Pharmaceutical Biology

ISSN: 1388-0209 (Print) 1744-5116 (Online) Journal homepage: https://www.tandfonline.com/loi/iphb20

Biologically Active Substances from the Genus

Scrophularia

J. de Santos Galíndez, A.M.a Díaz Lanza & L. Fernández Matellano

To cite this article: J. de Santos Galíndez, A.M.a Díaz Lanza & L. Fernández Matellano (2002)
Biologically Active Substances from the Genus Scrophularia, Pharmaceutical Biology, 40:1, 45-59,
DOI: 10.1076/phbi.40.1.45.5864

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Published online: 29 Sep 2008.

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2002, Vol. 40, No. 1, pp. 45–59 © Swets & Zeitlinger

Review

Biologically Active Substances from the Genus Scrophularia

J. de Santos Galíndez, A.M.a Díaz Lanza and L. Fernández Matellano

Department of Pharmacology, Faculty of Pharmacy, University of Alcalá, Alcalá de Henares, Madrid, Spain

Abstract phenolic acids, flavonoids and saponins. Some of these

compounds were shown to have antiinflammatory, antibacte-
Scrophularia species have been used since ancient times as rial, hepatoprotective, immuno-modulator, cardiovascular,
folk remedies for some medical treatments including scro- diuretic, protozoocidal, fungicidal, molluscicidal, cytotoxic,
phula, scabies, tumours and inflammatory affections. Some cytostatic, antitumour activities (Ghisalberti, 1998; Bermejo
compounds isolated from these species, such as iridoids Benito et al., 1998; Emam et al., 1997; Nishibe, 1994;
and phenylpropanoids, are considered responsibles for these Lacaille-Dubois & Wagner, 1996).
activities. This review summarizes mainly the biological A survey of the presently available chemical and biolog-
activity associated with this genus. ical data suggests that the iridoid glycosides are the main
classes of substances of interest to pharmacologists, and it
Keywords: Biologically active substances, iridoids, phenyl- was suggested that the therapeutic action of these plants
propanoids, Scrophularia, Scrophulariaceae. depends on the presence of iridoids (Ghisalberti, 1998). A
number of reports have been published which demonstrate
that iridoids possess a number of biological properties, such
Introduction as choleretic, vasoconstrictor, hepatoprotective, antiviral and
The genus Scrophularia, consisting of about 300 species, is antimicrobial activities, and these compounds could act syn-
one of the most important genera belonging to the Scrophu- ergically with other active substances (Tables 1 and 2).
lariaceae. Many species belonging to this genus have been
used since ancient times as folk remedies for some medical Antiinflammation
treatments (scrophulas, scabies, tumours, eczema, psoriasis,
inflammatory affections, etc.) (Heather & Henderson, 1994; Most species belonging to the Scrophularia genus have been
Paris & Moyse, 1976). One species, Scrophularia ningpoen- used as antiinflammatory drugs by folk medicine. Iridoids
sis (officially indexed drug in the Chinese Pharmacopoeia), and phenylpropanoids are considered to be the active princi-
is even cultivated as a medicinal plant in China. It has been ples of these drugs (García et al., 1996; Fernández et al.,
used for the treatment of fever, swelling, constipation, 1998).
pharyngitis, neuritis, and laryngitis in traditional Chinese The roots of Scrophularia ningpoensis have been used for
medicine (Miyazawa et al., 1998). S. grossheimi and S. the treatment of inflammation in Chinese traditional medi-
nodosa have been used as diuretic plants in traditional med- cine (Kajimoto et al., 1989). This plant has also been pre-
icine (Akhmedov et al., 1969; Schaunbenger & Paris, 1977) scribed as an antipyretic and antiiflammatory in diseases
and S. oldhamii has been used as an antipyretic and for the causing heat or fever, dry cough and pulmonary tuberculo-
treatment of inflammation (Won Sick Woo, 1963). Others sis. This antiinflammatory effect has been demonstrated in
species have been used as antiinflammatory, antihyperten- animals (Qian et al., 1991). The hydrophilic extract of the
sive, and antihypercholesterolemic agents (Kajimoto et al., roots from S. ningpoensis had intense antiinflammatory
1989). activity with the carrageenin-induced rat paw model for
According to the literature, many Scrophularia species edema. From this species were isolated harpagide (1),
have been investigated and found to contain many classes of harpagoside (2), aucuboside (3), 6-O-methylcatalpol (4),
secondary metabolites including iridoids, phenylpropanoids, ningpogenin (5), ningpogoside A (6), ningpogoside B (7),

Accepted: August 15, 2001

Address correspondence to: A.M.a Díaz Lanza, Department of Pharmacology, Faculty of Pharmacy, University of Alcalá, Alcalá de
Henares, 28871 Madrid, Spain. Tel.: 91 885 46 42, Fax: 91 885 46 79, E-mail: a.diaz@uah.es
46 J. de Santos Galíndez et al.

Table 1. Activities of some species from the Scrophularia genus.

S. auriculata S. frutescens S. ningpoensis S. scorodonia S. nodosa

ANTIINFLAMMATORY (Giner et al., (Garcia et al., (Kajimoto et al., (Bermejo (Paris & Moyse,
1991, 2000; 1996; 1989; Quian Benito et 1976;
Cuellar et Fernandez et et al., 1991, al., 1998, Schaunbenger
al., 1998) al., 1996, 1992; Zhang 2000) & Paris,
1998) et al., 1194) 1977;
ANTIBACTERIAL (Swiatek, 1970, (Fernandez et Vigneau,
1973; Paris & al., 1996) 1985) (Paris
Moyse, 1976; & Moyse,
Van Hellemont, 1976;
1986) Schaunbenger
& Paris,
1977;
Rombouts and
Links, 1956;
Swiatek,
1970)
(Swiatek, 1970)
HEPATOPROTECTIVE

IMMUNOMODULATOR
(Kajimoto et al., (Karimova et
CARDIOVASCULAR 1989; Ody, al., 1966)
1993)
(Fernandez (Akhmedov et
DIURETIC Arche et al., 1969;
al., 1993) Schaunbenger
& Paris,
1977)
(Martin et al.,
PROTOZOOCIDAL 1998;
FUNGICIDAL AND Emam et
MOLLUSCICIDAL al., 1997)
(Garcia et al., (Miyazawa et
ANTITUMOR CYTOTOXIC 1998) al., 1998;
AND CYTOSTATIC Pinkas et al.,
1994; Liu &
Wu, 1993)
NEUROPROTECTIVE
(Tohda et al.,
ANTIPRURITIC 2000)
(Karimova et
OTHERS al., 1996)

verbascoside (8), angoroside A (9) and angoroside C (10) and 6-O-a-L-(4≤-O-acetyl 2≤,3≤-O-di-p-methoxycin-
(Kajimoto et al., 1989; Zhang et al., 1994; Qian et al., 1992). namoyl)-rhamnopyranosyl-catalpol (12)], isolated from S.
Pharmacological investigations are necessary for evaluating auriculata L., exert high antiinflammatory activity on mouse
their potential as antiinflammatory agents. ear edema induced by tetradecanoylphorbol acetate (TPA).
S. auriculata is a medicinal plant used in traditional med- When these products were assayed at the same dose as
icine against inflammatory skin diseases. Its aqueous alcohol indomethacin (0.5 mg/ear), they exhibited nearly the same
extract showed a marked effect on both acute and chronic effect as this reference drug with an edema percentage inhi-
models of inflammation (Cúellar et al., 1998). bition of 73.4% (Giner et al., 1991).
Two catalpol derivates [6-O-a-L-(2≤-O-acetyl-3≤,4≤-O- Two saponins, verbascosaponin A (13) and verbascos-
di-p-methoxycinnamoyl-rhamnopyranosyl)-catalpol (11) aponin (14), and two iridoids, scropolioside A (15) and
 Biologically active substances from Scrophularia 47

Table 1 (continued)

S. canina S. sambucifolia S. koelzii S. grosheimi S. buergeriana S. oldhamii S. scopolii

(Won Sick
Woo,
1963)

(Swiatek, 1970, (Fernandez et (Won Sick

1973; Paris al., 1996) Woo,
& Moyse, 1963)
1976; Van
Hellemont,
1986)

(Garg et al., (Akhmedov

1994) et al.,
(Garg et al., 1969)
1994)
(Akhmedov
et al.,
1969)
(Fernandez (Akhmedov
Arche et al., et al.,
1993) 1969;
Schaunbenger
& Paris,
1977)

(Saracoglu
et al.,
1997)

(Kim & Kim,

2000)

(Bhandari
et al.,
1992)

scrovalentinoside (16), isolated from S. auriculata ssp. corticoids. When the putative corticoid-like mechanism of
pseudoauriculata, assayed with various acute and chronic the two compounds was studied, verbascosaponin A (13)
experimental models, showed antiinflammatory activity activity was notably reduced by the mRNA synthesis
against all the inducers with the exception of arachidonic inhibitor, actinomycin D, while the effect of scropolioside A
acid (Giner et al., 2000). Both saponins significantly inhib- (15) was partially blocked by the anti-glucocorticoid drugs
ited mouse paw edema induced by single and multiple doses used. Both iridoids were active on the delayed-type hyper-
of 12-O-tetradecanoylphorbol 13-acetate (TPA). Verbascos- sensitivity reaction. They significantly reduced the inflam-
aponin A (13) showed a potency twice as high as that of matory lesion and suppressed cellular infiltration.
indomethacin in the acute TPA model. Verbascosaponin A The aqueous extract and harpagoside (2) isolated from S.
(13) and scropolioside A (15) were active after a long latency frutescens L. were tested for antiinflammatory activity on rat
period against ethyl phenylpropiolate edema, as are gluco- paw edema. The results obtained showed that the aqueous
48 J. de Santos Galíndez et al.

Table 2. Bioactive compounds, parts or fractions and activities derived from Scrophularia species.

Bioactive compound, parts

Plant sources or fraction and activites References

S. auriculata Plant, phenolic acids (antibacterial) (Swiatek, 1970, 1973; Paris & Moyse, 1976;
Van Hellemont, 1986)
(11–16) Iridoids and saponins (antiinflammatory), (Giner et al., 1991, 2000; Cuellar et al., 1998)
Plant, hidroalcoholic extract
S. buergeriana (17–19, 33, 38, 41–45) Chloroform methanol extract (Kim & Kim, 2000)
from roots, phenylpropanoids (neuroprotective)
S. canina Plant, phenolic acids (antibacterial) (Swiatek, 1970, 1973; Paris & Moyse, 1976;
Van Hellemont, 1986)
S. frutescens (2, 17–23) Aqueous extract, phenolic acids, iridoid (Garcia et al., 1996; Fernandez et al., 1996,
(antiinflammatory) 1998)
Aqueous extract of the aerial parts (ashes), (Fernandez Arche et al., 1993)
flavonoids and saponins (diuretic)
(17–23) Phenolic acids (antitumor, cytotoxic and (Garcia et al., 1998)
cytostatic)
(17–23, 31, 32) Aerial part, phenolic acids (Fernandez et al., 1996)
(antibacterial)
S. grossheimi Plant (diuretic) (Akhmedov et al., 1969; Schaunbenger &
Paris, 1977)
(36) Extract, flavonoids (cardiovascular) (Akhmedov et al., 1969)
Flavonoid fraction (hepatoprotective) (Akhmedov et al., 1969)
S. koelzii (2, 15, 34, 35) Alcoholic extract, chloroform fraction (Garg et al., 1994)
from alcoholic extract of the aerial parts, iridoids
(hepatoprotective and immunomodulator)
(34) Alcoholic extract of the whole plant, iridoid (Bhandari et al., 1992)
(CNS depressant)
S. nodosa (3, 19, 29, 30) Iridoids and phenolic acid (Paris & Moyse, 1976; Schaunbenger &
(antiinflammatory) Paris, 1977; Vigneau, 1985)
(1, 3, 19, 29, 30) Plant, iridoids and phenolic acids (Paris & Moyse, 1976; Schaunbenger &
(antibacterial) Paris, 1977; Rombouts and Links, 1956;
Swiatek, 1970)
(19) Phenolic acid (hepatoprotective) (Swiatek, 1970)
Infusion, saponin (cardiovascular) (Karimova et al., 1966)
Infusion (inhibited of motor activity) (Karimova et al., 1966)
Plant (diuretic) (Akhmedov et al., 1969; Schaunbenger &
Paris, 1977)
S. ningpoensis (1–10) Roots, hydrophilic extract, iridoids and (Kajimoto et al., 1989; Quian et al., 1991,
phenolic acids (antiinflammatory) 1992; Zhang et al., 1194)
Methanol extract from roots (antipruritic) (Tohda et al., 2000)
Aqueous extract (cardiovascular) (Kajimoto et al., 1989; Ody, 1993)
(33, 38–40) Plant, methanol extract from roots and (Miyazawa et al., 1998; Pinkas et al., 1994;
phenolic acids (antitumoral, cytotoxic and Liu & Wu, 1993)
cytostatic)
S. oldhamii (33) Ethanol extract from roots, phenolic acid (Won Sick Woo, 1963)
(antibacterial)
Plant (antiinflammatory) (Won Sick Woo, 1963)
S. sambucifolia (17–23, 31, 32) Aerial part, phenolic acids (Fernandez et al., 1996)
(antibacterial)
Aqueous extract of the aerial parts (ashes), (Fernandez Arche et al., 1993)
flavonoids and saponins (diuretic)
S. scopolii (9) Phenylpropanoid glycoside (antitumor, (Saracoglu et al., 1997)
cytotoxic and cytostatic)
S. scorodonia (24) Methanol extract from flowers, (Martin et al., 1998; Emam et al., 1997)
Buddlejasaponin I (protozoocidal, fungicidal and
molluscicidal)
(1–3, 24–28) Iridoids, Buddlejasaponin I (Bermejo Benito et al., 1998, 2000)
(antiinflammatory)
 Biologically active substances from Scrophularia 49

HO OH

R CH3
O
OH
O
OH
HO
OH

COMPOUND R SPECIES REFERENCES

(1) Harpagide R = OH S. scorodonia (Bermejo Benito et al., 2000)

S. ningpoensis (Zhang et al., 1994)
(Kajimoto et al., 1989)
(2) 8-O-trans-Cinnamoylharpagide R = C6H5-CH = CH-CO-O- S. scorodonia (Bermejo Benito et al., 2000)
(Harpagoside) S. ningpoensis (Kajimoto et al., 1989)
(Zhang et al., 1994)
S. koelzii (Garg et al., 1994)
S. frutescens (Garcia et al., 1996)
(26) 8-O-Acetylharpagide R = CH3-CO-O- S. scorodonia (Bermejo Benito et al., 2000)

CH2OH

O
OH
HO O
OH
OH

COMPOUND R SPECIES REFERENCES

(3) Aucuboside R = OH S. nodosa (Paris & Moyse, 1976)

(Schaunbenger & Paris, 1977)
(Vigneau, 1985)
(Rombouts & Links, 1956)
S. ningpoensis (Qian et al., 1992)
S. scorodonia (Bermejo Benito et al., 2000)

(25) Bartsioside R=H S. scorodonia (Bermejo Benito et al., 2000)

Figure 1. Structures and sources of compounds from Scrophulania ssp.

extract from this species can be considered as a potential been reported already that some of these compounds have
mild antiinflammatory agent on an acute inflammation antiinflammatory action (Fernández et al., 1998). These
process, although harpagoside is not considered the princi- authors showed that p-coumaric (17), caffeic (18), ferulic
pal responsible of the antiinflammatory effect (García et al., (19), gentisic (20), protocatechuic (21), syringic (22) and iso-
1996). Probably, other bioactive substances are involved, vanillic (23) acids isolated from S. frutescens are moderate
such as phenolics acids, previously isolated from the aqueous systemic antiinflammatory agents but have a strong anti-
extract of this species (Fernández et al., 1996), since it has inflammatory effect when applied locally at the site of
50 J. de Santos Galíndez et al.

H OR

O
O

CH2OH
O
OH
O
OH
HO
OH

COMPOUND R SPECIES REFERENCES

(4) 6-O-Methylcatalpol R = CH3 S. ningpoensis (Qian et al., 1992)

(Zhang et al., 1994)
(29) Catalpol R=H S. nodosa (Paris & Moyse, 1976)
(Schaunbenger & Paris, 1977)
(Vigneau, 1985)
(30) Catalposide R = p-hidroxybenzoyl S. nodosa (Paris & Moyse, 1976)
(Schaunbenger & Paris, 1977)
(Vigneau, 1985)

H O

H
R2O
H OR1

COMPOUND R SPECIES REFERENCES

(5) Ningpogenin R1 = R2 = H S. ningpoensis (Qian et al., 1992)

(6) Ningpogoside A R1 = GLC R2 = H S. ningpoensis (Qian et al., 1992)

(7) Ningpogoside B R1 = H R2 = GLC S. ningpoensis (Qian et al., 1992)

OR2
O

R1O O OH
O OH

R3
CH3
HO O
OH
OH
COMPOUND R SPECIES REFERENCES

(8) Verbascoside R1 = caffeoyl S. ningpoensis (Kajimoto et al., 1989)

R2 = H
R3 = OH

(8) Angoroside A R1 = caffeoyl S. scopolii (Saracoglu et al., 1997)

R2 = arabinose S. ningpoensis (Kajimoto et al., 1989)
R3 = OH

(10) Angoroside C R1 = (E)feruroyl S. scopolii (Saracoglu et al., 1997)

R2 = arabinose S. ningpoensis (Zhang et al., 1994)
R3 = OCH3

R1 = caffeoyl
(10) Angoroside C R2 = arabinose S. scopolii (Saracoglu et al., 1997)
R3 = OCH3

Figure 2. Structures and sources of compounds from Scrophulania ssp.

 Biologically active substances from Scrophularia 51

OR2

OR1
R3O
H3C O

O O

CH2OH
O
CH2OH

OH O
OH
OH

COMPOUND R SPECIES REFERENCES

(11) 6-O-α−α − L-(2″ -O-acetyl-3″ , 4″ -O-di-p-methoxy- R1 = CH3-CO- S. auriculata (Giner et al., 1991)
cinnamoyl-rhamnopyranosyl)-catalpol R2 = R3 = p-CH3O-C6H4-CH = CH-CO-

(12) 6-O-αα− − L-(4″ -O-acetyl 2″ , 3″ -di-p–methoxycinnamoyl)- R1 = R2 = p-CH3O-C6H4-CH = CH-CO- S. auriculata (Giner et al., 1991)
rhamnopyranosyl-catalpol R3 = CH3-CO-

(27) 6-O-αα− − L-(3″ -O-acetyl–2″ -trans-O-cinnamoyl)- R1 = C6H5-CH = CH-CO-

rhamnopyranosyl-catalpol (Scorodioside) R2 = CH3-CO- S. scorodonia (Bermejo Benito et al., 2000)
R3 = H

(28) 6-O-αα− − L-(2″ -O-acetyl–3″ , 4″ -di-O-trans-cinnamoyl)- R1 = CH3-CO- S. scorodonia (Bermejo Benito et al., 2000)
rhamnopyranosyl-catalpol (Scropolioside B) R = 2 R3
= C6H5-CH = CH-CO-

(15) 6-O-αα− − L-(2″ , 4″ -di-O-acetyl-3″ -O-p-methoxy-trans- R1 = R3 = CH3-CO-

cinnamoyl)-rhamnopyranosyl-catalpol R2 = CH3O-C6H4-CH = CH-CO- S. auriculata (Giner et al., 2000)
(Scropolioside A) S.koelzii (Garg et al., 1994)

(16) 6-O-αα− − L-(2″ , 3″ -di-O-acetyl-4″ -O-p-methoxy-cinnamoyl)- R1 = R3 = CH3-CO-

rhamnopyranosyl-catalpol (Scrovalentinoside) R2 = CH3O-C6H4-CH = CH-CO- S. auriculata (Giner et al., 2000)

(34) 6-O-αα− − L-(4″ -O-acetyl–2″ , 3″ -di-O-cinnamoyl)- R1 = R2 = C6H5-CH = CH-CO-

R3 = CH3-CO- S. koelzii (Garg et al., 1994)
rhamnopyranosyl-catalpol (Koelzioside)
(Bhandari et al., 1992)

(35) 6-O-αα− − L-(3″ -O-p-methoxcinnamoyl)- R1 = R2 = H

rhamnopyranosyl-catalpol S. koelzii (Garg et al., 1991)
R3 = p-CH3O-C6H4-CH = CH-CO-

Figure 3. Structures and sources of compounds from Scrophulania ssp.

inflammation. In the topical model, the best antiinflamma- and ferulic (19) acids, showed good antiinflammatory activ-
tory activity might be afforded by compounds related to ity. Their effect on leukocyte migration to the inflamed site
benzoic acid derivates, compounds with methoxy group sub- might be an important aspect of their mechanism of action.
stitution at C-3 or C-5, or both. After topical administration, It seems that the phenolic acids that are the active principles
the compounds, especially syringic (22), protocatechuic (21) of some orally administered medicinal plants might merely
52 J. de Santos Galíndez et al.

CH=CH-COOH

R3 R1

R2

COMPOUND R SPECIES REFERENCES

(17) p-coumaric R1 = CH = CHCOOH S. sambucifolia (Fernandez et al., 1996)

R2 = R4 = H S. frutescens (Fernandez et al., 1996)
R3 = OH (Fernandez et al., 1998)
(Garcia et al., 1996)
(Garcia et al., 1998)
(Kim & Kim, 2000)

(18) Caffeic R1 = CH = CHCOOH S. buergeriana (Fernandez et al., 1996)

R2 = R3 = OH (Fernandez et al., 1996)
R4 = H S. sambucifolia (Fernandez et al., 1998)
S. frutescens (Garcia et al., 1996)
(Garcia et al., 1998)
S. buergeriana (Kim & Kim, 2000)

(19) Ferulic R1 = CH = CHCOOH S. sambucifolia (Fernandez et al., 1996)

R2 = OCH3 S. frutescens (Fernandez et al., 1996)
R3 = OH (Fernandez et al., 1998)
R4 = H (Garcia et al., 1996)
S. nodosa (Garcia et al., 1998)
(Paris & Moyse, 1976)
(Schaunbenger & Paris, 1977)
(Vigneau, 1985)
(Swiatek, 1970)
(Rombouts & Links, 1956)
S. buergeriana (Kim & Kim, 2000)

(22) Syringic R1 = CH = CHCOOH S. sambucifolia (Fernandez et al., 1996)

R2 = R4 = OCH3 S. frutescens (Fernandez et al., 1996)
R3 = O-glucose (Fernandez et al., 1998)
(Garcia et al., 1996)
(Garcia et al., 1998)

R1 = CH = CHCOOH S. ningpoensis (Miyazawa et al., 1998)

(33) Methoxycinnamic
R2 = R4 = H R3 = OCH3 S. oldhamii (Won Sick Woo, 1963)
S. buergeriana (Kim & Kim, 2000)

(38) Trans-cinnamic R1 = CH = CHCOOH S. ningpoensis (Miyazawa et al., 1998)

R2 = R3 = R4 = H S. buergeriana (Kim & Kim, 2000)

(39) 3,4-dimethoxycinnamic R1 = CH = CHCOOH S. ningpoensis (Miyazawa et al., 1998)

R2 = R3 = OCH3 R4 = H

(40) 4-hydroxy-3-methoxycinnamic R1 = CH = CHCOOH S. ningpoensis (Miyazawa et al., 1998)

R2 = OCH3 R3 = OH
R4 = H

R1 = CH = CHCOOCH3 S. buergeriana (Kim & Kim, 2000)

(45) p-methoxycinnamic methylester
R2 = R4 = H R3 = OCH3

Figure 4. Structures and sources of compounds from Scrophulania ssp.

 Biologically active substances from Scrophularia 53

COOH
R1

R4 R2

R3

COMPOUND R SPECIES REFERENCES

(20) Gentisic R1 = R4 = OH S. frutescens (Fernandez et al., 1996)

R2 = R3 = H (Fernandez et al., 1998)
S. sambucifolia (Fernandez et al., 1996)

(21) Protocatechuic R1 = R4 = H S. frutescens (Fernandez et al., 1996)

R2 = R3 = OH (Fernandez et al., 1998)
(Garcia et al., 1996)
(Garcia et al., 1998)
S. sambucifolia (Fernandez et al., 1996)

(23) Isovanillic R1 = R4 = H S. frutescens (Fernandez et al., 1996)

R2 = OCH3 (Fernandez et al., 1998)
R3 = OH (Garcia et al., 1996)
(Garcia et al., 1998)
S. sambucifolia (Fernandez et al., 1996)

(31) p-Hydroxybenzoic R1 = R2 = R4 = H S. frutescens (Fernandez et al., 1996)

R3 = OH S. sambucifolia (Fernandez et al., 1996)

(32) Vanillic R1 = R4 = H S. frutescens (Fernandez et al., 1996)

R2 = OCH3 S. sambucifolia (Fernandez et al., 1996)
R3 = OH

Figure 5. Structures and sources of compounds from Scrophulania ssp.

act synergistically with other active substances, for example, any significant effect on prostaglandin E2 (PGE2) and
harpagoside (2), isolated from S. frutescens, might be leukotriene C4 (LTC4) released from calcium ionophore-
another bioactive compound involved in its action stimulated mouse peritoneal macrophages. In the PGE2-
(Fernández et al., 1998). release assay, only harpagoside (2) and 8-O-acetyl-harpagide
Buddlejasaponin I (24), a biologically active compound (26) showed an inhibition rate of 30–40%. In the LTC4 assay,
from S. scorodonia L., exerts potent in vivo antiinflammatory only aucuboside (3) showed a significant effect, with a IC50
effects on mouse ear edema induced by phorbol myristate value of 72 mM. Harpagoside (2) and harpagide (1) also
acetate (PMA). The screening for in vitro effects of this inhibited release of LTC4, but it was not a very significant
saikosaponin on cellular systems generating cyclooxygenase effect. However, most iridoids assayed showed a significant
(COX) and lipoxygenase (LOX) metabolites showed a sig- effect on thromboxane B2 (TXB2) release from calcium
nificant effect. These data support the inhibition of arachi- ionophore-stimulated human platelets, with inhibition per-
donic acid metabolism as one of the biochemical centages slightly lower than the reference drug ibuprofen.
mechanisms that might be the rationale for the putative Only harpagide (1), scorodioside (27) and scropolioside B
antiphogistic activity of this saikosaponin (Bermejo Benito (28) had no significant effect on TXB2-release. These results
et al., 1998). indicated that selective inhibition of thromboxane synthase
Seven iridoid glycosides isolated from different extracts enzyme may be the primary target of action of most of these
of S. scorodonia L., namely bartsioside (25), aucuboside (3), iridoids, and one of the mechanisms through which they exert
harpagide (1), harpagoside (2), 8-O-acetylharpagide (26), their antiinflammatory effects. This result does not contra-
scorodioside (27) and scropolioside B (28), have been eval- diction information in the literature, where some authors
uated for their in vitro antiinflammatory activity in cellular found negative results with in vivo models after oral admin-
systems generating cyclooxygenase (COX) and lipoxygenase istration (Lanhers et al., 1992) and other authors obtained
(LOX) metabolites (Bermejo Benito et al., 2000). Iridoids positive results in topical processes (Recio et al., 1994).
did not show a cytotoxic effect even at the higher concen- Further conclusions about iridoid structure-activity relation-
tration of 100 mM. Most compounds assayed did not exhibit ships are that substitutions with an additional moiety at C-8
54 J. de Santos Galíndez et al.

CH3O

CH2OH

R1O CH2OH

COMPOUND R SPECIES REFERENCE

(13) Verbascosaponin A R1 = Rha (1→ 4) Glc(1→ 3)[Glc(1→ 2)] Fuc S. auriculata (Giner et al., 2000)

O
CH3 CH2OH
OH
OH O
O
OH O
OH
OH O O
O OH OH
CH3
OH
OH
OH OH

COMPOUND R SPECIES REFERENCES

(14) Verbascosaponin R=H S. auriculata (Giner et al., 2000)

(24) Buddlejasaponin I R = OH S. scorodonia (Emam et al., 1997)
(Bermejo Benito et al., 1998)

OH

HO O
OH

OH O

COMPOUND SPECIES REFERENCE

(36) 5,7,3′− trihydroxy-4′ -flavone (tetrahydroxy-m-hydroxyflavone) S. grossheimi (Akhmedov et al., 1969)

Figure 6. Structures and sources of compounds from Scrophulania ssp.

is a positive chemical feature for thromboxane-synthase S. nodosa has also been considered to possess antiinflam-
activity [8-O-acetylharpagide (26) and harpagoside (2) matory properties. From this species have been isolated aucu-
versus harpagide (1)]. The presence of a foreign moiety at boside (3), catalpol (29), catalposide (30), ferulic acid (19)
C-6 is unfavourable, as is apparent when the activity of bart- and ester derivatives of harpagide. These compounds could
sioside (25) (iridoid with no hydroxyl substituents in the be responsible of the activity, together with other substances
body of the molecule, and only active on thromboxane syn- (Paris & Moyse, 1976; Schaunbenger & Paris, 1977; Vigneau,
thase) is compared with scorodioside (27) and scropolioside 1985). S. oldhamii has been used traditionally in medicine for
B (28), which are inactive. the treatment of inflammation (Won Sick Woo, 1963).
 Biologically active substances from Scrophularia 55

OH

H3C O

R3O
OR1
OR2

COMPOUND R SPECIES REFERENCES

(41) Buergeriside A1 R1 = CH3-CO- S. buergeriana (Kim & Kim, 2000)

2
R = (E) p-CH3O-C6H4-CH = CH-CO-
R3 = (E) p-CH3O-C6H4-CH = CH-CO-

(42) Buergeriside B1 R1 = CH3-CO- S. buergeriana (Kim & Kim, 2000)

2
R = (E) p-CH3O-C6H4-CH = CH-CO-
R3 = OH-

(43) Buergeriside B3 R1 = CH3-CO- S. buergeriana (Kim & Kim, 2000)

R2 = (Z) p-CH3O-C6H4-CH = CH-CO-
R3 = OH-

(44) Buergeriside C1 R1 = OH- S. buergeriana (Kim & Kim, 2000)

R2 = OH-
3 = (E) p-CH O-C H -CH = CH-CO-
R 3 6 4

Figure 7. Structures and sources of compounds from Scrophulania ssp.

Antibacterial
syringic (22), caffeic (18), gentisic (20), protocatechuic (21),
S. nodosa, S. auriculata and S. canina have been used since p-coumaric (17) and vanillic (32) acids]. Therefore, these
the Middle Ages as a remedy for scrophulas and several der- species could be considered as potentially antiseptic agents
matoses (scabies, tumours) (Paris & Moyse, 1976). Also, dif- on bacteriologic infections, especially in processes where
ferent reports have suggested that the antiseptic properties of Gram-positive bacteria are involved (Fernández et al., 1996).
these species could be attributed to the presence of phenolic Methoxycinnamic acid (33), isolated by EtOH extract from
acids (Swiatek, 1970, 1973; Van Hellemont, 1986). At roots of S. oldhamii, showed good antipyretic action. Both
present, S. nodosa is considered by several authors to pos- p-methoxycinnamic (33) and the EtOH extract from S.
sess basteriostatic properties (Schaunbenger & Paris, 1977; oldhamii exhibited good antipyretic activity when tested on
Swiatek, 1970). The following glycosides have been isolated typhoid-vaccinated rabbits (Won Sick Woo, 1963).
from this species: aucuboside (3), catalpol (29), catalposide
(30), ferulic acid (19) and ester derivates of harpagide (1).
Hepatoprotective
The therapeutic properties of the Figwort, S. nodosa, prob-
ably depend of these constituents. For example, aucuboside The alcoholic extract of the aerial parts of S. koelzii sig-
(3) and ferulic acid (19) possess antibacterial properties nificantly protected against thioacetamide-induced hepatic
(Rombouts & Links, 1956; Davini et al., 1986; Fernández damage (Garg et al., 1994). This extract was fractionated
et al., 1998). with different solvents (hexane, chloroform, butanol and
The phenolic fractions of the aerial parts of S. frutescens water). Hepatoprotective activity was localized in the
and S. sambucifolia showed potent antibacterial activity chloroform fraction from which four iridoid glycosides,
(Fernández et al., 1996). However, S. frutescens, the species namely, scropolioside A (15), koelzioside (34), harpagoside
most rich in phenolic acids, demonstrated a more pronunced (2) and 6-O-a-L-(3≤-O-p-methoxycinnamoyl)-rhamnopyra-
activity than S. sambucifolia. The phenolic fractions of both nosyl-catalpol (35), were isolated. Among these, scropolio-
species showed more activity against Gram-positive bacteria, side A (15) showed the greatest hepatoprotective activity.
specifically against Bacillus sp. The higher concentration of The activity of this compound was comparable to that of
the phenolic compounds detected in S. frutescens could silymarin, a clinically used hepatoprotective drug. The
explain the more potent activity of this species. These pre- important observation, however, is that the greatest protec-
liminary results suggest that the antibacterial activity of tion was achieved with the alcoholic extract only. Hence, it
these species can be attributed to the presence of phenolic is likely that the hepatoprotective activity of S. koelzii may
acids [ferulic (19), isovanillic (23), p-hydroxybenzoic (31), not be due to any single constituent. Rather, there may be
56 J. de Santos Galíndez et al.

certain other constituents acting synergistically for a better Diuretic

activity profile.
S. nodosa and S. grossheimi have been used in traditional
Ferulic acid (19), isolated from S. nodosa, has been shown
medicine as diuretic agents (Akhmedov et al., 1969;
to possess cholagogue properties (Swiatek, 1970) and the
Schaunbenger & Paris, 1977). The aqueous extract and the
flavonoid fractions of S. grossheimi showed weak but posi-
ash from the aerial parts of S. frutescens and S. sambucifo-
tive cholagogue activity (Akhmedov et al., 1969).
lia subsp. sambucifolia have also shown pronounced diuretic
activity. The increase in urine volume was more significant
Immunomodulating with S. frutescens than with S. sambucifolia. Flavonoids and
saponins, which are present in the extract tested, were sug-
Scropolioside A (15), koelzioside (34), harpagoside (2) and
gested as being responsibles for the activity (Fernández
6-O-a-L -(3≤-O-p-methoxycinnamoyl)-rhamnopyranosyl-
Arche et al., 1993).
catalpol (35), were isolated from the chloroform soluble frac-
tion of an alcoholic extract of the aerial parts of S. koelzii.
This fraction was shown to have immunomodulating activity Protozoocidal, fungicidal and molluscicidal
(Garg et al., 1994). Therefore, an immunostimulant response
was observed with all the four iridoids. Maximum induction The methanol extract from flowers of S. scorodonia revealed
of immune response with respect to all the parameters protozoocidal activity against Trichomonas vaginalis (LC100
studied (macrophage migration index, haemagglutinating = 100 mg/ml) and Leishmania infantum (LC100 = 250 mg/ml)
antibody titre and plaque forming cell) was observed with (Martín et al., 1998). From this extract, a saikosaponin,
harpagoside (2) and 6-O-a-L-(3≤-O-p-methoxy-cinnamoyl)- buddlejasaponin I (24), has been isolated. The biological
rhamnopyranosylcatalpol (34) when administered intraperi- activity of this saikosaponin was evaluated in vitro as a
toneally. The immunostimulant activity observed with pure protozoocidal agent against Trichomonas vaginalis and
glycosides was of nearly equal intensity and suggests that the Leishmania infantum, as a molluscicidal agent against Bio-
catalpol nucleus of the iridoid is responsible for this activity. mphalaria alexandrina snails, and as a fungicidal agent
The hepatoprotective activity and immunostimulant activity against nine yeast strains. The results showed that the saponin
of these four iridoids seem to be complimentary. killed 100% of the snails at 10 mg/ml within 24 h, whereas
Some of the catalpol glycosides are reported to show the LC100 values against Trichomonas, Leishmania and the
immunostimulant activity (Pandey & Das, 1988) and these nine yeast strains were 20, 40, and 100 mg/ml, respectively
compounds are present in a number of species from the Scro- (Emam et al., 1997).
phularia genus (Bhandari et al., 1992, 1997; Calis et al.,
1993; De Santos et al., 1998; Giner et al., 1998; Zhang et al.,
Antitumour, cytotoxic and cytostatic
1992).
Several phenylpropanoid glycosides were found to show anti-
tumour activity. Angoroside A (9) isolated from S. scopolii
Cardiovascular
showed cytotoxic and cytostatic activities, but the methylated
In sedated rabbits, cats and dogs, an infusion of S. nodosa derivates [angoroside B (37) and C (10)] isolated from the
considerably reduced arterial pressure, stimulated respira- same species did not show any cytotoxic activity at 1–
tion, caused bradycardia, lengthened the PQ segment (inter- 200 mg/ml concentrations against cancer cell lines.
val between auricle and ventricle contraction) and changed Angoroside A (9) (1–50 mg/ml) exhibited cytostatic activ-
the configuration of the T wave (representing repolarization ity against HeLa cells (human epithelial carcinoma) and also
of the ventricles) of the electrocardiogram. S. nodosa showed slight cytotoxic activity at higher concentrations
increased the amplitude and slowed down the frequency of (>50 mg/ml) against HeLa cells. Angoroside A (9) exhibited
contractions of an isolated frog heart. This activity of S. cytostatic activity against S-180 cells (sarcoma) at 1–40 mg/
nodosa apparently could be due to the saponins present in ml concentrations. This compound, at a concentration of 12.7
the plant extract (Karimova et al., 1966). However, the mg/ml, showed cytostatic activity against P-388/D1 cells
dependence of the cardiovascular activity on these com- (mouse lymphoid neoplasma). By contrast, when angoroside
pounds is still obscure. A (9) was used at 119 mg/ml, it showed cytotoxic activity
Small doses of an extract from S. grossheimi showed (biphasic effect). Phenylpropanoid glycosides did not show
hypotensive activity and increased capillary tonicity. Differ- any cytotoxic effects against primary-cultures of rat hepato-
ent flavonoid aglycones, mainly 5,7,3¢-trihydroxy-4¢-flavone cytes. Against dRLh-84 cells (rat hepatoma), angoroside A
(36) and its derivates (tetrahydroxy-m-hydroxyflavones), (9) exhibited significant cytotoxic activity. As a result, the
have been isolated from this species (Akhmedov et al., 1969). cytotoxic and cytostatic activies of phenylpropanoid glyco-
Some authors (Kajimoto et al., 1989; Ody, 1993) have sides were found to be mainly dependent on the ortho-dihy-
attributed hypotensive activity to the aqueous extract of S. droxy aromatic systems in their structures. Methylation of at
ningpoensis. However, pharmacological investigations are least one of the phenolic hydroxyl groups abolished the activ-
necessary for assessing the potential as a hypotensive agent. ity which may explain why the methylether derivatives,
 Biologically active substances from Scrophularia 57

angorosides B (37) and C (10), completely lost their activ- Neuroprotective

ities (Saracoglu et al., 1997). The mechanism by which
A chloroform-methanol extract from the roots of S. buerge-
phenylpropanoid glycosides exhibit these activities is under
riana Miq. exhibited significant neuroprotective activity
investigation.
against glutamate-induced neurotoxicity (Kim & Kim,
Seven phenolic acids: p-coumaric (17), caffeic (18),
2000). Ten phenylpropanoids [buergerisides A1 (41), B1 (42),
ferulic (19), gentisic (20), protocatechuic (21), syringic (22),
B2 (43), C1 (44) and cinnamic (38), p-methoxycinnamic (33),
and isovanillic (23) acids, isolated from S. frutescens, have
p-methoxycinnamic methyl ester (45), p-coumaric (17),
been tested on two cell lines: Hep-2 and McCoy (derived
caffeic (18) and ferulic acids (19)] isolated from this species
from the synovial fluid in the knee joint of a patient suffer-
may exert significant protective effects against glutamate-
ing from degenerative arthritis) (García et al., 1998). All the
induced neurodegeneration in primary cultures of cortical
compounds tested showed higher activity against Hep-2
neurons. At concentrations of 0.1–10.0 mM, compounds
and McCoy cells. Since the phenolic acids of the cinnamic
41–44 blocked the release of lactate dehydrogenase (LDH)
group demonstrated an ID50 value below those recommended
from glutamate-insulted primary cultures of rat corticals
by protocols of the National Cancer Institute of U.S.A.
cells significantly and also preserved the cell survival rate.
(for natural products, 6 mg/ml for first stage and 4 mg/ml
At higher concentrations (above 10 mM), these compounds
for the second stage), this could be interesting for further
showed no improvement in the cell survival rate due to inher-
investigations.
ent cytotoxicity. Compounds 17–19, 33, 38, 45 also reduced
However, the data obtained with the phenolic acid of the
the release of LDH and showed some improvement in the cell
benzoic group showed the ID50 for these samples were higher
survival rate in a dose-dependent manner. On the basis of
than those recommended by the National Cancer Institute,
these results, phenylpropanoids bearing a cinnamoyl moiety
except for syringic acid (22) (ID50 = 3.87 ± 0.34) and iso-
exerted significant neuroprotective effects on primary cul-
vanillic acid (23) (ID50 = 5.25 ± 0.70) against McCoy cells.
tures of rat cortical cells injured by glutamate.
The results are in accord with the popular uses of different
species of the Scrophularia genus, traditionally used in scro-
phulas, and indicate that some of the phenolic acids assayed Antipruritic
may be promising for the therapy malignant skin inflamma- In a search for new antipruritic drugs, some authors (Tohda
tory affections. Related to this application, these authors et al., 2000) screened a methanol extract from the roots
demonstrated previously the antiseptic and antiinflammatory of S. ningpoensis using substance P (SP) as a pruritogen in
effects of the phenolic acids isolated from S. frutescens mice. This extract inhibited SP-induced scratching response
(García et al., 1996; Fernández et al., 1998). in mice and showed clear dose-dependent inhibition of the
On the other hand, the methanol extract from S. ning- scratching. The methanol extract did not inhibit locomotor
poensis showed antimutagenic activity. Trans-cinnamic acid activity at 200 mg/kg, a dose which was effective against SP-
(38), p-methoxycinnamic acid (33), 3,4-dimethoxycinnamic induced scratching. Therefore, the scratch-inhibition action
acid (39) and 4-hidroxy-3-methoxycinnamic acid (40), iso- of this extract may be due to inhibition of the itching sen-
lated from this extract, exhibited the same activity, especially sation and/or scratching reflex, rather than to sedation or
trans-cinnamic acid (38). Methyl esters of these compounds depression of general functions of the central nervous
showed greater suppressive potency against all mutagens system.
assayed, especially the methyl ester of p-methoxycinnamic
acid (33) (Miyazawa et al., 1998). Miscellaneous
S. ningpoensis is present in a formula officially used
for bronchopulmonary cancers. No mention for any anti- The chloroform fraction of the alcoholic extract of the whole
cancer activity in vitro or in vivo has been found until now plant of S. koelzii showed significant CNS depressant activ-
for this species. According to Chinese medicine, bron- ity. From this active fraction, koelzioside (34) (triacyl-
chopulmonary cancer could be due to a fluid or mucous rhamnopyranosyl catalpol derivate) has been isolated
concentration in lungs. This could be the reason why S. (Bhandari et al., 1992). However, investigations are needed
ningpoensis (considered as expectorant) is included in this for the pharmaceutical potential of this product.
formula. Clinical research work should be necessary to Infusions of S. nodosa injected in mice inhibited locomo-
support the justification of traditional medicine theories, tor activity and prolonged sleep caused by hexenal. This infu-
the possible complementary contribution of which could be sion dilated capillary of an isolated rabbit ear and decreased
very useful for modern occidental therapy in this difficult tone of an isolated rabbit or cat intestine (Karimova et al.,
field (Pinkas et al., 1994). S. ningpoensis has also been 1966).
shown to alleviate the adverse effects of high-dose
methotrexate plus vincristine which is utilized in chemoter-
Discussion
apy of postoperative osteogenic sarcoma (Liu & Wu, 1993).
S. nodosa has been used as a folk medicine for cancer (Pauli Undoubtedly, the plant Kingdom still holds many species of
et al., 1995). plants containing substances of medicinal value which have
58 J. de Santos Galíndez et al.

yet to be discovered; large numbers of plants are constantly Emam AM, Díaz Lanza AM, Matellano Fernández L, Faure R,
being screened for their possible pharmacological value. Moussa AM, et al. (1997): Biological activities of budle-
Some of these plants belong to the Scrophularia genus. This jasaponin isolated from Budleja madagascariensis and
genus may prove to be a richer source of compounds with Scrophularia scorodonia. Pharmazie 52: 76–77.
possible pharmacological values, but more pharmacological Fernández Arche MA, García Jiménez MD, Saenz Rodríguez
investigations are neccesary. MT, De la Puerta Vázquez R (1993): Action de Scrophu-
However, most of the reported biological studies of Scro- laria frutescens L. et Scrophularia sambucifolia subsp.
phularia constituents and extracts were carried out in vitro, sambucifolia maire sur L’excretion renale. Plantes Médici-
although bioactive iridoids found in Scrophularia can often nales et phytotherapie XXVI, Vol. 4: 362–367.
lead to a multiplicity of compounds after in vivo administra- Fernández MA, García MD, Saenz MT (1996): Antibacterial
tion. For this reason more biological and chemical attention activity of the phenolic acids fractions of Scrophularia
is needed. frutescens and Scrophularia sambucifolia. J Ethnopharma-
col 53: 11–14.
Fernández MA, Saenz MT, García MD (1998): Antiinflam-
Acknowledgements matory activity in rats and mice of phenolic acids isolated
from Scrophularia frutescens. J Pharm Pharmacol 50:
This work was supported by: Acciones Integradas España-
1183–1186.
Francia (Rf.HF-211 & 98B) M.E.C. (Ministerio de Edu-
García D, Fernández A, Sáenz T, Ahumada C (1996): Antiin-
cación y Cultura); Ministerio de Sanidad (FISS Rf. 94/1671);
flammatory effects of different extracts and harpagoside
C.A.M. (Comunidad Autonoma de Madrid Rf. C101/91); isolated from Scrophularia frutescens. Il Farmaco 51:
U.A.H. (Ref. EO01/99); A Grant from Consejería de Edu- 443–446.
cación y Cultura de Madrid, Comunidad Autónoma de García MD, Ahumada MC, Saenz MT (1998): Cytostatic activ-
Madrid (Conv. 98). ity of some phenolic acids of Scrophularia frutescens L. var
frutescens. Z Naturforsch 53c: 1093–1095.
Garg HS, Bhandari SPS, Tripmatisis C, Patnaik GK, Puri A, et
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