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bioactivos presentes en pelargonium sidoides, p. reniforme

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ARTICLE IN PRESS
Phytomedicine 14 (2007) SVI 9–17
www.elsevier.de/phymed
REVIEW
Fascinating metabolic pools of Pelargonium sidoides and Pelargonium
reniforme, traditional and phytomedicinal sources of the herbal medicine
Umckaloabos
Herbert Kolodziej
Institut für Pharmazie, Pharmazeutische Biologie, Freie Universität Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany
Abstract
The metabolic pools of Pelargonium sidoides DC and Pelargonium reniforme CURT, associated with the origin of
the herbal medicine Umckaloabos, exhibit remarkable diversity and complexity. They comprise a variety of phenolic
and polyphenolic compounds, a notable wealth of highly oxygenated simple coumarins and a number of miscellaneous
uncommon metabolites. Noteworthy, the roots of both species express conspicuously distinct coumarin variations that
facilitate their identification. Of the range of coumarins identified the titled species shared the ubiquitous scopoletin
and the unique members 6,7,8-trihydroxycoumarin and 8-hydroxy-5,6,7-trimethoxycoumarin merely. Furthermore,
the current data on the coumarin profiles suggest the occurrence of coumarin sulphates and coumarin glycosides to be
apparently confined to P. sidoides, while the occurrence of conventional proanthocyanidins was a common chemical
feature. An unprecedented diterpene, designated as reniformin, was encountered in the roots of P. reniforme,
possessing a novel diterpene skeleton linked to a unique p-oxyphenethansulfonic moiety. Coumarins were less
abundant in the aerial parts of both species. These were rich in flavonoids and hydrolysable tannins including a unique
series of O-galloyl-C-glucosylflavones (P. sidoides and P. reniforme) and novel ellagitannins with a 1C4 glucopyranose
core in P. reniforme, trivially named pelargoniins, accompanied by the new 4-allyl-2,5-dimethoxyphenol-1-b-Dglucoside. These Pelargoniums have thus represented an attractive source of fascinating secondary metabolites.
A proprietary extract of the roots of P. sidoides, EPss 7630, has been developed from this traditional herbal medicine
and introduced into modern phytotherapy in Europe. Structural examination of EPss 7630 constituents showed
excellent agreement of the profile with that of P. sidoides.
r 2006 Elsevier GmbH. All rights reserved.
Keywords: Pelargonium sidoides; Pelargonium reniforme; EPss 7630; Coumarins; Phenols
Introduction
The genus Pelargonium (Geraniaceae) comprises
approximately 270 distinct species of perennial small
shrubs of which about 80% occur in southern Africa
with the centre of diversity in the Cape Province (Van
der Walt and Vorster, 1988). Although Pelargoniums
Tel.: +49 30 83 85 37 31; fax: +49 30 83 85 37 29.
E-mail address: kolpharm@zedat.fu-berlin.de.
0944-7113/$ - see front matter r 2006 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2006.11.021
have a long tradition as ornamental and medicinal
plants (Lis-Balchin, 2002), limited chemical sampling of
members of this genus produced mainly common
organic acids, derivatives of cinnamic acid, flavonoids,
tannins, some coumarins and phytosterols (Hegnauer,
1966, 1989; Williams and Harborne, 2002). With the
exception of the detection of the unique alkaloids
(epi)elaeocarpidin in hybrids (Lis-Balchin et al., 1996),
all recent papers deal with these types of secondary
products. Owing to the persistent interest in perfumery,
ARTICLE IN PRESS
10
H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17
reflected by numerous papers on ‘Geranium oil’
(P. graveolens, hybrids and other Pelargonium species!)
(Van der Walt and Vorster, 1981; Kaiser, 1984; Van der
Walt and Demarne, 1988), essential oils of distinct
Pelargonium species, have been the subject of detailed
studies (Demarne and van der Walt, 1990, 1992, 1993;
Demarne et al., 1993).
Initial chemical investigation of Pelargonium reniforme/Pelargonium sidoides was prompted by the
discovery of a herbal medicine for the treatment of
tuberculosis. The English Major Charles Henry Stevens
who has been heavily suffering from this respiratory
disease travelled to South Africa for a cure and had the
believe that he has been restored to health by decoctions
of a root material given by a traditional healer (Bladt,
1977; Helmstädter, 1996). The true botanical nature of
this herbal medicine was debated for many years until
1974 when its origin was claimed to be P. reniforme
(Bladt, 1974, 1977; Wagner and Bladt, 1975). Current
evidence points to erroneous identification of the plant
material in the earlier investigation and suggests
P. sidoides as plant origin (vide infra) (Kolodziej and
Kayser, 1998). However, it should be stressed that
chemical studies have not been carried out on distinct
plant extracts of either Pelargonium species.
With botanically defined plant materials available
through cultivation, studies on the individual patterns of
constituents of each Pelargonium species were permitted
for the first time. It should be noted that the plant
material of P. reniforme studied conformed with ssp.
reniforme. Although current interest focuses on the
composition of root metabolites, this communication
also includes the fascinating metabolic pools of the
aerial parts in view of the hitherto limited information
on the chemical constituents of Pelargoniums and their
various traditional uses. In addition, extended knowledge of the chemical profile of both species may provide
a clue for the detection of key compounds in terms of
their pharmacological profiles. Due to the indicated
taxonomic ambiguity, this report represents a summary
of the compositional studies of the titled Pelargonium
species mainly carried out in our research group.
Structures depicted represent unusual and typical
metabolites.
Pelargonium reniforme CURT
The pink-flowered P. reniforme is an attractive erect
shrublet, developing from a tuberous rootstock. The
zygomorphous flower heads are borne on tall slender
stalks. Each flower has five lanceolate petals, with two
distinctive stripes on the upper two petals. The reniform
leaves are a characteristic feature of this species that is
reflected in its botanical name ‘‘reniforme’’ (Van der
Walt and Vorster, 1983, 1988). Noteworthy is that the
two subspecies of P. reniforme not only differ morphologically, but also in area of distribution (Dreyer et al.,
1995). P. reniforme ssp. reniforme is confined to the
region at Port Elizabeth where it is fairly widespread at
low altitudes. All the material extending in the coastal
districts further north and south and in inland areas is
apparently represented by the ssp. velutinum. The only
notably morphological difference between the two
subspecies lies in the shape and arrangement of leaves
and in the length of petioles; ssp. velutinum shows
reniform to predominantly cordate leaves and conspicuously longer petioles, reminiscent of those of P. sidoides
(vide infra).
The aqueous acetone and methanol extracts of the
roots of P. reniforme afforded a total of 24 various
metabolites including ten simple phenolic acids, six
coumarins, four flavonoids, two flavan-3-ols with
associated proanthocyanidins, one phytosterol and an
unprecedented diterpen, reniformin (Table 1). With
the exception of gallic acid and its methyl ester,
all these metabolites have been encountered in
relatively low yields. The presence of catechin and
gallocatechin in the roots of P. reniforme has only been
qualitatively demonstrated by TLC as trace compounds.
In contrast, structurally related oligomeric and polymeric proanthocyanidins occurred in exceptionally high
concentrations with the indicated flavanyl entities as
chain extender units. An illustrative structure of these
complex molecules is presented as depicted in formula
‘proanthocyanidin’.
Our systematic examination of root extracts has
revealed a remarkable series of highly oxygenated simple
coumarins as characteristic constituents of P. reniforme
(Lattè et al., 2000). Apart from the widely distributed
disubstituted scopoletin, all the coumarins possess triand tetrasubstituted oxygenation patterns on the aromatic nucleus, oxygenation patterns that are very rarely
found in the plant kingdom (Murray, 1997). Amongst
these notable structural variants, 6,7,8-trihydroxycoumarin and 8-hydroxy-5,6,7-trimethoxycoumarin represent novel metabolites of the above class of secondary
products. It should be noted that the natural occurrence
of the former coumarin has recently been demonstrated
in P. sidoides (Table 1 and Fig. 1).
The heterogeneity of metabolites in P. reniforme root
extracts was further demonstrated by the characterization of an unprecedented diterpen ester, linked to the
hydroxy group of p-hydroxyphenethansulfonic acid
which, in turn, presents an unusual natural acyl moiety
(unpublished). This unique metabolite, designated as
reniformin, was apparently accompanied by analogous
compounds. Low quantities and their decomposition
excluded the isolation and structural assessment of
additional fascinating analogues with a view to evaluate
their biological activities.
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H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17
Table 1.
11
Constituents of the root material of P. reniforme, P. sidoides and EPss 7630
P. reniforme
P. sidoides
EPss 7630
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Coumarin glycosides
Magnolioside
Isofraxoside
Umckalin-7-b-D-glucoside
+
+
+
+
Coumarin sulfates
5,6-Dimethoxycoumarin-7-sulfate
6,7-Dihydroxycoumarin-8-sulfate
6-Hydroxy-5,7-dimethoxycoumarin-8-sulfate
8-Hydroxy-5,7-dimethoxycoumarin-6-sulfate
+
+
+
+
Compound
Phenolic acids, phenylpropanoids and derivatives
Gallic acid
Gallic acid methyl ester
p-Hydroxybenzoic acid
Protocatechuic acid
Vanillic acid
Caffeic acid
Ferulic acid
p-Coumaric acid
p-Coumaraldehyde
Shikimic acid
Shikimic acid 3-O-gallate
Coumarins
6,7-Dioxygenation
7-Hydroxy-6-methoxycoumarin (Scopoletin)
5,6,7-Trioxygenation
7-Hydroxy-5,6-dimethoxycoumarin (Umckalin)
7-Acetoxy-5,6-dimethoxycoumarin
5,6,7-Trimethoxycoumarin
6-Hydroxy-5,7-dimethoxycoumarin (Fraxinol)
5,6-Dihydroxy-7-methoxycoumarin (Isofraxetin)
6,7,8-Trioxygenation
6,7,8-Trihydroxycoumarin
6,8-Dihydroxy-7-methoxycoumarin
8-Hydroxy-6,7-dimethoxycoumarin (Fraxidin)
7,8-Dihydroxy-6-methoxycoumarin (Fraxetin)
5,6,7,8-Tetraoxygenation
6,8-Dihydroxy-5,7-dimethoxycoumarin
5,6,7,8-Tetramethoxycoumarin (Artelin)
8-Hydroxy-5,6,7-trimethoxycoumarin
+
+
+
+
+
+
Flavonoids
Kaempferol-3-O-b-D-glucoside
Kaempferol-3-O-b-D-galactoside
Quercetin-3-O-b-D-glucoside
Myricetin-3-O-b-D-glucoside
+
+
+
+
Flavan-3-ols/Proanthocyanidins
Afzelechin
Catechin
Gallocatechin
Proanthocyanidins
+
+
+
+
Miscellaneous
Reniformin
b-Sitosterol
b-Sitosterol-3-O-b-D-glucoside
+
+
+
+
+
+
+
+
+
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H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17
In contrast to the roots, the aerial parts of P.
reniforme have not been the subject of chemical studies,
which may be attributed, at least in part, to less relevant
therapeutic uses. Benzoic and cinnamic acid derivatives,
flavonoids and tannins are the principal phenolic
substances found in the aerial parts of P. reniforme
(Table 2). That these plant parts again represented an
R1
H
OCH3
OCH3
OCH3
OCH3
OH
H
H
H
H
OCH3
OCH3
OCH3
H
H
OCH3
coumarin
Scopoletin
Umckalin
7-Acetoxy-5,6-dimethoxycoumarin
5,6,7-Trimethoxcoumarin
Fraxinol
Isofraxetin
6,7,8-Trihydroxycoumarin
6,8-Dihydroxy-7-methoxycoumarin
Fraxidin
Fraxetin
6,8-Dihydroxy-5,7-dimethoxycoumarin
Artelin
8-Hydroxy-5,6,7-trimethoxycoumarin
Magnolioside
Fraxetin-7-ß-D.glucoside
Umckalin-7-ß-D-glucoside
R4
R
3
8
7
R2
6
O
O
5
Rv1
attractive metabolic pool was demonstrated by the
isolation of a wealth of new and rarely found secondary
products. For example, the occurrence of glycerol-1gallate has hitherto been shown only in Mallotus
japonicus (Euphorbiaceae) (Saijo et al., 1990) and in a
Rheum species (Polygonaceae) (Nonaka and Nishioka,
1983), while that of (a,b)-3,4-di-O-galloylglucopyranoside
R2
OCH3
OCH3
OCH3
OCH3
OH
R3
OH
OH
OAc
OCH3
OCH3
OH
OCH3
OH
OH
OH
OCH3
OCH3 OCH3
OCH3 OH
OH
OCH3
OCH3 OCH3
OCH3 OCH3
OGlc OCH3
OCH3 OGlc
OCH3 OGlc
R4
H
H
H
H
H
H
OH
OH
OH
OH
OH
OCH3
OH
H
OH
H
HO
HO
HO
CH2OH
HO
O
O
RO
galloyl
CO
O
RO
O
HO
OH
HO
OH
glcerol-1-gallate
OH
O
HO
OH
(α,ß)-3,4-di-O-galloylglucoside
salidroside-6“-gallate
HOH2C
OH
HO
O
OH
O
O
O
O
HO OH
HO
OH
HO
HO
OH
C O
O C
H2 C
O-galloyl
HO
O C
H 2C
O-galloyl
O
OH
O
O
HO
C O
OH
OH
OH
O C
C O
O
H2 C
O-galloyl
O
O
O-galloyl
O
O
O
HO
O
HOC O C O
C O
HOOC
OH
HO
HO OH
O
HO C O C O
HO
HO
O
O
corilagin
HO OH
isostrictinin
(R = galloyl)
OH
C O
O
O
OH
HO
OH
HO
O
O
HO OH
C O
HO
OH
strictinin
(R = galloyl)
OH
HO
O
O C
OR
HO
OH
HO OH
O
H 2C
C O
O
phyllanthusiin E (R = H)
methyl ester ( R = CH3)
OH
O C
O
HO
HO
O
brevifolin
carboxylic acid
HO
OH
O
C-O-CH2
HO
ROOC
OR
O
HO
HOOC
O
HO
HO
HO
OH
HO
OH
O OH
OH
O
phyllanthusiin C
pelargoniin A
Fig. 1.
O
OH
OH
OH
pelargoniin E
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H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17
CH2OH
OH
CH2OH
O-galloyl
O
O
C O C O
O C
OH
OH
OH
HO
O
HO
OH
HOOC
OHC
HO
O
O
HO
O
HO C O C O
HOOC
O-galloyl
O
O
O
O
CH2OH
OH
O-galloyl
OH
O
13
OH
OH
O
O
pelargoniin B
pelargoniin C
pelargoniin D
H
H3CO
CH3
OH
C
OGlc
HO
H
OCH3
O
OGlc
HO
OH
OH
cyclolariciresinol2a-ß-D-glucoside
4,6-dihydroxyacetophenone2-O-ß-D-glucoside
OH
OH
HO
HO
O
R
HO
OH
R
OH
HO
HO
HO
HO
O
R
O
galloyl-O
HO
OH
OH
OH
HO
O
O
R
OH
O
galloyl-O
OH
OH
OH
OH
O
OH
OH
HO
O
n
OH
O
R
OH
OH
2“-O-galloyl-isovitexin (R = H)
2”-O-galloyl-isoorientin (R = OH)
2“-O-galloyl-vitexin (R=H)
2”-O-galloyl-orientin (R = OH)
HOH2C
CH3
proanthocyanidin
(R=H or OH)
CH3
O
O
SO3H
reniformin
Fig. 1. (Continued)
is confined to Macaranga tamarius (Euphorbiaceae) (Lin
et al., 1990) and that of salidroside-600 -gallate to Quercus
phillyraeoides (Fagaceae) (Nonaka et al., 1989) and
Q. stenophylla (Nonaka et al., 1982). On the other hand,
gallic acid butyl ester represents a new natural product
(Lattè, 1999). This species thus provided a remarkable
broad range of O-galloylated compounds. As regards
flavonoids, the extracts afforded a complex mixture of
flavonols, flavanones, dihydroflavonols and flavones.
Noteworthy is the presence of a unique series of 200 -Ogalloyl derivatives of orientin, isoorientin, vitexin and
isovetixin, respectively, representing the first described
ARTICLE IN PRESS
14
Table 2.
sidoides
H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17
Constituents of the aerial parts of P. reniforme, P.
Compound
P. reniforme
Phenolic acids, phenylpropanoids and derivatives
Gallic acid
+
Gallic acid methyl ester
+
Gallic acid ethyl ester
+
Gallic acid butyl ester
+
Shikimic acid 3-O-gallate
+
Shikimic acid 3,5-di-O-gallate
+
p-Hydroxyphenylethanol
+
p-Hydroxyphenyl acetic acid
+
p-Hydroxybenzyl alcohol
+
Protocatechuic acid
p-Coumaric acid
+
p-Coumaroyl-4-O-b-D-glucoside +
Glycerol-1-gallate
+
Glucogallin
+
(a,b)-3,4-Di-O+
galloylglucopyranoside
Salidroside-600 -O-gallate
+
Coumarins
Scopoletin
Umckalin
6,8-Dihydroxy-5,7dimethoxycoumarin
Fraxetin
Fraxetin-7-b-D-glucoside
Magnolioside
6,7-Dihydroxycoumarin-8sulfate
Flavonoids
Kaempferol 7-O-b-D-glucoside
Kaempferol 3-O-b-D-rutinoside
Quercetin
Quercetin 3-O-b-D-rutinoside
Quercetin 7-O-b-D-glucoside
Dihydrokaempferol
Dihydrokaempferol 3-O-b-Dglucoside
Dihydroquercetin (Taxifolin)
Taxifolin-7-O-b-D-glucoside
Taxifolin-3-O-b-D-glucoside
Naringenin 7-O-b-D-glucoside
Luteolin 7-O-b-D-glucoside
Vitexin
Vitexin 200 -O-gallate
Orientin
Orientin 200 -O-gallate
Isovitexin
Isovitexin 200 -O-gallate
Isoorientin
Isoorientin 200 -O-gallate
Epigallocatechin-3-O-gallate
Hydrolysable tannins
Brevifolin carboxyclic acid
Phyllantusiin E
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Compound
P. reniforme
Phyllantusiin E O-methyl ester
Strictinin
Isostrictinin
Corilagin
Isocorilagin
Phyllantusiin C
Pelargoniin A
Pelargoniin B
Pelargoniin C
Pelargoniin D
Pelargoniin E
+
+
+
+
+
+
+
+
+
+
+
P. sidoides
P. sidoides
+
+
+
+
+
Table 2. (continued )
+
+
+
+
+
+
+
+
+
+
Miscellaneous
(+)-Cyclolariciresinol-2a-b-Dglucoside
4,6-Dihydroxyacetophenone 2O-b-D-glucoside
4-Allyl-2,5-dimethoxyphenol-1b-D-glucoside
+
+
+
O-galloyl derivatives of C-glucosylflavones (Latté et al.,
2002).
Proanthocyanidins were associated with ellagitannins,
which were conspicuously absent from the root material.
Identified members of the ellagitannins included strictinin and isostrictinin, composed of a central glucose core,
adopting the 4C1 conformation, a b-linked galloyl group
at C-1 and a hexahydroydiphenoic (HHDP) moiety,
formed by oxidative C–C coupling of two adjacent
galloyl groups (Fig. 1).
Noteworthy was the co-occurrence of a series of
structural variants, similarly based on a 1-O-galloyl-b-Dglucopyranose precursor which itself adopts the less
favourable 1C4 conformation. However, the galloyl ester
groups at C-3 and C-6 are ideally aligned in an axial
position for the feasible coupling in this energetically
unfavourable chair conformation. These metabolites
included corilagin, its unique a-isomer and a series of
corilagin-based ellagitannins such as the rarely found
phyllantusiin C (Yoshida et al., 1992b; Liu et al., 1999;
Amakura et al., 1999) and five structurally related
unique ellagitannins, designated as pelargoniins A–D
(Latté and Kolodziej, 2000) including the recently
identified pelargoniin E (unpublished). A remarkable
common structural feature of these analogues is the
presence of an oxidized DHHDP entity, bridging the
2,3-position. From their close structural relationship to
geraniin, a biogenetic relationship may be postulated,
though geraniin itself appears to be conspicuously
absent from members of the genus Pelargonium.
Generally oxidative coupling of galloyl ester groups
via the 4C1 form of the glucopyranose precursor is much
more widely encountered in plants than that via the
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H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17
alternative 1C4 conformation (Haslam, 1998). This is the
first example of the co-occurrence of ellagitannins with
4
C1 and 1C4 glucose cores demonstrated for plants
belonging to Geraniaceae. Up to now, only a few plants
of the Euphorbiaceae (Saijo et al., 1989a, b), Melastomataceae (Yoshida et al., 1992a) and Onagraceae
(Haddock et al., 1982) have been shown to contain
both forms of metabolites.
Our detailed chemical study on P. reniforme has also
led to the isolation of two structurally closely related
lignan glucosides, (+)-isolariciresinol-2a-b-glucopyranoside and an isomer of undefined stereochemistry
due to limited sample quantity, the first members of
this group of secondary products to be reported for the
Geraniaceae (Lattè, 1999). Noteworthy is also the
detection of 4,6-dihydroxyacetophenone 2-O-b-D-glucopyranoside in that acetophenones being reported to
occur only in a limited number of plant families (Singh
et al., 1997).
Pelargonium sidoides DC
In its unadulterated form, this species can readily be
distinguished by the cordate shape of the leaves and the
dark red, but commonly almost black flowers borne on
long, slender stalks (Van der Walt and Vorster, 1988).
P. sidoides is predominantly found over large parts of
the interior of southern Africa, but also occurs in coastal
mountain ranges (Van der Walt and Vorster, 1983,
1988).
Compositional studies of the roots of P. sidoides
provided a similar picture of a broad metabolic
profile as found in P. reniforme, reflecting a close
botanical relationship between these two species. Again,
proanthocyanidins were present in significant amounts.
Here, the putative precursors afzelechin, catechin and
gallocatechin could be successfully isolated.
In addition, the root extract of P. sidoides also
contained a wealth of highly oxygenated simple
coumarins, unique in its composition (Table 2 and
Fig. 1). For example, 6,8-dihydroxy-5,7-dimethoxycoumarin and 7-acetoxy-5,6-dimethoxycoumarin represent
new natural products; the latter being the first natural
compound known hitherto within this group possessing
an acetoxy function (Kayser and Kolodziej, 1995). As
for the exclusive 7-hydroxy-5,6-dimethoxycoumarin
(umckalin) and 5,6,7-trimethoxycoumarin, earlier work
has documented their natural occurrence by their
isolation from P. reniforme (Wagner and Bladt, 1974,
1975), which, however, is subject to taxonomic ambiguity. Noteworthy is also the characterization of three
novel coumarin sulphates, obtained from polar fractions
(Lattè et al., 2000). This group of analogues has hitherto
been restricted to three examples reported from a single
plant source, Seseli libanotis (Apiaceae) (Lemmich and
15
Shabana, 1984). In this context it should be noted that
6-hydroxy-5,7-dimethoxycoumarin-8-sulfate and 8-hydroxy-5,7-dimethoxycoumarin-6-sulfate could only be
obtained as an inseparable mixture despite extensive
chromatographic efforts. Their identification not only
extends the unique series of naturally occurring coumarin sulphates but also introduces the first analogues
in which sulfation occurred at a phenolic function.
Extensive chromatographic efforts have additionally
yielded three coumarin glycosides in traces.
In the aerial parts, proanthocyanidins were again
associated with members of hydrolysable tannins, as
evidenced by the identification of brevifolincarboxyclic
acid and corilagin. Additional notes concern the very
limited occurrence of coumarins, in contrast to the
abundance in the roots, the distinct presence of
C-glycosyl flavones including members of the exclusive
series of 200 -O-galloyl analogues (vide supra) and
the new metabolite, 4-allyl-2,5-dimethoxyphenol 1-b-Dglucoside (Gödecke, 2005). The identification of
6,7-dihydroxycoumarin-8-sulfate not only extends the
range of unique natural coumarin sulphates, but also
introduces the first member found in the aerial parts
(Gödecke et al., 2005).
EPss 7630
Following the well-documented therapeutic benefits
in infectious conditions of the respiratory tract, a
proprietary extract of the roots of P. sidoides, EPss
7630 (exclusively contained in Umckaloabos, marketed
by Spitzner Arzneimittel, Ettlingen, Germany), has been
developed from this traditional herbal medicine and
introduced into modern phytotherapy in Europe, in the
Commonwealth of Independent States, in Baltic states
and in Mexico. EPss 7630 is a special aqueous ethanolic
(11% m/m) extract of P. sidoides. Naturally enough,
conditions of the extraction procedure have a significant
impact on the chemical composition of the final product.
Therefore, our fundamental structural studies on the
titled Pelargonium species were recently extended to this
medicinal product. The identified coumarin pattern is
strongly reminiscent of that of P. sidoides (Table 1).
Also, the limited range of phenolic acids, as evident
from our current data, supports this note. In addition, a
considerable proportion of high molecular weight
proanthocyanidins was found to occur in EPss 7630.
No detailed chemistry has yet been carried out on these
polyphenols, their characterization being limited to the
production of cyanidin and delphinidin upon treatment
with acid. On this basis, (epi)catechin and (epi)gallocatechin were shown to be the chain extender units, while
the sequence of constituent units, the mode of interflavanyl bondings and the stereochemistry remain to be
defined.
ARTICLE IN PRESS
16
H. Kolodziej / Phytomedicine 14 (2007) SVI 9–17
Conclusion
Initially, P. reniforme has been suggested to form the
plant source of a South African originating herbal
medicine for the treatment of respiratory diseases such
as tuberculosis (Bladt, 1974), but, according to present
evidence, erroneous identification of the plant material
claimed to be P. reniforme is evident. For example,
the coumarin pattern and here the striking presence
of 7-hydroxy-5,6-dimethoxycoumarin (umckalin), typical of P. sidoides, in the previous paper on alleged
P. reniforme conflicts with current information (vide
supra). Independent support for this conjecture is also
provided by the geographical origin of the former plant
material, i.e. Grahamstown, an area where P. reniforme
ssp. velutinum commonly occurs. Thus, it would be of
great interest to extend phytochemical studies to this
subspecies.
Notably, the roots of P. reniforme and P. sidoides
express conspicuously distinct coumarin variations,
although they contained similarly highly oxygenated
simple coumarins based on tri- and tetraoxygenated
substitution patterns. Of the identified coumarins,
the two species share the ubiquitous scopoletin, the
unique analogues 6,7,8-trihydroxycoumarin and 8-hydroxy-5,6,7-trimethoxycoumarin only that may therefore serve as useful chemical markers. Although the
coumarin pools encountered in the two Pelargonium
species were very similar, a distinguishing feature
appeared to be the presence of a 5,6-dimethoxy
arrangement within the group of 5,6,7-trioxygenated
members of P. sidoides and an unsubstituted 6-hydroxyl
function in that of P. reniforme. Another discriminating
chemical character was the distinct occurrence of
coumarin sulphates and glucosides in P. sidoides. The
concurrent presence of the unique umckalin in both
root and aerial parts of P. sidoides may facilitate the
identification of this species without harvesting roots.
With the exception of the characteristic umckalin and
6,7,8-trihydroxycoumarin in the respective species, the
remaining coumarins are only present in relatively small
amounts.
The occurrence of tannins may explain the traditional
use of the aerial parts as wound healing agent, which
may be attributed, at least in part, to their astringent
action. A similar rationale explanation based on the
presence of tannins may be provided for the treatment
of gastrointestinal disorders such as diarrhoea in
traditional medicine. Owing to the high degree of
polymerization of proanthocyanidins present in appreciable concentrations, absorption of these tannins from
the digestive tract with an intact mucosa is highly
unlikely, thereby acting as an effective astringent. For
example, the hitherto assumed precipitation of proteins
in the epithelial surface of the gut should form a
protective layer along the intestinal lumen. Also, some
of the beneficial antisecretory effects which tannins exert
in these conditions may well follow from their interaction with toxins produced by pathogenic bacteria in the
intestine (Hör et al., 1995). Besides, owing to the various
reported biological activities of proanthocyanidins
(Haslam, 1996, 1998) and their possible impact on the
efficacy of EPss 7630, these are the subject of current
studies.
Coumarins and phenolic compounds including simple
phenolic acids and proanthocyanidins are the principal
compounds found in the special extract, EPss 7630.
Although compositional studies are still in progress, the
present data clearly point to a kind of selective
extraction, as evident from some ‘missing’ and lowyield occurring substances in this phytotherapeutical
product. For example, gallic acid was consistently
obtained in fairly high concentrations when the plant
material was extracted under more rigorous conditions,
whereas it occurred in low amounts in EPss 7630. While
the Pelargonium species under study represented attractive sources for a wealth of unusual metabolites, the
efficacy of EPss 7630 entails a particularly fascinating
account, involving the identification of biologically
active substances contributing to the hitherto poorly
defined underlying active principle.
Acknowledgements
Sincere appreciation is expressed to Drs. O. Kayser,
K.P. Latté, T. Gödecke and M. Kaloga (FU Berlin)
for the diligent efforts in this research programme.
The plant material was kindly provided by the
pharmaceutical company Dr. Willmar Schwabe, Karlsruhe, Germany.
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