Fitoterapia 78 (2007) 85 106

www.elsevier.com/locate/fitote

Review

Chemical components of Fraxinus species

I. Kostova , T. Iossifova
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria
Received 11 August 2005; accepted 31 August 2006
Available online 14 November 2006

Abstract
A wide range of chemical components including coumarins, secoiridoids, phenylethanoids, flavonoids, and lignans has been isolated
from Fraxinus species. Extracts and metabolites have been found to possess antiinflammatory, immunomodulatory, antimicrobial,
antioxidative, skin regenerating, photodynamic damage prevention, liverprotecting, diuretic and antiallergic activities. Some species find
application in contemporary medicine.
In the present review the literature data on the phytochemical and biological investigations on the genus Fraxinus are summarized up
to the middle of 2004.
2006 Elsevier B.V. All rights reserved.
Keywords: Fraxinus spp.; Chemical components; Biological activity

Contents
1.
2.
3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ethnopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Coumarins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Secoiridoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1. Secoiridoids of oleoside (24) and 10-hydroxyoleoside (25)
3.2.2. Derivatives with O-function at C-2 . . . . . . . . . . . .
3.2.3. Acylated secoiridoid glucosides . . . . . . . . . . . . . .
3.2.4. Methylated secoiridoid glucosides . . . . . . . . . . . . .
3.2.5. Macrocyclic secoiridoids . . . . . . . . . . . . . . . . . .
3.2.6. Dimeric secoiridoids . . . . . . . . . . . . . . . . . . . .
3.2.7. Non-glucosidic secoiridoids . . . . . . . . . . . . . . . .
3.2.8. Secoiridoids having a rearranged secoiridoid nucleus . . .
3.2.9. Others . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Phenylethanoid glycosides . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +359 2 9606 141; fax: +359 2 8700225.

E-mail address: kostiv1@yahoo.com (I. Kostova).
0367-326X/$ - see front matter 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.fitote.2006.08.002

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86

I. Kostova, T. Iossifova / Fitoterapia 78 (2007) 85106

3.4.
3.5.
3.6.
3.7.

Compounds belonging to two different structural classes

Lignans . . . . . . . . . . . . . . . . . . . . . . . . .
Flavonoids . . . . . . . . . . . . . . . . . . . . . . . .
Simple phenolic compounds . . . . . . . . . . . . . . .
3.7.1. Phenolic acids and their derivatives . . . . . .
3.7.2. Phenylpropanoid glucosides . . . . . . . . . .
3.7.3. Other simple phenolic compounds . . . . . . .
3.8. Sterols and triterpenes . . . . . . . . . . . . . . . . . .
3.9. Other compounds . . . . . . . . . . . . . . . . . . . .
4. Biological activity of extracts and pure compounds . . . . . .
4.1. Antimicrobial activity . . . . . . . . . . . . . . . . . .
4.2. Complement inhibition and antiinflammatory activity . .
4.3. Antioxidative activity . . . . . . . . . . . . . . . . . .
4.4. Skin-regenerating properties . . . . . . . . . . . . . . .
4.5. Photodynamic damage prevention . . . . . . . . . . . .
4.6. Antiviral activity . . . . . . . . . . . . . . . . . . . . .
4.7. Inhibition of enzyme activity . . . . . . . . . . . . . .
4.7.1. cAMP-phosphodiesterase inhibition . . . . . .
4.7.2. Inhibition of lipoxygenase . . . . . . . . . . .
4.8. Diuretic activity . . . . . . . . . . . . . . . . . . . . .
4.9. Anti-platelet aggregation activity . . . . . . . . . . . .
4.10. Anti-hepatotoxic activity . . . . . . . . . . . . . . . . .
4.11. Sensitizing capacity of coumarins . . . . . . . . . . . .
4.12. Other activities . . . . . . . . . . . . . . . . . . . . . .
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction
The genus Fraxinus (Oleaceae) is distributed mostly in the temperate regions and the subtropics of the Northern
hemisphere [1,2].
The classifications of Knoblauch, Taylor and Johnson place the Fraxinus species into the tribe Fraxineae of the
subfamily Oleoideae of the Oleaceae family [1]. Knoblauch [3] describes 39 Fraxinus spp. divided in two sections:
Ornus and Fraxinaster. Lingelsheim [4] recognizes 63 spp. grouped in the same two sections. In a recent classification
of Oleaceae the subfamily level is abandoned, the family is split into 5 tribes and the genus Fraxinus of 4050 spp. is
placed in the subtribe Fraxininae of the tribe Oleeae [1]. The taxonomy of some species is still under discussion [5].
The cladogram of the simplified chloroplast DNA phylogeny showing the tribal division is reported [6]. A new
classification of the entire genus Fraxinus in sections and subsections based on the molecular phylogeny of the genus is
expected to appear soon in the literature [6]. There are lots of synonyms in Fraxinus and this creates problems in summarizing
the literature data [3,58].
Description (from Flora of China): trees or rarely shrubs, deciduous or rarely evergreen. Leaves are odd-pinnate,
opposite or rarely whorled at branch apices; petiole and petiolule are often basally thickened. Inflorescences are terminal or
axillary toward end of branches, or lateral on branches of previous year, paniculate; bracts linear to lanceolate, caduceus or
absent. Flowers are small, unisexual, bisexual, or polygamous. The calyx is 4-toothed or irregularly lobed, sometimes
absent. The corolla is white to yellowish, 4-lobed, divided to base or absent. Stamens are two, inserted at base of corolla
lobes; filaments are short, exserted at anthesis. Ovules are two in each locule, pendulous. Style short; stigma 2-cleft. The
fruit is a samara with elongated wing. The seed is usually one, ovate-oblong; endosperm fleshy; radicle erect [2].
The Fraxinus species have economical, commercial and medicinal importance [1,2,9]. The plants from this genus
are widely used for timber [1]. Many species attract considerable attention for their medicinal properties and find
application in the folk medicine, as well as in the contemporary medicine [1012]. Some species grow as garden plants;
others are cultivated as ornamentals [10,11].

I. Kostova, T. Iossifova / Fitoterapia 78 (2007) 85106

87

In this review, the ethnopharmacology, the phytochemistry and the biological activity of Fraxinus species are
considered covering the literature up to the middle of 2004 and using the synonyms adopted by Hegnauer [8].
2. Ethnopharmacology
The Fraxinus species have been used in folk medicine in different parts of the world for their diuretic and mild
purgative effects as well as for treatment of constipation, dropsy, arthritis, rheumatic pain, cystitis and itching scalp [13].
In China the Li-shu, Miao and Wa tribes use the roots of F. malacophylla as an antipyretic, antimalaria, antirhinitis
and antiinflammatory agent as well as a remedy for excretory organ infection; the Han tribe uses the bark of the same
species in treating stomatitis, toothache, pyrexia and urinary organ infection, while the Bai tribe uses the whole plant in
treating stomatitis, haemostatic and urinary organ infection [14].
The bark ofF. japonica, which is on the market as the oriental medicine shinpi, has been used since olden times as a diuretic,
antifebrile and analgetic agent and against rheumatism and gout in Japan [15,16]. The bark of F. americana finds a similar
application [17]. F. bungeana, a medicinal plant in China, has been applied for treatment of diarrhea, arthritis and fever [18].
Leaves and bark of F. excelsior, native in Europe and Asia, are known as a diuretic and rheumatic remedy since
Hippocrates [12]. From the beginning of the 20th century the leaves of this species are mainly recommended against
fever and rheumatism [19].
The bark and the leaves of F. excelsior and F. ornus are applied in the Bulgarian and Polish folk medicine against
various diseases, including wound healing, diarrhea and dysentery [9,20,21].
3. Phytochemistry
The presence of coumarins, secoiridoids, and phenylethanoids is a characteristic feature of Fraxinus species. The
secoiridoids occur mainly in the form of glucosides and esters of hydroxyphenylethyl alcohols. Lignans, flavonoids
and simple phenolic compounds are also common, but they appear to have more limited distribution.
The occurrence of coumarins distinguishes the genus Fraxinus from the other genera in Oleaceae. Traditionally, the
genus has always been associated with investigations on coumarins. In recent years the increased interest in the
phytochemistry of Fraxinus is motivated by the discovery of the secoiridoid glucosides that constitute major metabolites
of the genus and the family Oleaceae.
3.1. Coumarins
The coumarins are found in a free form or as glucosides in all investigated Fraxinus species so far [8,22]. Some
species are a rich source for industrial production of coumarins. In this connection various analytical methods for
qualitative and quantitative analysis of the coumarin content of extracts and fractions have been developed [23,2528].

1
2
3
4
5
6
7
8
9

R1
H
H
H
H
H
H
H
H
H

R2
OH
OGlc
OH
OMe
OMe
OH
OGlc
OMe
OMe

R3
OH
OH
OGlc
OH
OGlc
OMe
OMe
OMe
OH

R4
H
H
H
H
H
H
H
H
OH

Trivial name
Esculetin
Esculin
Cichoriin
Scopoletin
Scopolin
Isoscopoletin
7-Methylesculin
Scoparon
Fraxetin

88

I. Kostova, T. Iossifova / Fitoterapia 78 (2007) 85106

H
H
H
H
H
H
H
H
OH
OMe
OMe
H
OH

10
11
12
13
14
15
16
17
18
19
20
21
22

OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OH
OH
OGlc
H
OMe

OH
OMe
OMe
OH
OGlc
OMe
OH
OH
OMe
OMe
OMe
H
H

OGlc
OH
OGlc
OMe
OMe
OMe
OAc
ORha-Rha-Glc
H
H
H
OMe
H

Fraxin
Fraxidin
Fraxidin-O--D-glucoside
Isofraxidin
Calyncantoside
6,7,8-Trimethoxycoumarin
8-Acetyl-7-hydroxy-6-methoxycoumarin
Stylosin
Isofraxetin
Fraxinol
Mandshurin
8-Methoxycoumarin
Floribin

Heliettin

23

The coumarins found in the genus Fraxinus are presented in Table 1.

Table 1
Coumarins in Fraxinus species
Plant source

Coumarins

References

F. americana
F. angustifolia Vahl = F. oxycarpa Willd. = F. oxyphylla M. Bieb.
F. borealis Nakai = F. longicuspis Sieb. et Zucc.
F. bungeana DC.
F. californica Mill.
F. caroliniana Mill.
F. chinensis Roxb. var. rhynchophylla Hemst.
F. excelsior L.
F. floribunda Wall
F. greggi
F. insularis
F. japonica Blume = F. kantoensis Koidz. = F. intermedia
Nakai = F. spaethiana Lingelsh.
F. lanceolata Borkh.
F. mandshurica Rupr.
F. mandshurica Rupr. var. japonica Maxim. = F. excelsissima Koidz
F. micrantha
F. nigra Marsh.
F. oregona Nutt.
F. ornus L.
F. pallisiae Wilmott
F. pennsylvanica March.
F. potamophila Herd.
F. pubinermis Bl.
F. quadrangulata Michx.
F. rotundifolia Mill.
F. rhynchophylla
F. sabucina Koidz.
F. sieboldiana var. angstata
F. sieboldiana Bl.
F. sogdiana Bange
F. stylosa
F. syriaca Boiss.
F. toumeyi Britt.
F. verecunda Koidz. = F. spaethiana Lingelsh. = F. commemoralis Koidz.
F. xanthoxyloides Wall.

1, 2, 3, 10, 19
1, 2, 3, 4, 6, 9, 10, 19
1, 2, 9, 10
2, 10
2, 10
2, 3
1, 2, 3, 4, 10
1, 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 14, 19, 20
1, 2, 9, 10, 16, 21, 22
23
1, 2, 3
1, 2, 4, 9, 10, 11, 13, 20

[23,30]
[23,29,3133]
[34,50]
[31]
[31]
[8,32]
[8,26,27,31,3537]
[8,23,29,31,32,3842]
[4345]
[46]
[47]
[23,48,49,5255]

1, 2, 3, 10, 19
1, 10, 18, 19, 20
2, 9, 10, 19, 20
1, 10
1, 2, 9, 10
1, 2, 3, 10, 19
1, 2, 3, 4, 7, 8, 9, 10, 15
1, 2, 4, 6, 9, 10
1, 2, 3, 10, 19
1, 10, 18, 19, 20
2, 9
2, 3, 10
2, 3, 10
1, 2, 3, 5, 10
1, 10
10
1, 2, 9, 10
1, 2, 3, 10, 19
1, 2, 9, 10, 17, 19
1, 2, 3, 10, 19
1, 2, 3, 10, 19
1
3, 10

[23]
[8,48,5456]
[52,5760]
[61]
[31,62]
[23]
[2325,29,53,63]
[29,30]
[23]
[31,56,64,65]
[49]
[8,31,32,66]
[8,31]
[67,68]
[49]
[69]
[51,69,70,71]
[23]
[26,72]
[23,31]
[23]
[62]
[31,32]

I. Kostova, T. Iossifova / Fitoterapia 78 (2007) 85106

89

The coumarin glucosides esculin (2) and fraxin (10) occur in almost all Fraxinus species (Table 1). However, their
ratio varies for different plant sources [2329]. For example, esculin predominates in F. ornus bark, F. sogdiana and F.
syriaca, while in F. excelsior and F. oxycarpa it is the opposite [23,29]. Methods exist for the preparation of esculin
from the bark of F. ornus and of cichoriin from the flowers of the same species [63].
3.2. Secoiridoids
3.2.1. Secoiridoids of oleoside (24) and 10-hydroxyoleoside (25) type
Secoiridoids of oleoside (24) and 10-hydroxyoleoside (25) type having an ethylidene or hydroxyethylidene group at
C-9 occur in Fraxinus species [5]. All natural secoiridoids of this type have the same relative configuration (H-1 is
trans to H-5) and E-configuration of the C8/C9 double bond. The absolute configuration of oleuropein as depicted
in 29 has been confirmed through synthesis [73,74].

24
25
26
27
28

R1
H
OH
H
H
H

R2
H
H
H
Me
Me

R3
H
H
Me
H
Me

29

Me

30

Me

31

Me
H

32

33

OH

Me

10-Hydroxyligstroside

34

OH

Uhdenoside

35

OH

Me

10-Hydroxyoleuropein

36

Me

Angustifolioside

Trivial name
Oleoside
10-Hydroxyoleoside
Oleoside-7-methylester
Oleoside-11-methylester
Oleoside-7,11-dimethylester

Oleuropein

(1)--D-Glc

7--D-glucopyranosyl-11-methyloleoside
Ligstroside

Demethylligstroside

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37

Me

Angustifolioside B

38

Me

Excelsioside/formoside

39

Me

1-O--D-glucosyl-formoside

40

Me

Neuzhenide

41

Me

Isoligstroside

42

Isoligstrosidic acid

43

CH2CH2CH2CH3

Butylisoligstrosidate

44

Fraxiformoside

45

1-O--D-glucosylfraxiformoside

46

Framoside

47

Hydroxyframoside A

48

Hydroxyframoside B

49

Neooleuropein

50

Angustifolioside C

51

Insuloside

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91

The secoiridoids in Fraxinus usually occur as glycosides and only few have been isolated with the sugar
moiety missing. With some exceptions, they are found as esters of the hydroxylated phenylethyl alcohols
tyrosol (4-hydroxyphenylethylalcohol, 52) and dopaol (3, 4-dihydroxyphenylethylalcohol, 53), the usual
place of esterification being at C-7. In compounds 4143 the esterification with 52 and 53 is at C-11, while
4551 contain two ester bound phenethoxy moieties at C-7 and C-11. In some cases, the ester bond is
through the phenolic OH group [38,39,45,46] of the hydroxyphenethylalcohol or through a sugar residue
[40,41].
3.2.2. Derivatives with O-function at C-2
The 2-hydroxyoleuropeins 54 (2R) and 55 (2S) and their 2-methoxyderivatives 56 and 57 have been isolated
from F. americana [17]. No interconversion between the two glucosides 54 and 55 or their transformation to 56 and 57
during the separation procedure was observed.

R1
OH
H
OMe
H

54
55
56
57

R2
H
OH
H
OMe

3.2.3. Acylated secoiridoid glucosides

The acylated derivatives of 10-hydroxyoleuropein (35) designated as fraxicarboside A (58), fraxicarboside B (59)
and fraxicarboside C (60) were isolated from F. oxycarpa. The location of the acyl unit (p-coumaroyl or caffeoyl) was
confirmed to be at 6-position of the glucosyl moiety [11].

58
59
60

R1
H
H
Ac

R2
H
OH
OH

Trivial name
Fraxicarboside A
Fraxicarboside B
Fraxicarboside C

3.2.4. Methylated secoiridoid glucosides

The methylated derivatives 61 and 62 of oleoside-7, 11-dimethylester (28) and ligstroside (31) have been reported to
occur in F. angustifolia [75].

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R
Me

61
62

3.2.5. Macrocyclic secoiridoids

The macrocyclic secoiridoids are found only in F. ornus, F. uhdei and F. insularis [10,18,47,7681]. In them the
two hydroxyphenethyl units are coupled through a diphenylether linkage which gives rise to the formation of a flexible
macrocyclic ring. The use of these compounds as chemotaxonomic markers was suggested by Iossifova et al. [29].

63
64
65
66
67
68

R1
H
H
OH
H
H
H

R2
H
H
H
-D-Glc
H
-D-Glc

R3
H
H
H
H
-D-Glc
-D-Glc

R4
H
OH
H
H
H
H

Trivial name
Insularoside, uhdoside, ornoside
Hydroxyornoside
Uhdoside B
Fraxuhdoside, oleayunnanoside
Insularoside-3-O--D-Glc
Insularoside-3,6-di-O--D-Glc

Fraxamoside (69) is another type of macrocyclic secoiridoid, found in the leaves of F. americana [17].

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93

3.2.6. Dimeric secoiridoids

Complex dimeric secoiridoids consisting of two oleoside moieties linked to glucose and/or tyrosol have been also found in
the genus Fraxinus. This type of secoiridoids is characteristic for Jasminum spp. and occurs rarely in other genera of
Oleaceae. The secoiridoids Gl-3 (70) and Gl-5 (71) are reported from F. americana [82], while fraximalacoside (72) from
F. malacophyla [14].

3.2.7. Non-glucosidic secoiridoids

Oleobutyl (73) and ligstrobutyl (74) are found in F. oxycarpa [75].

73
74

R
OH
H

Trivial name
Oleobutyl
Ligstrobutyl

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3.2.8. Secoiridoids having a rearranged secoiridoid nucleus

Ligstral (75) is the only secoiridoid of this type in Fraxinus. It could be considered as obtained from ligstroside (31)
by hydrolysis and rearrangement of the oleoside nucleus [83].

3.2.9. Others
The unique compound frameroside (76), containing a cyclopentanoid monoterpene esterified with oleoside-type
secoiridoid glucoside, was isolated from F. americana [17]. Epiqingiside (77) is considered to be a biogenetic
precursor of the oleoside-type secoiridoids [86,87].

Table 2 summarizes the secoiridoids found in the genus Fraxinus.

3.3. Phenylethanoid glycosides
Nine phenylethanoid glycosides have been reported to occur in Fraxinus spp. Of them verbascoside (78) is found in
F. angustifolia (F. oxycarpa) [11], F. americana [17,84], F. excelsior [89], F. formosana [90], F. insularis [47], F.
malacophyla [14], F. ornus [97], F. sieboldiana [71], F. velutina [95] and F. uhdei [78]. Salidroside (79) is isolated
from F. formosana [90], while calceolarioside A (80) from F. insularis and F. sieboldiana [47,71] and
calceolarioside B (81) from F. insularis, F. sieboldiana and F. ornus [47,71,97]. The occurrence of lugrandoside
(82) isolugrandoside (83), isoacteoside (84), and 2-(4-hydroxyphenyl)-ethyl-(6-O-caffeoyl)--D-glucopyranoside (85)

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95

Table 2
Occurrence of secoiridoids in Fraxinus species
Species

Compounds

References

F. americana
F. angustifolia (F. oxycarpa)
F. chinensis
F. excelsior
F. formosana
F. griffithii
F. insularis
F. japonica
F. malacophyla
F. mandshurica
F. ornus
F. uhdei
F. velutina
F. pallisiae

27, 28, 31, 32, 33, 40, 54, 55, 56, 57, 69, 70, 71, 76
28, 29, 31, 33, 35, 36, 37, 40, 50, 58, 59, 60, 61, 62, 70, 71, 73, 74, 75
29, 49
28, 29, 30, 31, 33, 38
31, 38, 39, 41, 42, 44, 45, 46, 77
31
29, 31, 51, 63, 66, 67, 68
29
41, 42, 43, 44, 45, 72
29, 31
29, 31, 46, 47, 48, 63, 64
31, 33, 34, 35, 44, 63, 65, 66
26, 29, 31
28, 29, 31, 33

[17,82,88]
[11,13,29,33,75]
[84]
[29,40,89]
[90,91]
[92]
[47,76,77]
[16]
[14]
[93]
[29,80,81,85,94,96]
[10,18,78,79]
[95]
[29]

is reported from F. ornus [97]. Campneoside I (86) is isolated from F. americana [17]. Except salidroside (79), the
phenylethanoids in Fraxinus are present as caffeoyl esters. The derivatives of dopaol predominate.

78
79
80
81
82
83
84
85
86

R1
OH
H
OH
OH
OH
OH
OH
H
OH

R2
H
H
H
H
H
H
H
H
OMe

R3
Rha
H
H
H
H
Caff
Rha
H
Rha

R4
Caff
H
Caff
H
Caff
H
H
H
Caff

R5
H
H
H
Caff
Glc
Glc
Caff
Caff
H

Trivial name
Verbascoside, acteoside
Salidroside
Calceolarioside A
Calceolarioside B
Lugrandoside
Isolugrandoside
Isoacteoside
Campneoside I

3.4. Compounds belonging to two different structural classes

Frachinoside (87), isolated from F. chinensis [84] and escuside (88), isolated from F. ornus [85,96], belong to this
group. Their molecules consist of a coumarin glucoside and a secoiridoid glucoside, ester linked through the glucose of
the coumarin part and the carboxyl group at C-7 of the secoiridoid. Compound 87 is the first example of secologanoside
type secoiridoid glucoside to be isolated from this genus.

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Desrhamnosyloleoacteoside (89) was isolated from F. insularis [77]. It contains the ester linked phenylethanoid
calceolarioside A (80) and the secoiridoid oleoside-11-methylester (27).

3.5. Lignans
The lignans in the Fraxinus are mainly of tetrahydrofurofuran (sesamine) type [98,99]. They are found free or as
glucosides.

90
91
92
93
94
95
96
97
98
99
100

R1
H
OH
OCOCH3
OH
H
OH
H
OH
H
OGlc
H

R2
H
H
H
H
H
H
Glc
Glc
H
H
Glc

R3
H
H
H
OMe
OMe
OMe
H
H
H
OMe
OMe

R4
H
H
H
H
OMe
OMe
H
H
OMe
H
OMe

R5
H
H
H
H
H
H
H
H
H
H
Glc

Trivial name
Pinoresinol
8-Hydroxypinoresinol
Acetoxypinoresinol
Fraxiresinol
Syringaresinol
8-Hydroxysyringaresinol
Pinoresinol-4-O--D-glucopyranoside
8-Hydroxypinoresinol-4-O--D-glucopyranoside
Medioresinol
Fraxiresinol-8-O--D-glucopyranoside
Liriodendrin

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97

Olivil (101) and cycloolivil (102) were detected in F. mandshurica and F. mandshurica var. japonica [59,60,99]:

The lignans found in Fraxinus are presented in Table 3.

3.6. Flavonoids
Flavones and flavonols are characteristic for the genus Fraxinus. Kaempferol (114) and quercetin (103) and their
glycosides are frequently found. In the flavones the glycosidation is predominantly at C-7, while in the flavonols it is at C-3.

Table 3
Lignans in the genus Fraxinus
Plant species

Compounds

References

F. angustifolia (F. oxycarpa)

F. chinensis Roxb.
F. japonica
F. mandshurica and F. mandshurica var. japonica
F. micrantha
F. sieboldiana
F. uhdei

90, 96, 97, 99

90, 92, 96, 102
90, 91, 93, 95, 96, 97, 101, 102
90, 91, 93, 94, 95, 96, 97, 98, 101, 102
91
101
97, 100

[11,33]
[100]
[99]
[59,60,99]
[61]
[71]
[79]

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103
104
105
106
107
108
109
110

R1
OH
OH
O-Glc6-Rha
O-Glc
O-Rha
O-Gal
O-Gal

111

112
113
114
115
116
117
118
119
120
121
122
123
124

O-Gal6-Rha
O-Glc2-Glc
OH
O-Glc
O-Glc6-Rha
OH
O-Gal6-Rha
H
H
H
H
H
H

R2
OH
OMe
OH
OH
OH
OH
O-Gal
OH

R3
OH
OH
OH
OH
OH
OH
OH
OH

OH

OH

OH
OH
OH
OH
OH
O-Glc2-Rha
OH
OH
O-Glc6-Rha
O-Glc
O-Glc
O-Glc6-Rha
OH

OH
OH
H
H
H
H
H
H
H
H
OH
OH
O-Glc

Trivial name
Quercetin
Rhamnetin
Rutin
Isoquercetrin
Quercetrin
Hyperoside
Quercetin-3,7-digalactoside

Quercetin-3-O-robinobioside
Quercetin-3-O-sophoroside
Kaempferol
Astragalin
Nicotiflorin
Kaemferol-7-O-hesperidoside
Kaempferol-3-O-robinobioside
Apigenin
Rhoiflorin
Cosmosiin
Luteolin-7-glucoside
Luteolin-7-rutinoside
Luteolin-3-glucoside

(+)-Catechin (125) and ()-epicatechin (126) were isolated from F. excelsior [42].

The flavonoids found so far in Fraxinus are summarized in Table 4.

3.7. Simple phenolic compounds
3.7.1. Phenolic acids and their derivatives
The following benzoic acid derivatives were found: p-hydroxybenzoic acid (127), protocatehuic acid (128), vanillic
acid (129), syringic acid (130), 2,4-dihydroxybenzoic acid (131) and gallic acid (132).

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99

Table 4
Flavonoids in Fraxinus species
Plant species

Compounds

References

F. americana
F. angustifolia (F. oxycarpa)
F. chinensis Roxb. var. rhynchophylla Hemsl.
F. excelsior L.
F. insularis
F. lancheolata
F. malacophylla
F. mandshurica Rupr.
F. ornus
F. pallisiae Willmot
F. pennsylvanica
F. raibocapra
F. velutina

105, 110, 111, 112, 117, 118, 120, 121, 122, 123, 124
105, 115, 116
120, 121
103, 105, 106, 107, 114, 115, 116, 119, 125, 126
105, 107
113
121
106
103, 104, 105, 106, 107, 108, 109, 119
105, 106
105
105, 106, 115
105, 116

[17,101104]
[11,105]
[103]
[21,42,66,106108]
[47]
[109]
[14]
[110]
[103,108,111]
[103]
[102]
[112]
[95]

The cinnamic acid (133) and its hydroxy derivatives p-coumaric (134), caffeic (135), ferulic (136) and sinapic (137)
acids occur free or as esters linked to the -glucopyranosyl moiety in phenylethanoids and secoiridoid glucosides. The
presence of 2-methoxy-cis-cinnamic acid (138) and 6-O-trans-caffeoyl--D-glucopyranoside (139) has been reported.
3.7.2. Phenylpropanoid glucosides
Of these, coniferin (140), syringin (141) and sinapic aldehyde-4-O--glucoside (142) are found in Fraxinus.

140
141
142

R1
CH2OH
CH2OH
CHO

R2
H
OMe
OMe

Trivial name
Coniferin
Syringin
Sinapic aldehyde-glucoside

3.7.3. Other simple phenolic compounds

The phenylethanoids tyrosol (52) and dopaol (53) and their derivatives 3-methoxy-4-hydroxyphenylethanol (143)
and 1-O-acetyltyrosol (144) are reported to occur free. 2,6-Dimethoxy-p-benzoquinone (145) and 2,5-dihydroxy-6methoxy-acetophenone (146) also have been found. Ornosol (147) was detected in trace amount.
The simple phenolic compounds found in Fraxinus are presented in Table 5.

3.8. Sterols and triterpenes

The triterpenes ursolic acid (148), oleanolic acid (149), betulinic acid (150), betulin (151) and -amirin (152) and
the sterols sitosterol (153) and sitosterol glucoside (154) are found. Their distribution in Fraxinus is summarized in
Table 6.

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Table 5
Simple phenolic compounds in Fraxinus spp.
Plant species

Compounds

References

F. americana
F. chinensis
F. excelsior
F. floribunda
F. formosana
F. griffithii
F. japonica Blume
F. malacophyla
F. mandshurica
F. micrantha
F. ornus
F. oxycarpa
F. stylosa
F. spaethiana
F. uhdei
F. velutina
F. verecunda

52, 53, 131, 134, 135, 141

141, 145
127, 128, 129, 130, 132, 134, 135, 136, 137
52, 146
52
141, 142
52, 53, 143, 145
52
140, 141
52
52, 129, 130, 131, 132, 134, 135, 136, 147
139
141
141
52, 141, 142, 144
53, 138
141

[17,88,111]
[27,37]
[21,111]
[43,44]
[90,91]
[92]
[113]
[14]
[114]
[61]
[80,111]
[11]
[72]
[48,50]
[79]
[95]
[48,50]

3.9. Other compounds

The polyalcohol mannitol (155) is considered to be the main component of the water soluble part of bark extracts of
many Fraxinus: F. borealis [50], F. excelsior [116], F. floribunda [44], F. greggi [46], F. uhdei [79], F. mandshurica
[57], F. ornus [117] and F. sieboldiana [50]. The seasonal pattern of mannitol content in the leaves of F. ornus and
F. angustifolia has been determined by gas chromatography or enzymatically [118,119].
The bark of F. ornus was found to contain tannins of pyrocatechol type [120]. Studies carried out by Murko et al.
[121] revealed the presence of carotene in the leaves of F. ornus. The occurrence of amino acids in the pollen of
F. excelsior is reported [122].
Abscisic acid, indole-3-acetic acid, jasmonic acid, methyl jasmonate and gibberellins were identified in the seeds of
F. excelsior by gas chromatographymass spectrometry [123].
4. Biological activity of extracts and pure compounds
4.1. Antimicrobial activity
The ethyl ether fraction of the alcoholic extract of F. excelsior bark was inhibitory to Bacillus subtilis [124]. Extracts
of the leaves of F. excelsior suppressed the growth of the fungi Gloeosporum limetticola and Alternaria tennis [125].
Grujic-Vacic and co-workers tested the antimicrobial activity of aqueous extracts of the leaves and the barks of F.
ornus and F. excelsior against 11 microorganisms and found that the leaves of both species showed strong inhibition on
the growth of Candida albicans with zones of inhibition of 25 and 22 mm, while the extracts of their barks expressed

Table 6
Sterols and triterpenes in Fraxinus spp.
Plant species

Compounds

References

F. excelsior
F. greggi
F. malacophyla
F. mandshurica Rupr. var. japonica Maxim.
F. ornus
F. sieboldiana
F. uhdei

148, 150, 151, 153

149, 152, 153
154
153
153
153
148, 149, 150, 151, 153

[115]
[46]
[57]
[14]
[108]
[70]
[79]

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101

inhibitory activity against Staphylococcus aureus (zones of inhibition 13 and 15 mm). Only the bark of F. excelsior
was active against Proteus mirabilis and exhibited zone of inhibition 12 mm [111].
Studies carried out by Lambrev et al. [126] revealed a clear antibacterial activity of the ethanolic extract and
decoctions from the bark of F. ornus against S. aureus and B. subtilis, as well as a marked activity against Leptospira
ponoma.
The antimicrobial properties of three bark extracts of F. ornus and their main constituents 1, 2, 9, 10 against S.
aureus, Candida sp., Escherichia coli and Pseudomonas aeruginosa were studied [127]. Evaluation of the microbial
growth on the contact surface was performed by measuring the Contact Growth Index (CGI). All tested extracts and
compounds were not active against E. coli and P. aeruginosa. Against Candida sp. only fraxetin (9) and fraxin (10)
exhibited some activity (CGI = 3) at concentrations of 0.84 and 0.62% (w/w). Of the pure compounds 9 caused a full
inhibition (CGI = 0) of S. aureus, followed by esculetin (1) (CGI = 1) and fraxin (10) (CGI = 3) at concentrations of
0.2% (0.1% for fraxin); 2 was totally deprived of activity. The activity of the extracts against S. aureus was dependent
on their hydroxycoumarin content.
The antimicrobial activity of different groups of bark constituents of F. ornus was investigated [128]. In the group of
the coumarins 1, 2, 610, 15 a clear correlation between structure and antimicrobial activity against S. aureus and E.
coli was observed. Compared to the aglucones esculetin and fraxetin (MIC 500 and 125 g/ml, respectively) the
glucosides esculin and fraxin showed a negligible activity (MIC N 1000 g/ml). The secoiridoid glucosides 31 and 63
and the phenylethanoid ornosol (147) inhibited the growth of S. aureus and Cladosporum cucumerinum. In another
study the caffeoyl esters of phenylethanoid glycosides 78, 8186 showed no activity against Pseudomonas stutzeri,
while verbascoside (78) and isoacteoside (84) were inhibitors of B. subtilis at 2.5 g/spot [129].
The inhibitory effects of 1, 4, and 8 on the growth of 22 species of bacteria, yeast and molds have been measured
[130].
4.2. Complement inhibition and antiinflammatory activity
The water soluble and methanol extracts of the bark of F. japonica as well as the bark constituents esculetin (1) and
esculin (2) were found to inhibit the rat edema induced by carrageenan, yeast and dextran. Esculin (2) and esculetin (1)
were potent inhibitors of UV erythema in guinea pigs and decreased capillary permeability in mice [131].
A powder prepared from the cold MeOH extract of F. japonica bark containing esculin (2) was more effective than 2
in inhibiting edema induced in rats by carrageenan, formaldehyde and histamine during antiinflammatory testing [132].
The antiinflammatory drugs Esqusan, Esflazid and Anavenol are based on esculin (2) [133].
Bark and leaves of F. excelsior have been used as rheumatic remedy since olden times. The ethanolic extract of the
bark of this plant is a component of the plant drug Phytodolor N. Various in vitro and especially in vivo studies proved
its antiinflammatory and antirheumatic properties often comparable to non-steroidal antiinflammatories, but with little
or no side effects [12].
As a correlation between the antiinflammatory activity and dihydrofolate reductase inhibition has been reported in
the literature, Strehl and co-authors investigated the inhibition of this enzyme by the drug Phytodolor N and its
components, the extracts of F. excelsior, Populus tremula and Solidago virgaurea. The following concentrations as
percentage in the test volumes represent the individual I50 values: F. excelsior 0.26% (v/v); P. tremula 0.46% (v/v) and
S. virgaurea 0.6% (v/v). The combined extract in the drug exhibits an I50 at 0.3% (v/v). Testing the activity of the water
soluble compounds of the corresponding dry extracts reveals that, the inhibitory effect of F. excelsior with an apparent
I50 value of 0.008% (w/v) by far dominates the inhibitory activity of the combination (I50 0.014%, w/v) [134].
The effects of the ethanolic extract of F. ornus bark and its main component esculin (2) on some in vitro and in vivo
reactions related to acute inflammatory processes were studied [135]. The extract caused a more pronounced reduction
of CP (classical pathway) hemolysis compared to esculin (2). The concentration causing 50% inhibition of CP (ICP50)
was found to be 5 g/ml for the extract and 10 g/ml for esculin. In the AP (alternative pathway) assay they exhibited
nearly equal dose-dependent inhibition of complement-mediated lysis. The full inhibition of AP activity was achieved
at esculin and total extract concentration of 50 g/ml. Both the extract and 2 significantly reduced the formation of the
zymosan-induced paw edema in mice. In the case of carrageenin-induced edema, only the extract significantly reduced
the inflammation at a dose of 15 mg/kg, while esculin was ineffective.
The in vitro effects of the coumarins 1, 2, 4, 610 on the classical and alternative complement activity in normal
human serum were examined at different concentrations. All the substances tested had a moderate or weak ability to

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affect at least one of the complement pathways. The effect was not strictly dose dependent. Some of the compounds
exhibited combined effect, activating one of the pathways and inhibiting the other. The data suggest that the coumarins
8 and 7 are the most potent inhibitors of AP and CP activities and deserve attention as possible antiinflammatory agents
[136].
In another study esculetin (1) was found to reduce edema and granulocyte infiltration caused by croton oil in mice
[137].
Pure secoiridoid glucosides 29, 31, 46, 63, 64 were studied in vitro for their anticomplement action and for their
ability to prevent cobra venom-induced complement activation in normal human serum [138]. The results showed that
most of the secoiridoids possess the ability to suppress CP and AP activities. The most effective inhibitors of CP in
guinea pig serum were ligstroside (31) (IC50 33 g/ml) and insularoside (63) (IC50 33 g/ml). Alternative pathway
activity was slightly altered, although the substances were used in a higher concentration (1 mg/ml) than in CP assay
(250 g/ml).
The immunosuppressive properties of verbascoside (78) are also known [139].
4.3. Antioxidative activity
Investigations of Meyer et al. reveal the antioxidative activities of the alcoholic extract of F. excelsior bark, a
component of the antiinflammatory plant drug Phytodolor N [140]. Xanthine oxidase, diaphorase, lipoxygenase,
riboflavin and rose Bengal, producing reactive oxygen species, were studied as model reactions.
The antioxidative action of the total ethanolic extract of F. ornus bark and its main coumarin constituents 1, 2, 9, 10
was investigated using kinetically pure triacylglycerols of lard (TGL) and sunflower oil (TGSO) [141]. The
stabilization factor (F) and oxidation rate ratio of the tested antioxidants were determined. The ethanolic extract in a
concentration of 0.05% showed a pronounced activity during the oxidation of TGL (F = 4.8, ORR = 3.6) and TGSO
(F = 3.6, ORR = 0.6), comparable to that of butylated hydroxytoluene and butylated hydroxyanisole. The activity of
fraxetin (9) and esculetin (1) was higher than that of the corresponding glucosides fraxin (10) and esculin (2) and
comparable to that of other well known antioxidants such as caffeic acid. In the same study the presence of additional
antioxidative substances was revealed by TLC analysis.
Vesbascoside (78), calceolarioside B (81) and isoacteoside (84) are also found to have antioxidative properties
[139].
4.4. Skin-regenerating properties
Klouchek et al. investigated the skin-regenerating properties of the ethanolic bark extract and its main component
esculin (2) on male rats having standard oval wounds [142]. The animals treated with the bark extract exhibited a more
intense epithelization of the wounds in comparison with the control groups. On the 3rd day from the beginning of the
experiments 55.80% of epithelization was observed, the effect being more pronounced between the 7th (84.85%) and
10th (96.90%) days. A weaker regenerating effect was observed in the animals treated with esculin.
4.5. Photodynamic damage prevention
Lazarova et al. used the prevention of photodynamic yeast cell damage to investigate the protective activity of the
coumarins 1, 2, 9, 10, four bark extracts, caffeic acid and as a standard the sun screen p-aminobenzoic acid [143]. All of
the tested pure compounds showed protective activity. The protective effect of compounds 1 (F 97.6) and 9 (F 94.7) at
concentration of 20 mg/l was comparable to that of caffeic acid (F 98.5) and p-aminobenzoic acid (F 92.6) at
concentration of 25 mg/l.
4.6. Antiviral activity
Galabov et al. investigated the antiviral properties of the coumarins 1, 2, 6, 7, 8, 9, 15 isolated from F. ornus against
poliovirus 1, influenza virus, Newcastle disease virus (NDV) and pseudovirus [144]. Only esculetin (1) showed a
significant activity against NDV when applied at a dose of 2.8 mM/0.1 ml. Kernan et al. reported the antiviral
properties of verbascoside (78) [145].

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103

4.7. Inhibition of enzyme activity

4.7.1. cAMP-phosphodiesterase inhibition
A high inhibitory activity against cAMP-phosphodiesterase was shown by the coumarin compounds of the bark of
F. japonica scopoletin (4), fraxin (10) and isofraxidin (13). Esculetin (1), fraxetin (9) and the lignans pinoresinol (90)
and pinoresinol-4--D-glucoside (96) were also active [15,99,146].
4.7.2. Inhibition of lipoxygenase
The coumarins esculetin (1), esculetin (2), scopoletin (4), fraxetin (9) and fraxin (10) inhibit the formation of
leucotrienes from arachidonic acid by lipoxygenase and improve allergic conditions [147,148].
4.8. Diuretic activity
Traditionally, leaf extracts from F. excelsior have been used to facilitate renal excretion. This diuretic activity is
attributed to the presence of flavonoids. The spray-dried powders prepared from the aqueous and ethanolic extracts
from the leaves of this plant caused a significant dose-dependent increase in the excretion of sodium and chloride ions,
potassium and urea and were qualified as potentially useful medicinal products [149].
4.9. Anti-platelet aggregation activity
The methanol extract of the bark of F. japonica was bioassayed for inhibitory activity on rabbit platelet aggregation
induced by arachidonic acid and found to be active. By bioassay guided investigation of this extract 3-methoxy-4hydroxyethanol (143), tyrosol (52), 2,6-dimethoxy-p-benzoquinone (145) and esculetin (1) were identified [113,150].
4.10. Anti-hepatotoxic activity
The liver protecting properties of some coumarin and flavonoid components of Fraxinus spp. are reported in the
Ref. [151]. Isofraxidin (13) and scopoletin (4) exert pronounced choleritic activity; esculetin (1), isoscopoletin (6),
scoparon (8), esculin (2) and 7-methylesculin (7) given i.v. to dogs exhibited cholagogue effect; astragalin (115) and
apigenin (119) showed choleritic effects in rats; quercetin (103) was found to increase bile secretion and the detoxifying
function of the liver in experimental animals and rutin (105) and nicotiflorin (116) showed low toxicity and marked
choleritic effects when tested on rabbits, rats and mice.
4.11. Sensitizing capacity of coumarins
Studies on the sensitizing capacity of coumarins used in perfumery, cosmetics, therapeutic ointments show a
sensitizing potency of esculetin (1). Scoparone (8) and isoscopoletin (6) were weak sensitizers, while fraxetin (9) was
nearly inactive [152154].
4.12. Other activities
The secoiridoids were found to possess a potent coronary vasodilatating activity [75].
The phenylethanoid glycoside verbascoside (78) is reported to have cytotoxic properties [155,156].
5. Conclusions
The phytochemical investigations on the Fraxinus species reveal the occurrence of a wide range of chemical
compounds including coumarins, secoiridoids, phenylethanoids, lignans, flavonoids and simple phenolics. Out of the
155 different components described in the present review 78 belong to the groups of the coumarins and the secoiridoids.
The coumarins in Fraxinus are the best investigated. The coumarin content of 35 species has been investigated.
Esculetin (1), esculin (2), cichoriin (3), scoparon (8), fraxetin (9), fraxin (10) and fraxinol (19) are most frequently
found. Some Fraxinus are used for industrial production of coumarins.

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I. Kostova, T. Iossifova / Fitoterapia 78 (2007) 85106

The 52 secoiridoids prevail among the chemical constituents in Fraxinus, although only 13 species have been
investigated in this direction. The macrocyclic secoiridoid glucosides attract attention as a new subgroup of the
secoiridoids. For now they are found in F. ornus, F. insularis and F. uhdei. Some unique compounds like frachinoside
(87), escuside (88) and desrhamnosyloleoacteoside (89) have been also isolated.
Extracts and fractions possess antimicrobial, antiinflammatory, antioxidative, skin regenerating, diuretic,
liverprotecting and photodynamic damage prevention activities. The contemporary plant drug Phytodolor N contains
extract of F. excelsior and finds application as an antiinflammatory agent.
It could be concluded that the genus Fraxinus is a rich source of phenolic compounds, interesting chemical
structures and various biologically active products (extracts, fractions and individual compounds).
All this shows that future phytochemical and biological investigations on Fraxinus species are of great importance.
Acknowledgements
The financial support of this work from the Bulgarian Academy of Sciences is gratefully acknowledged.
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