PHARMACOLOGICALLY ACTIVE TANNINS ISOLATED FROM MEDICINAL PLANTS Takuo Okuda, Takashi Yoshida, and Tsutomu Hatano Faculty of Pharmaceutical Sciences Okayama University Tsushima, Okayama 700 Japan
ABSTRACT Starting with the isolation of a crystalline tannin (geraniin) of mild property from a popular herb medicine (Geranii herba), various polyphenolic compounds including those belonging to new classes of tannins (oligomeric hydrolyzable tannins, complex tannins, and other metabolites and condensates) have been isolated from various medicinal plants. Noticeable biological and pharmacological activities (inhibition of carcinogenesis, host-mediated antitumor activity, antiviral activity, and inhibition of active oxygen, such as inhibition of lipid peroxidation and lipoxygenase, xanthine oxidase, and monoamine oxidase) have been found for several of these polyphenolic compounds.
INTRODUCTION The first tannin isolated in our tannin research was a crystalline compound, geraniin (1).1,2 It forms yellow crystals that look like a flavonoid and has almost no astringent taste. 3 This taste may conflict with the general concept of tannin, but it is no surprise to anybody who has tasted an infusion of the geraniin-rich, Geranium thunbergii (more than 10 percent in the dried leaf).4 In spite ofthe large quantity of total tannin (about 20 percent in the dried herb collected in summer 5 ), the boiling-water extract of this herb, appropriately prepared so that no extensive decomposition of geraniin 6 occurs, has almost no astringent taste and is in accord with the property of geraniin. This herb is one of the most popular herb medicines in Japan, taken by enormous numbers of people for hundreds of years and is also Plant Polyphenois, Edited by R.W. Hemingway
and P.E. Laks, Plenum Press, New York, 1992
539
540
Okuda
listed in the Japanese Pharmacopoeia. It has been used mainly as antidiarrheic and also for controlling intestinal function without encountering any notable toxicity. This property of geraniin differs from that of commercially available tannic acid, which has a strongly irritating and astringent taste, characteristics that make free tannic acid inadequate for oral administration because of the anorexia and indigestion often induced by this gallotannin mixture. This discovery of a mild tannin from a very popular medicinal plant prompted us to investigate the tannin constituents in various 'tannin-rich' medicinal plants widely used in Japan and other Asian countries. There was also a large number of traditional medicines in which the main components have been regarded as tannin without detailed chemical investigation. Our tannin research thus started, applying new analytical methods 7 has revealed the distribution of numerous polyphenolic compounds of different chemical structures contained in hundreds of species of medicinal plants. Several new classes of tannin, such as oligomeric hydrolyzable tannins including those having macroring structure,s complex tannins,9 the condensate with ascorbic acid,lo caffeic acid tetramer,l1 and highly galloylated proanthocyanidins12 have also been isolated. Marked biological and pharmacological activities of such isolated tannins, which are different in activity and strength, depending on the structure of each compound, have also been found. 13 ,14 The structural features of these new classes ofpolyphenolic compounds and some of their biological and pharmacological activities are summarized in this paper. OLIGOMERIC HYDROLYZABLE TANNINS After the isolation of agrimoniin (2), the first dimeric hydrolyzable tannin, from Agrimonia pilosa,15 over 100 oligomers, up to tetramers, have since been isolated.
These oligomeric hydrolyzable tannins are biogenetically regarded as the products of intermolecular C-O oxidative coupling between two or more monomeric hydrolyzable tannins. 7 ,s,16 They can be classified in three ways:s (1) Structure of the constituent monomer, (2) extent of condensation among monomers, and (3) structure of the linking unit formed between two smaller hydrolyzable tannin molecules. The classification based on the third criterion follows. Classification of Oligomers According to the Type of Linking Unit The linking unit in the oligomeric hydrolyzable tannins hitherto characterized can be classified basically into four types as shown in figure 1: (1) Dehydrodigalloyl (DHDG) (bisgalloyl) group (Type 1), (2) valoneoyl (trisgalloyl) group (Type 2), (3) sanguisorboyl (trisgalloyl) group (Type 3), and doubly C-O coupled polyphenol (tris- or tetrakisgalloyl) group (Type 4). Oligomers of type 1. Agrimoniin (2) is a dimer of Type 1 in which two moles of potentillin (monomer) are linked through a dehydrodigaUoyl (DHDG) group, which is biogenetically regarded as the product of the C-O oxidative coupling between a-oriented gaUoyl groups at the anomeric centers of monomers. 15 Its
Pharmacologically Active Tannins
541
-Q---P-
HO HO HO
OH OH OH
co co
c6 /
/±1
H2
o \
o
0- G
0
I
co
COH
~ HO"
HO'-
OH G .. -COQOH OH
OH
OH
OH
o
1 OH HO HO
I
~
HO
-0-
HO
co -OCH2
o
CO"O
HO
\O~O
HO OH HO
06
-Q-bOC
f_
HOHO
o-OC \....(;..,OH \
-
OH OH HO
OHOH
OH
CO-O
I
P
-Q-bOC
-
HO HO
OH
0
'co
I OH
OC
OH OH OH
OH OH
2
congeners lacking one or two hexahydroxydiphenoyl groups [laevigatins B (3), C (4), and E (5)-G (7)], besides (2), were isolated from Rosa laevigata. 17,18 Gemins A (8) - C (10) frornGeum japonicum,19 and coriariins A (11) and C (12) from Coriaria japonica,20,21 also belong to Type 1. The configurations at the anomeric centers of the two glucose residues in gemins are a and (3, whereas, those in coriariins are both (3. Among these dimers, agrirnoniin (2) is the main tannin in several other Rosaceous plants such as Potentilla kleiniana,15 P. erecta,22 and Rosa davurica. 23 Gemin A (8), characteristic of Geum species, and agrimoniin (2), distributed mainly in Agrimonia, Rosa, Potentilla, and Duchesnea species, can be taxonomical markers. 24 Davuriciin Tl (13),23 obtained from the root of Rosa davurica, has a DHDG group and a valoneoyl group as the linking units and is the only example to date of a trimer possessing the agrimoniin (2) core. Very recently, this type of dimer, hirtellins A (14)25 and C (15),26 have been found in the Tamaricaceous plants (Reaumuria hirtella and Tamarix pakistanica), which are taxonomically far apart from the Rosaceae and Coriariaceae. In the hirtellins, the two ester linkages on the DHDG group are at 0-1 of one monomer and 0-2 of another monomer, unlike the previously mentioned dimers. Hirtellin C
Okuda
542
Type 1 OH [Monomer +-CO-QOH
-bo
a(R.H) HO
OH
-f
oc
Monomer
I
HO
dehydrodigalloyl (OHOG) Type 2
HO AOH [Monomer +- oc -YOH
Monomer
[
o
~o-~
-O}-O, -0
0-
1
oc
a(R=GA)
OH CO-QOH
HO-d~a HOHO
-
(OH OH
)b
f
HO%' HO co Monomer] HO 1f? I Co-t HO HO
valoneoyl
-0
0' [J}-o,]
Type 3
HOy-C01-~o-
AOH
[Monomer +-
Monomer
RzH or :¢-co-
oc ~
HogHO0
b(R=GA)
HO HO
HO
(GA)
I
1f?
f
CO Monomer] Co-t
HO HO
sanguisorboyl Type 4 OH [Monomer +- COD-OH ale (R= GA)
I
OC
)--{OH
0HOOHOH
HO-o-O~OH HO HO
OC I
OC I
[ Monomer
I
doubly C-O coupled linking unit (e,g., euphorbinoyl) Figure 1. Classification according to the type of linking unit/coupling mode.
543
Pharmacologically Active Tannins
R' {
_ ...
a) '>=i co-oja 00~0\. Va~CH20-} OCH 2
Hh HO
0
~
oc od
-Q
HO -
O-OC
.r\~
~
HO
OH
3 4 5 6 7
0~0_
OH \
OH
HO~OH HO
0
R3
0
~ If
OH
(S)-HHDP =
Ff
R'
Ff
H,H (S)-HHDP (S)-HHDP (S)-HHDP H,H (S)-HHDP H,H (S)-HHDP H,H H,H
do do
HOQ--trOH
(S)-HHDP H,H H,H (S)-HHDP (S)-HHDP
HO HO
OH OH
COOH
GA=
-Q-OH OH OH
a
HO
~
HO-Q-CO-Oj
-Q "'IO~O-OC
R' { -
OCH2
\
HO
o~~) ~
G
k'O~CH~-} R2
0
o~o_
P
OH \
OH;t0~ HO~OH HO HO
8 9 10
~ OCH2 )
co
HO OH
R
~
HO
HO
OH
(S)-HHDP (S)-HHDP H,H (S)-HHDP (S)-HHDP H,H
OH
HO
OH
HO
I
)
HOQCO _ 'O~H~CO 0t;;J HO 0,0 0 co' 0 G 0 'co o 'oc OH I 0 ~ G OH I G
cf
-Q
11:R=H 12: R=GA
0 OH OH OH OH
544
Okuda
OH
HO~
HO
I
HO HO
co -OCH2 CO ....
I
OH OH
O~~
OCO-QOH
HO~ ~O
OH
I
:
HD'hco_o~ ~OH '>=r OH
hl
CO-OCH, CO ....
I
HO
O
0
HO
o
-
~- O H
HO HO
co
P
OHQ-trOC OC
Q--O-0C OC HO
CHPCO 0
0
HO
OH OH
~- O H
_" HO HO
OH
OH
~OH
HO~ O~ -0O~CHP'cO' I
OH
.&"
CO- OCH2
0 .... G
G
G
\
0-
OH I CO.&" OH
I
co .... 0 0 \ lOCO
HO
HO .... OH
,
ABSTRACT Starting with the isolation of a crystalline tannin (geraniin) of mild property from a popular herb medicine (Geranii herba), various polyphenolic compounds including those belonging to new classes of tannins (oligomeric hydrolyzable tannins, complex tannins, and other metabolites and condensates) have been isolated from various medicinal plants. Noticeable biological and pharmacological activities (inhibition of carcinogenesis, host-mediated antitumor activity, antiviral activity, and inhibition of active oxygen, such as inhibition of lipid peroxidation and lipoxygenase, xanthine oxidase, and monoamine oxidase) have been found for several of these polyphenolic compounds.
INTRODUCTION The first tannin isolated in our tannin research was a crystalline compound, geraniin (1).1,2 It forms yellow crystals that look like a flavonoid and has almost no astringent taste. 3 This taste may conflict with the general concept of tannin, but it is no surprise to anybody who has tasted an infusion of the geraniin-rich, Geranium thunbergii (more than 10 percent in the dried leaf).4 In spite ofthe large quantity of total tannin (about 20 percent in the dried herb collected in summer 5 ), the boiling-water extract of this herb, appropriately prepared so that no extensive decomposition of geraniin 6 occurs, has almost no astringent taste and is in accord with the property of geraniin. This herb is one of the most popular herb medicines in Japan, taken by enormous numbers of people for hundreds of years and is also Plant Polyphenois, Edited by R.W. Hemingway
and P.E. Laks, Plenum Press, New York, 1992
539
540
Okuda
listed in the Japanese Pharmacopoeia. It has been used mainly as antidiarrheic and also for controlling intestinal function without encountering any notable toxicity. This property of geraniin differs from that of commercially available tannic acid, which has a strongly irritating and astringent taste, characteristics that make free tannic acid inadequate for oral administration because of the anorexia and indigestion often induced by this gallotannin mixture. This discovery of a mild tannin from a very popular medicinal plant prompted us to investigate the tannin constituents in various 'tannin-rich' medicinal plants widely used in Japan and other Asian countries. There was also a large number of traditional medicines in which the main components have been regarded as tannin without detailed chemical investigation. Our tannin research thus started, applying new analytical methods 7 has revealed the distribution of numerous polyphenolic compounds of different chemical structures contained in hundreds of species of medicinal plants. Several new classes of tannin, such as oligomeric hydrolyzable tannins including those having macroring structure,s complex tannins,9 the condensate with ascorbic acid,lo caffeic acid tetramer,l1 and highly galloylated proanthocyanidins12 have also been isolated. Marked biological and pharmacological activities of such isolated tannins, which are different in activity and strength, depending on the structure of each compound, have also been found. 13 ,14 The structural features of these new classes ofpolyphenolic compounds and some of their biological and pharmacological activities are summarized in this paper. OLIGOMERIC HYDROLYZABLE TANNINS After the isolation of agrimoniin (2), the first dimeric hydrolyzable tannin, from Agrimonia pilosa,15 over 100 oligomers, up to tetramers, have since been isolated.
These oligomeric hydrolyzable tannins are biogenetically regarded as the products of intermolecular C-O oxidative coupling between two or more monomeric hydrolyzable tannins. 7 ,s,16 They can be classified in three ways:s (1) Structure of the constituent monomer, (2) extent of condensation among monomers, and (3) structure of the linking unit formed between two smaller hydrolyzable tannin molecules. The classification based on the third criterion follows. Classification of Oligomers According to the Type of Linking Unit The linking unit in the oligomeric hydrolyzable tannins hitherto characterized can be classified basically into four types as shown in figure 1: (1) Dehydrodigalloyl (DHDG) (bisgalloyl) group (Type 1), (2) valoneoyl (trisgalloyl) group (Type 2), (3) sanguisorboyl (trisgalloyl) group (Type 3), and doubly C-O coupled polyphenol (tris- or tetrakisgalloyl) group (Type 4). Oligomers of type 1. Agrimoniin (2) is a dimer of Type 1 in which two moles of potentillin (monomer) are linked through a dehydrodigaUoyl (DHDG) group, which is biogenetically regarded as the product of the C-O oxidative coupling between a-oriented gaUoyl groups at the anomeric centers of monomers. 15 Its
Pharmacologically Active Tannins
541
-Q---P-
HO HO HO
OH OH OH
co co
c6 /
/±1
H2
o \
o
0- G
0
I
co
COH
~ HO"
HO'-
OH G .. -COQOH OH
OH
OH
OH
o
1 OH HO HO
I
~
HO
-0-
HO
co -OCH2
o
CO"O
HO
\O~O
HO OH HO
06
-Q-bOC
f_
HOHO
o-OC \....(;..,OH \
-
OH OH HO
OHOH
OH
CO-O
I
P
-Q-bOC
-
HO HO
OH
0
'co
I OH
OC
OH OH OH
OH OH
2
congeners lacking one or two hexahydroxydiphenoyl groups [laevigatins B (3), C (4), and E (5)-G (7)], besides (2), were isolated from Rosa laevigata. 17,18 Gemins A (8) - C (10) frornGeum japonicum,19 and coriariins A (11) and C (12) from Coriaria japonica,20,21 also belong to Type 1. The configurations at the anomeric centers of the two glucose residues in gemins are a and (3, whereas, those in coriariins are both (3. Among these dimers, agrirnoniin (2) is the main tannin in several other Rosaceous plants such as Potentilla kleiniana,15 P. erecta,22 and Rosa davurica. 23 Gemin A (8), characteristic of Geum species, and agrimoniin (2), distributed mainly in Agrimonia, Rosa, Potentilla, and Duchesnea species, can be taxonomical markers. 24 Davuriciin Tl (13),23 obtained from the root of Rosa davurica, has a DHDG group and a valoneoyl group as the linking units and is the only example to date of a trimer possessing the agrimoniin (2) core. Very recently, this type of dimer, hirtellins A (14)25 and C (15),26 have been found in the Tamaricaceous plants (Reaumuria hirtella and Tamarix pakistanica), which are taxonomically far apart from the Rosaceae and Coriariaceae. In the hirtellins, the two ester linkages on the DHDG group are at 0-1 of one monomer and 0-2 of another monomer, unlike the previously mentioned dimers. Hirtellin C
Okuda
542
Type 1 OH [Monomer +-CO-QOH
-bo
a(R.H) HO
OH
-f
oc
Monomer
I
HO
dehydrodigalloyl (OHOG) Type 2
HO AOH [Monomer +- oc -YOH
Monomer
[
o
~o-~
-O}-O, -0
0-
1
oc
a(R=GA)
OH CO-QOH
HO-d~a HOHO
-
(OH OH
)b
f
HO%' HO co Monomer] HO 1f? I Co-t HO HO
valoneoyl
-0
0' [J}-o,]
Type 3
HOy-C01-~o-
AOH
[Monomer +-
Monomer
RzH or :¢-co-
oc ~
HogHO0
b(R=GA)
HO HO
HO
(GA)
I
1f?
f
CO Monomer] Co-t
HO HO
sanguisorboyl Type 4 OH [Monomer +- COD-OH ale (R= GA)
I
OC
)--{OH
0HOOHOH
HO-o-O~OH HO HO
OC I
OC I
[ Monomer
I
doubly C-O coupled linking unit (e,g., euphorbinoyl) Figure 1. Classification according to the type of linking unit/coupling mode.
543
Pharmacologically Active Tannins
R' {
_ ...
a) '>=i co-oja 00~0\. Va~CH20-} OCH 2
Hh HO
0
~
oc od
-Q
HO -
O-OC
.r\~
~
HO
OH
3 4 5 6 7
0~0_
OH \
OH
HO~OH HO
0
R3
0
~ If
OH
(S)-HHDP =
Ff
R'
Ff
H,H (S)-HHDP (S)-HHDP (S)-HHDP H,H (S)-HHDP H,H (S)-HHDP H,H H,H
do do
HOQ--trOH
(S)-HHDP H,H H,H (S)-HHDP (S)-HHDP
HO HO
OH OH
COOH
GA=
-Q-OH OH OH
a
HO
~
HO-Q-CO-Oj
-Q "'IO~O-OC
R' { -
OCH2
\
HO
o~~) ~
G
k'O~CH~-} R2
0
o~o_
P
OH \
OH;t0~ HO~OH HO HO
8 9 10
~ OCH2 )
co
HO OH
R
~
HO
HO
OH
(S)-HHDP (S)-HHDP H,H (S)-HHDP (S)-HHDP H,H
OH
HO
OH
HO
I
)
HOQCO _ 'O~H~CO 0t;;J HO 0,0 0 co' 0 G 0 'co o 'oc OH I 0 ~ G OH I G
cf
-Q
11:R=H 12: R=GA
0 OH OH OH OH
544
Okuda
OH
HO~
HO
I
HO HO
co -OCH2 CO ....
I
OH OH
O~~
OCO-QOH
HO~ ~O
OH
I
:
HD'hco_o~ ~OH '>=r OH
hl
CO-OCH, CO ....
I
HO
O
0
HO
o
-
~- O H
HO HO
co
P
OHQ-trOC OC
Q--O-0C OC HO
CHPCO 0
0
HO
OH OH
~- O H
_" HO HO
OH
OH
~OH
HO~ O~ -0O~CHP'cO' I
OH
.&"
CO- OCH2
0 .... G
G
G
\
0-
OH I CO.&" OH
I
co .... 0 0 \ lOCO
HO
HO .... OH
,
