

The antimicrobial effects of juncusol (2) have been tested on several bacterial and fungal strains. Bacillus species were inhibited at all concentrations, while Plannococcus species were inhibited only at the highest concentration. Pseudomonas species, Mycobacterium smegmatis, Enterobacter aerogenes and Escherichia coli were not inhibited at any of the concentrations used (Chapatwala et al. 1981).

Dehydroeffusol (60) and juncusol (2) were tested against methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA), Bacillus subtilis and Candida albicans in normal (dark) and UVA irradiated conditions [MIC values were 1.6 (UV) and 25.0 µg/mL (dark) (MSSA), 1.6 (UV) and 25.0 µg/mL (dark) (MRSA), 3.1 (UV) and 12.5 µg/mL (dark) (B. subtilis), and 1.6 (UV) and 25.0 µg/mL (dark) (C. albicans) in case of dehydroeffusol (60), and 12.5 (UV) and 25.0 µg/mL (dark) (MSSA), 25.0 (UV) and 25.0 µg/mL (dark) (MRSA), 12.5 (UV) and 12.5 µg/mL (dark) (B. subtilis), and 12.5 (UV) and 50.0 µg/mL (dark) (C. albicans) in case of juncusol (2)]. The antimicrobial effect was increased 16- (in case of 60) and two-fold (in case of 2), against MRSA, by irradiation with UVA. Gentamicin (MIC values were 0.6 µg/mL for each bacteria, in both condition), methicillin (MIC values 1.6 µg/mL for MSSA, 500.0 µg/mL for MRSA, and 31.25 µg/mL for B. subtilis, in both conditions) and nystatin [MIC values > 10.0 (UV) and 2.5 µg/mL (dark), in case of C. albicans] were used as positive controls. Photosensitized DNA-binding activities of these compounds were also determined by using restriction enzymes and a specially prepared 1.5 kb DNA fragment (Hanawa et al. 2002).

Four monophenanthrenes from J. inflexus [juncusol (2), dehyrojuncuenin B (65), juncuenin D (25), jinflexin B (16)] possessed antibacterial activity against MRSA with MIC values of 94 µM, 95 µM, 44 µM, and 338 µM, respectively. The occurrence of these compounds in the most active extracts prepared from other Juncus species (J. acutus, J. effusus, J. gerardii, J. maritimus, and J. tenuis) was tested by LC–MS measurements. Juncusol (2) was detected in all extracts, while the presence of jinflexin B (16) was confirmed in the extracts of J. acutus, J. effusus and J. gerardii (Tóth et al. 2016b).

Effusol (4) was proved to be active (MIC 19 µg/mL, IC50 9.98 µg/mL, respectively) against the wheat pathogen fungi Zymoseptoria tritici (Sahli et al. 2017).

Anti-inflammatory activity

The anti-inflammatory properties of juncutol (53) was evaluated by an assay involving the inhibition of iNOS protein expression in LPS-stimulated RAW 264.7 cells. Compound 53 at 10 μM showed pro-anti-inflammatory activity (protein expression 11.2%). Juncusol (2) and dehydrojuncusol (57) displayed moderate inhibitory activity, and 6-hydroxymethyl-1-methyl-5-vinyl-9,10-dihydrophenanthrene-2-ol (9) was the least active (Behery et al. 2007). Dehydrojuncusol (57) and its dimer (86) were also assayed by the same procedure. According to an immunoblot analysis, the inhibitory effect of dehydrojuncusol (57) (protein expression 59.0%) on iNOS protein expression decreased dramatically (protein expression > 88.0%) using this dimeric compound (Behery et al. 2013).

The potential anti-inflammatory activity of phenanthrenes, isolated from J. effusus, were determined by the inhibition of LPS-induced NO production using RAW 264.7 cells. Compound 15 (IC50 14.4 µM), effususol A (50), IC50 11.1 µM), effusol (4, IC50 15.1 µM), dehydroeffusol (60, IC50 12.7 µM), dehydroeffusal (67, IC50 10.5 µM), compounds 33 (IC50 16.0 µM), 68 (IC50 16.3 µM), dehydrojuncusol (57, IC50 15.6 µM), and compound 12 and juncusol (2) (IC50 15.6 µM) showed inhibitory activities compared to the positive control quercetin (IC50 6.6 µM). Effususol A (50) and juncuenin G (49) had marked activity, while juncuenin F (48), 2,7-dihydroxy-1-methyl-5-aldehyde-9, 10-dihydrophenanthrene (51) and dehydrojuncuenin E (70) did not possess anti-inflammatory activity in the abovementioned assay (Ma et al. 2016). In another investigation, effususin B (83) inhibited the LPS-induced NO production on RAW 264.7 cells (7.4 µM), while the other three investigated dimers [effususin A (81), effususin C (87) and effususin D (82)] were less active (Ma et al. 2015).

The anti-inflammatory effects of juncusol (2) (IC50 3.1 µM), juncuenin B (23) (IC50 4.9 µM), and dehydrojuncuenin B (65) (IC50 3.2 µM) from L. luzuloides was observed in a superoxide anion generation assay. Juncuenin B (23) also inhibited the elastase release on human neutrophils in response to fMLP/CB activation, with an IC50 of 5.5 µM, which was comparable to that of the positive control [LY294002 (4.8 µM)]. Juncuenin D (25) and luzulin A (66) were inactive in both assays (Tóth et al. 2017).

Antioxidant activity

The antioxidant capacity of 8,8′-bidehydrojuncusol (86) were measured by an ABTS radical cation decolorization assay, and it was observed that the diphenanthrene possessed free radical scavenging activity (85.2%). This effect was comparable to that of the positive control ascorbic acid (88.7%) (Behery et al. 2013).

The dose-dependent cellular protective effect of dehydroeffusol (60) was proven by the use of reactive oxygen induced photohemolysis assay (τ50/control τ50 = 5.3 at 10 μM) on human neutrophils. The compound (60) showed 11.3% penetration rate into the erythrocyte membrane (it can affect the antioxidant activity), and it had a high antioxidant effect because of its strong ROS scavenging activity [the OSC50 of dehydroeffusol (60) and l-ascorbic acid was 1.7, and 0.41 μM, respectively] (Park et al. 2014).

Anxiolytic and sedative activities

Dehydroeffusol (60) reduced anxiety in animal studies [elevated plus-maze test: time mice stayed on open arms (OT) = 56.54 s, entries into open arms (OE) = > 6; and hole-board test (head dips > 80)] at 5 mg/kg, without change in motor function (Liao et al. 2011). Wang et al. proved the anxiolytic properties of effusol (4) and juncusol (2) on mice, at 2.5, 5 and 10 mg/kg, by using the same test (OT = 58.8 s, OE = 6.6 for effusol (4), and OT = 75.5 s, OE = 7.8 for juncusol (2), respectively). Their sedative activity was also confirmed by the decreased locomotion (516.1 for juncusol (2), 498.1 for effusol (4) and 365.6 for diazepam) in the open field test (Wang et al. 2012). In all cases, diazepam was used as positive control (OT = 111.9 s, OE = 13.6). A mechanism of action study revealed that effusol (4) and dehydroeffusol (60) 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 (4) and dehydroeffusol (60) were not attached to the benzodiazepine binding site of GABAA receptor (Singhuber et al. 2012). Later, the anxiolytic effect of compounds 63 and 89 (juncusin) was also confirmed (OT = 102.8 s, OE = 8.4 for 63, and OT = 83.6 s and OE = 8.0 for 89, respectively) (Wang et al. 2014).

Spasmolytic activity

Dehydroeffusol (60) inhibited KCl-, Bay-K8644-, pilocarpine- and histamine-induced smooth muscle spasms. However, at high doses (30–90 μM), it provoked contractions on the isolated rat jejunum. Therefore, it is suspected that dehydroeffusol (60) may have antagonist activity on L-type Ca2+ channels, with agonistic properties at high concentrations (Di et al. 2014).

Anticholinesterase activity

The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of juncunol (1) were investigated in vitro, and it was observed that this compound had a higher activity against BuChE (IC50 758 μM) than AChE (IC50 940 μM). Galanthamine was used as positive control [IC50 27.2 μM (AChE) and 1110 μM (BuChE)]. In the cell based-systems, juncunol (1) was able to inhibit the activity of AChE with IC50 values of 158 μM (SH-SY5Y) and 117 μM (N9) (Rodrigues et al. 2017).

Antialgal activity

The antialgal activities of 30 monomeric (14, 6, 1113, 18, 21, 22, 2731, 35, 37, 38, 4347, 55, 5760, 67) and 7 dimeric phenanthrenes (7377, 79, 80), isolated from J. effusus and J. acutus were investigated against Raphidocelis subcapitata (syn. Selenastrum capricornutum) in numerous studies (DellaGreca et al. 1995, 1996, 1997, 2002a, 2003). It was observed, that dimeric phenanthrenes possessed higher antialgal activities than those of the 9,10-dihydrophenanthrene monomers. Moreover, in case of monomeric 9,10-dihydrophenanthrenes, a reduction in the polarity caused a decrease in antialgal activity (DellaGreca et al. 2003).

Conclusion

Juncaceae family has been the subject of intense phytochemical examination in the past few decades. Despite of the comprehensive research focused on the family, until now only eight species, belonging to the genera Juncus and Luzula were investigated extensively. According to the literature data, the main bioactive constituents of Juncaceae species are phenanthrenes. To date, altogether 89 phenanthrenes (mono-, diphenanthrenes and phenanthrene glucosides) were isolated from eight Juncus and Luzula species. The most abundant sources of these compounds are J. effusus and J. acutus. More than half (n = 54) of the isolated compounds are vinyl substituted. In case of dimers, all of the connecting monomers are vinylated, and monomers are connecting through their vinyl groups. The dimerization between two monomers could be resulted in a cage-like carbon framework with complicated stereochemistry.

The isolation of phenanthrenes (2, 23, 65 and 66), including a novel one (66) from L. luzuloides, highlighted that not only Juncus species can produce phenanthrenes in family Juncaceae, but also Luzula plants are promising starting materials for further phytochemical investigations. Moreover, the presence of vinylated phenanthrenes in the plant further confirm the close botanical relationship between the genera Juncus and Luzula.

The chemical constituents of hundreds of species belonging to the family Juncaceae has not been discovered yet. Therefore, phytochemical investigation of other Juncaceae plants and further pharmacological studies of the isolated compounds would be very promising in consequence of their pharmacological potential, in particular their noteworthy antiproliferative, antibacterial and anti-inflammatory activities.

Notes

Acknowledgements

Financial supports from GINOP-2.3.2-15-2016-00012 and TÁMOP 4.2.4.A/2-11/1-2012-0001 are gratefully acknowledged.

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© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PharmacognosyUniversity of SzegedSzegedHungary

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