Iridoids from Genus Javier de Santos Galindez, Lidia Fernández Matellano and Ana M. Díaz Lanza* Laboratorio de Farmacognosia, Departamento de Farmacologfa, Facultad de Farmacia, Universidad de Alcalä, 28871 Alcalä de Henares, Madrid, Espana. Fax: 918854660. E-mail: [email protected] * Author for correspondence and reprint requests Z. Naturforsch. 56c, 513-520 (2001); received February 6/March 12, 2001 Iridoid Gglycosides, Scrophularia, We report here an updated summary about iridoid composition of a series from the genus Scrophularia which have been investigated until now from a phytochemistry point of view. In addition a list is included about iridoids isolated in our laboratory from different parts of Scrophularia scorodonia L.,which are compared with iridoids from some species of the Scrophularia genus. The present study may serve as a current information to researchers working on phytochemistry and pharmacological aspects from the Scrophularia genus and possibly to serve as a new starting point for future investigations.

Iridoid glycosides such as harpagoside, aucubo- Mnatsakanyan, 1989), Scrophularia chrisantha side and harpagide are of particular interest to (Babayan and Mnatsakanyan, 1989), Scrophularia botanists because of their potential value in chem- ningpoensis (Quian et al., 1992; Ming et al., 1999), osystematics to elucidate phylogenetic relation­ Scrophularia leucoclada (Saatov and Abdullaev, ships (Bianco, 1990; Luczak and Swiatek, 1978). 1996), Scrophularia vernalis (Swiatek and Krzac- The Scrophularia genus is represented by more zek, 1976) and Scrophularia koraiensis nakai than 300 species. But only a few species have been (Pachaly et a l, 1994) (Table II). Acylated 6-O-a- investigated from a phytochemical and pharmaco­ L-rhamnopyranosylcatalpol are common in genus logical point of view. We have now examined spe­ Scrophularia: Scrophularia scopolii var. scopolii cies from genus Scrophularia which have been in­ (Calis et al., 1988), (Weinges vestigated from a phytochemical point of view, and and von der Eltz, 1978), Scrophularia spicata report here the results of the literature search. In (Zhang et a l, 1992), Scrophularia ilwensis (Calis et genus Scrophularia the following iridoid glyco­ a l, 1993), (Giner et al., sides have been found till now: Aucuboside, 6'- 1991; 1998), Scrophularia koelzii (Bhandari et al., cinnamoylaucuboside (scrophularioside), 10-0-ß- 1992) and Scrophularia koraiensis nakai (Pachaly glucosylaucuboside and scropheanoside I in: Scro­ et al., 1994) (Table III). Catalpol, methylcatalpol, phularia canina (Berdini et al., 1991), Scrophularia ajugol and laterioside were found only in some alata Gilib (Swiatek and Broda, 1967), Scrophula­ species : (Qian et a l, ria grossheimi (Akhmedov, 1970), Scrophularia 1992), Scrophularia vernalis (Swiatek and Krzac- nodosa (Weinges and von der Eltz, 1978), Scro­ zek, 1976), Scrophularia lateriflora (Swiatek et a l, phularia ningpoensis (Qian et al., 1992), Scrophu­ 1981), Scrophularia ilwensis (Calis et a l, 1993). laria lateriflora (Swiatek et al., 1981), Scrophularia The presence of picroside I was detected only in vernalis (Swiatek and Krzacek, 1976), Scrophula­ one species, Scrophularia lateriflora (Swiatek et al ., ria ilwensis (Calis et al., 1993) and Scrophularia 1981) (Tables IV, V). koraiensis nakai (Pachaly et al., 1994) (Table I). In the course of a search for biologically active Ester derivates of harpagide in: Scrophularia substances in S. scorodonia we have isolated sev­ canina (Berdini et al., 1991), Scrophularia spicata eral iridoids from and stems, and (Zhang et al., 1992), Scrophularia ilwensis (Calis et roots from this species. al., 1993), Scrophularia buergeriana (Kitagawa et For leaves and stems we have reported, bartsio- al., 1967), Scrophularia grossheimi (Akhmedov, side, aucuboside, harpagoside, 8-O-ds-cinnamoyl- 1970), Scrophularia nodosa (Weinges and von der harpagide, 8-O-acetyl-harpagide and one new iri­ Eltz, 1978), Scrophularia variegata (Babayan and doid 6-0-a-L-(3"-0-acetyl-2"-0-rram-cinnamoyl)-

0939-5075/2001/0700-0513 $ 06.00 © 2001 Verlag der Zeitschrift für Naturforschung, Tübingen ■ www.znaturforsch.com • D 514 J. de Santos Galindez et al. ■ Iridoids from Scrophularia Genus rhamnopyranosylcatalpol (scorodioside) (Fernan­ side, harpagoside and 8-O-acetyl-harpagide. These dez Matellano et al., 1995a; Fernandez Matellano compounds have also been isolated from flowers et al., 1995b). of this species, except aucuboside. Scorodioside, Different catalpol derivates have been isolated the new iridoid glycoside isolated from leaves and in this species: 6-0-a-L-(3"-0-fram' and cis p- stems, has also been identified in flowers. As coumaroyl)-rhamnopyranosylcatalpol and 6-O-a- shown in Table VI there is a different distribution L-(2"-0-rra«5-p-coumaroyl)-rhamnopyranosyl- between all plant parts. catalpol (saccatoside) have been reported in flow­ Identification and assigment of the isolated ers; 6-0-a-L-(2"-0-acetyl-3",4"-0-di-frans-cinna- compounds were performed on the basis of UV moyl)-rhamnopyranosylcatalpol (scropolioside B) spectral data, !H and 13CNMR. and 6-O-methylcatalpol in roots from S. scoro- donia (De Santos et al., 1998). Results and Discussion It is of interest to compare the presence and dis­ We have compiled a first listing of iridoids oc­ tribution of some of these iridoids in different currence in Scrophularia genus (Table VII). From plant parts, because a different composition has the distribution of iridoids listed it can be con­ been found in leaves, stems, flowers and roots (Ta­ cluded that the presence of aucuboside (52.9%), ble VI). We have detected the presence of harpag- harpagide (47.05%), harpagoside (47.05%) and 8- ide for the first time in leaves, stems and roots O-acetylharpagide (41.17%) is not rare in species from S. scorodonia. In roots, we have isolated and of the genus, and we have also isolated these com­ identified different iridoids: bartsioside, aucubo- pounds from Scrophularia scorodonia.

Table I. Aucuboside, scrophularioside, bartsioside and 10-0-ß-glucosylaucuboside.

Compound R Species R eference

Aucuboside R1=R2=R3= H S. nodosa (Weinges and von der Eltz, 1978) R4=OH S. gross heim i (Akhmedov, 1970) S. lateriflora (Swiatek et al., 1981) S. canina (Berdini et al., 1991) S. ningpoensis (Quian et al., 1992) S. il wens is (Calis et al., 1993) S. scorodonia (Fernandez et al., 1995 a) S. alata (Swiatek and Broda, 1967) S. vernalis (Swiatek and Krzaczek, 1976)

Scrophularioside R1=R2=H S. lateriflora (Swiatek et al., 1981) R3=C6H sCH=CH-CO R 4=O H

10-0-ß-Glucosylaucuboside R1=R3=H S. canina (Berdini et al., 1991) R2=ß-D-GLUCOSA R4=OH

Bartsioside R1=R2=R3=R4=H S. scorodonia (Fernandez et al., 1995 a)

Scropheanoside I R1=R2=R3=H S. koraiensis (Pachaly et al., 1994) R4 = 4"-0-(p-0CH,-m-0H-ChHvCH=CH-C0) - ß-D-RHAMNOSA J. de Santos Galindez et al. • Iridoids from Scrophularia Genus 515

Table II. Derivatives of harpagide.

Compound R Species Reference

Harpagide R1=H S. nodosa (Weinges and von der Eltz, 1978) R2=H S. grossheimi (Akhmedov, 1970) S. variegata (Babayan and Mnatsakanyan, 1989) S. chrisantha (Babayan and Mnatsakanyan, 1989) S. ningpoensis (Quian et al., 1992) S. ilwensis (Calis et al., 1993) S. koraiensis (Pachaly et al., 1994) S. leucoclada (Saatov et al., 1996) S. scorodonia 8-O-Acetyl-harpagide Rl=CH^-CO- S. nodosa (Weinges and von der Eltz, 1978) R2=H S. vernalis (Swiatek and Krzaczek, 1976) S. variegata (Babayan and Mnatsakanyan, 1989) S. chrisantha (Babayan and Mnatsakanyan, 1989) S. canina (Berdini et al., 1991) S. ilwensis (Calis et al., 1993) S. scorodonia (Fernandez et al., 1995 a) S. leucoclada (Saatov et al., 1996) 8-0-(p-Methoxycinnamoyl)- r i =c h , o -c 6h 4c h =c h -c o harpagide R2=H S. buergeriana (Kitagawa et al., 1967) S. variegata (Babayan and Mnatsakanyan, 1989) S. chrisantha (Babayan and Mnatsakanyan, 1989) 8-O-fra/zs-cinnamoylharpagide Rl=C6Hs-CH=CH-CO (harpagoside) R2=H S. buergeriana (Kitagawa et al., 1967) S. vernalis (Swiatek and Krzaczek, 1976) S. variegata (Babayan and Mnatsakanyan, 1989) S. chrisantha (Babayan and Mnatsakanyan,,1989) S. ningpoensis (Quian et al., 1992) S. spicata (Zhang et al., 1992) S. koraiensis (Pachaly et al., 1994) S. scorodonia (Fernandez et al., 1995 a) 8-0-czs-cinnamoyI-harpagide Rl=C6Hs-CH=CH-CO- S. scorodonia (Fernandez et al., 1995 b) R2=H 8-0-ds-feruloyl-harpagide Rl=Feruloyl- S. ningpoensis (M ing et al., 1999) R2=H OH 8-0-(2-hydroxy-cinnamoyl)- Rl=C6H,-CH=C-CO- S. ningpoensis (M ing et al., 1999) harpagide R2=H 6-O-a-d-galactopyranosyl- R1=H S. ningpoensis (Ming et al., 1999) harpagide R2=d-galactopyranosyl

On the other hand, iridoids derived from aucu- some of this iridoids have been reported only in boside are rarer in the genus Scrophularia, they one species: koelzioside in S. koelzii, scropolio- appear only in some species, such as scrophulario- sides A and B in S. scopolii and S. auriculata , side in S. lateriflora , lO-O-ß-glucosylaucuboside in scrospioside B in S. spicata , scropheanoside II and S. canina and scropheanoside I in S. koraiertsis 6-0-a-L-(2"-0-acetyl-3",4"-0-di-/?-methoxycinna- (Table I). moyl) rhamnopyranosylcatalpol in S. koraiertsis Moreover it is well known that species of Scro­ and S.auriculata, respectively. Picroside I has been phularia contain catalpol derivates (Table III), but detected only in S. lateriflora and 6-0-(ß-D-xylo- 516 J. de Santos Galindez et al. • Iridoids from Serophularia Genus

Table III. Acylated derivates of 6-O-a-l-rhamnopyranosylcatalpol. ORj

/OR,

Compound R Species Reference

6-a-L-rhamnopyranosyl-catalpol R1=R2=R3=H S. nodosa (Weinges and von der Eltz, 1978)

6-0-a-L-(4"-0-acetyl-2", 3"-di-0-cinnamoyl)- R1 =R2=C6H,-CH=CH-CO- S. koelzii (Bhandari et al.. 1992) rhamnopyranosyl-catalpol (koelzioside) R3=CH3-CO- 6-0-a-L-(2", 4"-di-0-acetyl-3"-0-/7-methoxy-/ra/7s- Rl=R3=CH,-CO- S. scopolii (Calis et al.. 1988) cinnamoyl)-rhamnopyranosyl-catalpol R2=CH30-C 6H4-CH=CH-C0- var scopolii (scropolioside A) S. auriculata (Giner et al.. 1988)

6-0-a-L-(2"-0-acetyl-3'',4"-0-di-/rans-cinnamoyl)- r i =c h 3-c o - S. scopolii (Calis et al.. 1988) rhamnopyranosyl-catalpol (scropolioside B) R2=R3=C6H5-CH=CH-CO- var. Scopolii. S. scorodonia (De Santos et al.. 1998) S. ilwensis (Calis et al., 1993) 6-0-a-L-(2'\ 4"-di-0-acetyl-3''-0-f/ww-cinnamoyl)- Rl=R3=CH3-CO- S. spicata (Zhang et al., 1992) rhamnopydranosyl-catalpol (scropolioside D) R2=C6H5-CH=CH-CO- S. koraiensis (Pachaly et al.. 1994)

r i = c h 3-c o - 6-0-a-L-(2"-0-acetyl-3"-0-frans-cinnamoyl)- R2=C6H5-CH=CH-CO S. spicata (Zhang et al., 1992) rhamnopyranosyl-catalpol (scrospioside B) R3=H Scropheanoside II R1=R2=H S. koraiensis (Pachaly et al., 1994) R3=p-OCH3-m-OH-C6H3- CH=CH-CO- 6-0-a-L-(2"-0-acetyl-3", 4"-0-di-/?-methoxicinnamoyl- S. auriculata (Giner et al., 1991) rhamnopyranosyl)-catalpol R l= C H 3-CO- R2=R3=p-CH,0-C6H4-CH= CH-CO- 6-0-a-L-(3"-0-acetyl-2"-fra/M-cinnamoyl)- S. Scorodonia (Fernandez et al., 1995 b) rhamnopyranosyl-catalpol (scorodioside) R l=C „H s-CH=CH-CO- R2=CH3-CO- R3=H 6-0-a-L-(2"-0-rranir-/7-coumaroyl)-rhamnopyranosyl- S. scorodonia (De Santos et al., 1998) catalpol (saccatoside) R1 =HO-C6H4-CH=CH-CO- R2=R3=H 6-0-a-i--(3"0-trans and ds-p-coumarovl)- R1=R3=H rhamnopyranosyl-catalpol R2=HO-C6H4-CH=CH-CO- S. scorodonia (De Santos et al., 1998) 6-0-a-L-(2", 3"-di-0-acetyl-4''-0-p-methoxy-cinnamoyl)- Rl=R3=CH3-CO- rhamnopyranosyl-catalpol (scrovalentinoside) R2=CH30-C 6H4-CH=CH-C0- S.auriculata (Giner et al., 1988)

pyranosyl) methylcatalpol is unique in S. ilwensis and 6-0-a-L-(3"-0-trans and cis p-eoumaroyl)- (Table IV). rhamnopyranosylcatalpol which have not been re­ In S. scorodonia we have isolated three 6-O-a-L- ported previously in this genus. Also, bartsioside rhamnopyranosylcatalpol derivates as saccatoside, and S-O-c/s-cinnamoyl-harpagide are not present J. de Santos Galindez et al. ■ Iridoids from Scrophularia Genus 517

Table IV. Catalpol, methylcatalpol and picroside I.

Compound R Species Reference

Catalpol R1=R2=R3=R4=H S. lateriflora (Swiatek et al., 1981) Picroside I R1=R3=R4==H S. lateriflora (Swiatek et al., 1981) R2=C6H5CH=CH-CO- 6-Methylcatalpol R1=R2=R4=H S. vernalis (Swiatek and Krzaczek, 1976) R3=CH 3- S. lateriflora (Swiatek et al., 1981) S. ningpoensis (Quian et al., 1992) S. scorodonia (De Santos et al., 1998) 6-0-(ß-D-xylopiranosyl)- R1=R2=H S. il wens is (Calis et al., 1993) methylcatalpol R3= C H V R 4= 0-ß - xylopiranosyl

Table V. Ajugol and laterioside. OH

6 OR CH3 ? O / ch 2oh

« k b z - OH

Compound R Species Reference

Ajugol R=H S. lateriflora (Swiatek and Broda, 1967) S. ilwensis (Weinges and von der Eltz, 1978) Laterioside R=C6H5-CH=CH-CO- S. lateriflora (Swiatek and Broda, 1967) in Scrophularia genus, but we have isolated these With regard to the widespread occurrence of iri­ compounds in S. scorodonia. doids in members of genus Scrophularia, Scrophu­ Of special interest is scorodioside, a new catal­ laria scorodonia fits well into the genus, but the pol analog until now not reported as present in iridoid patterns were some different between this nature and which we have isolated from S. scoro­ species and others species from this genus. As donia. shown in Table VII S. scorodonia is the species Remarkably, catalpol, one of the most common which contains the major variety of iridoids, with iridoids, has not been found in the present investi­ 11 iridoids among 31 found until now in this genus gation. This compound has been isolated in the and with an unequal distribution in different plant genus Scrophularia only in S. lateriflora (Ta­ parts as shown in Table VI. ble IV). 518 J. de Santos Galindez et al. ■ Iridoids from Scrophularia Genus

Table VI. Iridoids from Scrophularia scorodonia.

Iridoids Scrophularia scorodonia

Flowers Leaves and stems Roots

Aucuboside * *

Bartsioside ***

Harpagide ** *

8-O-acetyl-harpagide * * *

Harpagoside * **

8-O-cis-cinnamoyl-harpagide *

Scropolioside B *

Scorodioside **

Saccatoside *

6-0-a-L-(3"0-frans and cis-p-coumaroyl)- * rhamnopyranosyl-catalpol

6-Methylcatalpol *

So, bartsioside, harpagide, 8-O-acetyl-harpagide ities (Recio et al., 1994). In addition, aucuboside is and harpagoside, are present in all plant parts. Ca- reported to exhibit antihepatotoxic, antispasmodic talpol derivatives are predominant in roots and and antitumoral activities (Ghisalberti, 1998). The flowers. Although scorodioside, the new iridoid presence of 8-O-acetyl-harpagide may also be im­ isolated from S. scorodonia, is present in leaves, portant, as the compound has shown antispas­ stems and flowers, it has not been detected in modic and vasoconstrictor activities (Breschi et al., roots. Aucuboside, a common iridoid, was not 1992). Catalpol derivatives have shown to possess found in flowers from this species, but it is present a lot of pharmacological properties, these type of in leaves, stems and roots. compounds also exhibit antiinflammatory activity. Iridoids are present in a number of folk medi­ Studies on antiinflammatory activity of these ca­ cines used as bitter tonics, sedatives, antipyretics, talpol derivatives and other iridoids isolated from cough medicines, remedies for wounds, skin disor­ S. scorodonia have exhibited an interesting activity ders and as hypotensives. Recently, intensive in­ (Bermejo et al., 1999). vestigations on their bioactivity in general, and on their potential pharmacological activity in particu­ lar, have revealed that these compounds exhibit a Acknowledgements wide range of bioactivity: cardiovascular, antihep- This work was supported by: Acciones Integra- atotoxic, choleretic, hypoglycemic and hypolip­ das Spanish-French Rf. HF-211 & 98B; M. E. C. idemic, antiinflammatory, antispasmodic, antitu­ (Ministerio de Educaciön y Cultura); Ministerio mor, antiviral, immunomodulator and purgative de Sanidad (FISS Rf. 9471671); CAM (Comunidad activities (Ghisalberti, 1998). Autönoma de Madrid Rf. C101/91); Proyectos Although S. scorodonia has not been used in Universidad de Alcala de Henares Ref. E006/2001. folk medicine, possible therapeutical properties of A Grant from Consejerfa de Educaciön y Cultura this species depend probably on a number of its de Madrid, Comunidad Autönoma de Madrid constituents. Among them harpagoside and aucu­ (Conv. 1998). boside should be mentioned as these compounds, they possess analgesic and antiinflammatory activ­ J. de Santos Galindez et al. ■ Iridoids from Scrophularia Genus 519

Table VII. Iridoids of the Scrophularia genus.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

S. nodosa ** **

S. gross he im i **

S. lateriflora * * * * * * *

S.canina ** *

S.ningpoensis * * * * * * *

S.ilwensis * * * * * *

S.scorodonia * * * * * * * * * * *

S.alata *

S. vernalis * ***

S. variegata * * **

S. chris ant a * * **

S.koraiensis * * * * *

S.buergeriana * *

S.spicata * * *

S.koelzii *

S.scopolii * * \ar.scopolii

S.leucoclada **

S.auriculata * * *

(1) Aucuboside (13) 6-O-a-L-galactopyranosyl- (23) Saccatoside (2) Scrophularioside harpagide (24) 6-0-a-L -(3"0-trans and cis-p- (3) lO-O-ß-glucosylaucuboside (14) 6-a-L-Rhamnopyranosyl-catalpol coumaroyl)-rhamnopyranosyl- (4) Bartsioside (15) Koelzioside catalpol (5) Scropheanoside I (16) Scropolioside A (25) Screovalentinoside (6) Harpagide (17) Scropolioside B (26) Catalpol (7) 8-O-acetyl-harpagide (18) Scropolioside D (27) Picroside I (8) (p-Methoxycinnamoyl)-harpagide (19) Scrospioside B (28) 6-Methylcatalpol (9) Harpagoside (20) Scropheanoside II (29) 6-0-(ß-D-xylopiranosyl)-methyl (10) 8-O-cis-cinnamoyl-harpagide (21) 6-0-a-L-(2"-0-acetyl-3", 4"-0-di- catalpol (11) 8-O-ferfuloyl-harpagide p-methoxicinnamoyl-rhamno- (30) Ajugol (12) 8-0-(2-hydroxy-cinnamoyl)- pyranosyl)-catalpol (31) Laterioside harpagide (22) Scorodioside 520 J. de Santos Galindez et al. ■ Iridoids from Scrophularia Genus

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