An approach to the genusTanacetum L. (Compositae): Phytochemical and pharmacological review

PHYTOTHERAPY RESEARCH, VOL. 9. 79-92 (19%)

An Approach to the Genus Tanacetum L. (Compositae): Phytochemical and Pharmacological Review

M. J. Abad, P. Bermejo and A. Villar Department of Pharmacology, Faculty of Pharmacy, University Complutense, 28040 Madrid, Spain

In view of the importance in folk medicine of some species of Tunacetum L. (Compositae), e.g. T . parthenium, this paper reviews reports of the past two decades on their phytochemistry and pharmacological actions. The facets of phytochemical composition to be reviewed concern mainly the compounds with a chemosystematic interest in the tribe: terpenoids, especially sesquiterpenes and sesquiterpene lactones and flavonoids. The pharmacological activities which make it possible to corroborate their use as a herbal remedy have also been reviewed.

Keywords: Tunaceturn L. (Compositae); phytochemistry ; chemosystematic; pharmacological activity.

INTRODUCTION

The Anthemideae tribe of the Asteraceae comprises a large number of species that have been and still are used as medicinal plants, particularly in folk medicine, e.g. various species of the genus Artemisia, Achillea and Tanacetum.

Tanacetum is one of the largest genera in this tribe (about 150-200 species), compiled mainly from the flora of Europe, Turkey and Russia (Johnson et al., 1985). However, this morphologically well-delimited genus is surprisingly heterogeneous regarding botanical classification. Botanists do not agree to a common and uniform picture with regard to the exact position of the genus Tanacetum, and some of its members are believed to belong to the genus Chrysanthemum, while others are classified under the genus Pyrethrum.

This confused situation doubtless poses some danger, especially in commerce where a good number of Tanacetum species have become important and useful. The literature does not show any attempt to detail the chemical classification of the genus; however, some studies on the chemosystematics of the Compositae in general, have been undertaken by some research groups (Heywood et al., 1977).

A survey of the present available chemical data suggests that the terpenoids, especially sesquiterpene lactones, and flavonoids, are the main classes of substances of interest to systematists. Their occurrence in the genus Tanacetum, as well as other constituents, and the chemical and biological relationships between them, have made them the subject of the present review.

Author to whom correspondence should be addrcssed.

PHYTOCHEMICAL COMPOSITION

Terpenoids

Terpenoid biosynthesis in Tanacetum. AS products of iso- prenoid synthesis, most regular monoterpenes can formally be derived by condensation of isopentenyl pyrophosphate and dimetilallyl pyrophosphate in a head-to-tail fashion.

However, in Tanacetum and Anthemideue in general, an additional group of biogenetically ‘irregular’ monoterpenes has been detected, not readily derived from head-to-tail, but as a product of a ‘middle- to-tail’ coupling (Epstein and Poulter, 1973). Chrysanthemic acid, the result of this condensation, represents the main precursor of this separate biogenetic group. Cleavage of the ring in three different ways, could lead to the three basic carbon skeletons of the ‘irregular’ monoterpenes (artemisia ketone, artemisia alcohol, and so on) (Fig. 1).

The occurrence of these biogenetically ‘irregular’ monoterpenes in Tanacetum, suggests that their distri- bution may represent a useful chemosystematic character. For this reason, the genus Tanacetum has under- gone many phytochemical investigations for several decades. While some investigations have referred to

A 1111111111

LA111111

Figure 1. Biosynthetic routes to irregular rnonoterpenes (from Heywood et a/., 1977).

CCC 09.51-418X/95/02(H)79- 14 0 1995 by John Wiley & Sons. Ltd Accepted 27 January 1994

80 M . J. ABAD E T A L

the composition of the essential oil and its relation to the geographical location of the species, and many others have centred upon the study of the non-volatile constituents, mainly sesquiterpenoids and sesquiterpene lactones.

Essential oil. The strong and aromatic odour of species of Tanacetum is due mainly to high concentrations of volatile terpenes, constituents of their essential oil, especially in leaves and flowers.

One of these species, Tanacefum uulgare L. (tansy), is an aromatic plant widely distributed in Europe, Asia and North America. Many studies have shown that this species displays a noteworthy infraspecific variation in the terpene constituents of its essential oil, revealing different chemotypes in which the concentration of the main component varied between 41% and 99%.

A study about T . oulgare growing in Hungary, revealed the presence of both pure and mixed chemotypes (Tetenyi ef al., 1975; Hethelyi et al., 1981). The ‘well-defined chemotypes’ were distributed among seven main groups: artemisia ketone, artemisia alcohol, y-campholenol, davanone, lyratol, lyratyl acetate and 4-thujen-2a-yl-acetate. The chemotype with artemisia ketone was also found in T . uulgare which grows in the Netherlands (Hendriks et al., 1990).

In Piedmont, North Italy, several chemotypes with chrysanthenyl acetate, P-thujone, terpinen-4-01, myrtenol, artemisia ketone and bornyl acetate as main components, are particularly present (Nano e f al . , 1979). The chemotype with chrysanthenyl acetate was also found in samples collected in the Netherlands (Hendriks et al. , 1990), and Belgium (De Pooter et al . , 1989).

An investigation of the composition of the essential oil of T . uulgare occurring in Finland (Dutch tansy), revealed different chemotypes: sabinene, thujone, umbellulone, camphor, bornyl acetate, a-pinene, 1.8- cineole and germacrene D (Holopainen ef al., 1987; Holopainen, 1989). In addition to these ‘well-defined chemotypes’, a number of ‘mixed chemotypes’ were also detected, but it was difficult to define the chemotype when the essential oil contained two components of almost equal size.

A study extended over ‘Tierra del Fuego’ (Argen- tina) revealed the presence of a pure P-thujone chemotype, in which this monoterpene makes up 92% of the oil (Gallino, 1988). T . uulgare coming from this region can be considered as a good source of this compound.

In view of the broad and important chemotaxonomic aspects of the essential oils of T . uulgare, it was of interest to study the incidence in all genera. The high and abnormal variability in the terpene constituents of its essential oil, suggests that the species of Tanacetum may well be sub-divided into chemical groups based upon the molecular terpenoid-type of the main component of their oils. Detailed studies in the oil chemistry of Tanacetum species are currently being undertaken in order to strengthen the above hypothesis.

To the ‘monoterpenoid’ group would remain species such as T . uulgare, Tanacetum parthenium (L.) Schultz Bip. (De Pooter et al., 1989), Tanacetum microphyllum DC. (Sanz et al., 1989), and Tanacefum boreale Fisch. (Dembitskii ef al., 1985a, 1985b). Chrysanthenyl acetate was identified for the first time in this last species, T . boreale (Dembitskii arid Suleeva, 1984).

Many investigations with species growing in Central and South East Europe, Tanacetum macrophyllum (Waldst. and Kit) Willd, Tanacetum cilicium Boiss., and Tanacetum corymbosum (L.) Schultz Bip., showed that they may belong to a ‘sesquiterpenoid-type’ group, sub-section cadinene (Thomas, 1989a, 1989b, 1989~). Tanacefum millefolium (L. ) Tzvelev., endemic species growing wild in the Macedonia region (Greece), may also belong in this section (Souleles and Stamatakov, 1991).

In addition, essential oils and terpenoids in general, are known to have a wide range of biological and chemical applications.

The so-called ‘pyrethrins’, well known for their insec- ticidal activity, are distinguished for commercial rea- sons The increased awareness of the dangers of synthe- tic insecticides has raised the demand for natural insecticides. Pyrethrins occur in highest concentration in the disc florets and achenes of Tanacetum cinerariifolium (Trev.) Schultz Bip. (Zito and Tio, 1990; Dhar and Pal, 1993), and Tanacefum odessanum (Klok.) Tzvel. (Bohlmann and Heinz, 1978).

It is also interesting to note that another species of the genus, T . macrophyllum, produces a significant amount of p-methyl benzyl alcohol, which is the main component of its essential oil (Thomas, 1989~). T . macrophyllum could represent a good possible source for the commercial preparation of benzyl alcohol and their derivatives, which may find use as antimicrobial preservatives and antioxidants in some products.

Sesquiterpenes. For a long time, T . uulgare has been known to contain bitter principles, most probably sesquiterpene compounds. Many studies have shown that this species displays an abnormally high infraspecific variability of its whole terpenoid pattern, and in the past two decades, systematic investigations have reported that oxygenated sesquiterpenoids are the major non-volatile constituents of T. uulgare (Appen- dino et al., 1984).

Reports on its sesquiterpene composition are recorded in the literature. In an investigation on the flowers of T . oulgare collected in Bulgaria, a sesquiterpene diketone, cis-longipinane-2,7-dione, was isolated (Ognyanov et al., 1983). Vulgarone B (a-Longipinene- l-one) has been isolated from the underground parts of T . uulgare of European origin, but cultivated in Japan (Uchio et al. , 1976). This compound, and some derivatives with hydroxyl groups in the seven-membered ring, have also been found in Tanacetum tunacetoides L. (Bohlmann et al., 1977).

A chemosystematic investigation of a rare chemotype of T . uulgare growing in North Italy, led the isolation of a series of non-volatile sesquiterpene alcohols all possessing an a-hydroxyisopropyl moiety, which have been called tanacetols A and B (Appendino et al., 1983; Calleri et al., 1983). In spite of the large area investigated by these authors, the chemotype containing tanacetols has only been found in an alpine valley, Vermenagma, to the South of Piedmont. These sesquiterpene alcohols were also found in specimens of T . uulgare collected in Germany (Sanz and Marco, 1991).

The Indian T . uulgare which widely occurs in the Kashmir valley of the Western Himalayas, has been chemically investigated by Chandra ef al. (1987a,

REVIEW OF TANACETUM 81

Table 1. Sesquiterpenoids in Tunaceturn L. reported between 1973-1993 Structure Name Plant species Reference

T. odessanum T. parthenium T. cilicium Thomas, 1989a T. corymbosum Thomas, 1989b T. macrophyllum Thomas, 1989c

T. parthenium T. vulgare Gallino, 1988

Bohlmann and Knoll, 1978 Bohlmann and Zdero, 1982

Bohlmann and Zdero, 1982

P-Farnesene

PJ Germacrene D

Davanone

Vulgarone B

T. vulgare Hethelyi et a/., 1981 Appendino eta/ . , 1984

T. vulgare Uchio eta/., 1976 T. tanacetoides Bohlmann eta/., 1977

T. vulgare Ognyanov et al.. 1983

lndicumenone T. indicum T. indicum

var. tuneful

Mladenova et a/., 1987 Mladenova eta/ . , 1988 @ M

Chrysentunone T. indicum var. tuneful

Mladenova et a/., 1988

Tanacetol A R = O

T. vu/gare Appendino et a/., 1983 Calleri eta/ . , 1983

Tanacetol B R = H

T. vulgare Appendino eta/., 1983 Calleri eta/ . , 1983 Sanz and Marco. 1991

Tanavulgarol Chandra eta/ . , 1987a,b T. vulgare

1987b), and afforded a new sesquiterpenoid, tanavulgarol, with a bergamotane skeleton.

In another species of the genus, Chrysanthemum indicum L. ( = T . indicum), Mladenova et al. (1987) isolated a new sesquiterpene ketodiol named indicumenone. This compound, together with a new sesquiterpenoid, the bisabolane type ketodiol called chrysentunone, were isolated from a closely related taxon, C . indicum var. tuneful, endemic species growing in Bulgaria (Mladenova et al., 1988).

In Table 1, we indicate the non-volatile sesquiterpenes which are characteristic of the genus Tanacetum.

Sesquiterpene lactones appear to have a common biosynthetic origin, and are likely to provide useful chemical characters in the tribe. Figure 2 outlines the biogenetic relationships of the three basic types of lactones characteristic of Compositae (Heywood et al . , 1977).

Biogenetic pathways start with the cyclization of farnesyl or nerolidyl pyrophosphates. Oxidation occurs in the isopropyl group of the precursor, and also at the adjacent C6 or C8 position. Biogenetic transformation of 2E, 6E (or frans, trans) farnesyl pyrophosphate provides the germacradiene skeleton, from which the germacranolides can be derived by bio-oxidation- lactonization processes.

The germacranolides, simple representatives of this group, can be considered the biogenetic precursors for the other skeletal types of lactone. Further ring closure then produces the guaianolides and santanolides or eudesmanolides. The last steps in lactone synthesis involve substitution of these basic CIS skeletons by hydroxylation, epoxidation or dehydrogenation. Reviews on selected skeletal types of sesquiterpene

Sesquiterpene lactones. These are another very important group of sesquiterpenoids found almost exclusively in the Compositae family. During the past two decades, sesquiterpene lactones have emerged as one of the largest groups of natural plant products. The number of lactones reported in the literature has increased from about 1000 well-defined compounds in 1980, to well over 3000 naturally occurring substances known nowadays.

82 M. J. ABAD E T A L .

Figure 2. Biogenetic route of major skeletal types of sesquiterpene lactones of the Compositae (from Heywood et a/., 1977).

lactones include, in addition to those mentioned above, pseudoguaianolides, seco-pseudoguaianolides, eremo- philanolides and bakkenolides. Recently, a biogenetic hypothesis proposed that parthenolide (4,5-epoxy- germacranolide) , main active principle in European feverfew (T . partheniurn), plays a central role in the biosynthesis of guaianolide and seco-guaianolide type sesquiterpene lactones (Fischer, 1990; Castaiieda- Acosta et al., 1993).

Germacranolides, and particularly guaianolides, dominate in the Compositae family, but eudesmanolides have also been reported from other genera such as Tanaceturn. In Tables 2 , 3, and 4, we show the sesquiterpene lactones characteristic of Tanaceturn, reported in the literature in the past two decades.

The occurrence of sesquiterpene lactones has special biogenetic importance in T. uulgare, species characterized by an abnormal and rare terpenoid pattern. All the sesquiterpene lactones isolated from T. uulgare possess an a-methylene-y-lactone moiety, and this feature has been claimed to be characteristic of the whole genus Tanaceturn.

During some studies on T. vulgare growing wild and/ or cultivated in different geographical locations, some

~~

Table 2. Germacranolides in Tunucetum L. reported between 1W3-1993 Structure Name Plant species References

Costunolide

Tatridin A

Tatridin B R = H , F O H R ' = H

Tanachin R = H, a-OH R ' = H

Tamarin R = O R'=H

T. vulgare

T. partheniurn

T. vulgare

T. cinerariifoliurn T. vulgare

T. cinerariifoliurn T. vulgare

T. argyrophyllurn T. vulgare

T. rnyricophyllurn T. chiliophyllurn

Nan0 et al., 1980 Sanz and Marco, 1991 Bohlmann and Zdero, 1982

Nan0 et al., 1980 Appendino etal. , 1982a Ognyanov and Todorova, 1983 Sanz and Marco, 1991 Sashida et al., 1983 Nan0 et a/., 1980 Appendino et al., 1982a Ognyanov and Todorova, 1983 Sanz and Marco, 1991 Sashida et a/., 1983 Yusunov et al., 1979 Nan0 etal., 1980 Sanz and Marco, 1991 Goren et a/., 1990 Yusunov eta/ . , 1979 Nan0 et al., 1980 Sanz and Marco, 1991 Mnatsakanyan and Revazova, 1973 Mnatsakanyan and Revazova, 1974

Tavulin T. vulgare Yusunov et a/., 1979 T. argyrophyllurn Goren et a/., 1990

cbl

lsospeciformin T. argyrophyllurn Goren et a/., 1990

& &

Artemorin T. vulgare Nan0 eta/ . , 1980

GJ-? R = H Appendino et al., 1982a

Sanz and Marco, 1991 Bohlmann and Zdero, 1982 T. partheniurn

Ridentin T. santolina Abduazimov et a/., 1980b R=OH T. santolinoides El Sebakhy et al., 1986

El Sebakhy and El Ghazouly, 1986


Table 2. continued

Structure Name Plant species

3/?-Hydroxyanhydroverlotorin T. parthenium

8a-Hydroxyanhydroverlotorin T. argyrophyllurn R=OH; R ’ = H

R=H; R’=OH

Tansanin T. santolina

Hanf ill in T. macrophyllum T. vulgare

Crispolide T. vulgare

Tanalbin A R = H

Tanalbin B R=OH

Mucrin R = H

Pyrethrosin R=Ac Parthenolide

Pyretin

Vulgarolide

References

Bohlmann and Zdero, 1982

Goren etal., 1990

Abduazimov etal., 1980a Yusunov etal. , 1981

Todorova and Ognyanov, 1985 Chandra etal. , 1987b

Appendino etal., 1982a

T. albipannosum

T. albipannosum

Goren and Jakupovic, 1990

Goren and Jakupovic, 1990

T. santolina Yusunov et al., 1981

T. vulgare Ognyanov and Todorova, 1983

T. parthenium Soucek et a/., 1961 Bohlmann and Zdero, 1982 Groenewegen et a/., 1986

Sanz and Marco, 1991 T. vulgare Nan0 eta;. , 1980

T. santolina Yusunov etal. , 1981

T. vulgare Appendino et a/ . , 1988

research groups reported the findings of several chemotypes characterized by the presence of sesquiterpene lactones with germacrane skeleton. However, since they are biosynthetically ‘simple’ sesquiterpene lactones, their occurrence may be regarded as systemati- cally less important.

Chemical investigation of samples of T. uulgare collected in the North of Italy, made it possible to ascertain the presence of different chemotypes in this area, producing at least seven germacranolides: parthenolide, costunolide diepoxide, artemorin, tatridin A and B, tanachin and tamirin (Nano et ul. , 1980; Appendino et al., 1982a, 1982b). These types of germacranolides, as well as isomeric molecules, have also been found in specimens collected in Cologne (Ger-

many) (Sanz and Marco, 1991), Bulgaria (Ognyanov and Todorova, 1983), and Russia (Yusunov et al., 1979).

New sesquiterpene lactones with a modified germacrane skeleton were isolated from several chemotypes of T. vulgare cultivated in Piedmont (Italy). Chemosystematic investigation of two chemotypes growing in Torino, and a closely related taxon T. vulgare var. crispurn, afforded a new hydroperoxysesquiterpene lactone, which was named crispolide (Appendino et al., 1982a). Crispolide itself might be the ultimate biogenetic precursor of vulgarolide, a new sesquiterpene lactone with a novel and rearranged skeleton. This compound was isolated from a cultivated chemotype of T. uulgare, and was characterized by the

x4 M . J. ABAD E T A L .

Table 3. Guaianolides in Tanaceturn L. reported between 1973-1993 Structure Plant species

T. vulgare

Name

Dehydrodesacetylrnatricarin

Reference

Ognyanov and Todorova, 1983

T. macrophyllum T. microphyllum Abad et a/.,1994

Todorova and Ognyanov, 1985 Hydroxyachillin

Curnarnbrin A

Curnambrin B R=Ac

R = H

T. santolina T. coronarium T. santolina

Yusunov et a/., 1978 El Masry et a/., 1984 Yusunov et al.. 1978 "y

T. macrophyllum Todorova and Ognyanov, 1985 Macrotanacin (i& k :

T. parthenium Bohlrnann and Zdero, 1982 Begley et a/ . , 1989

Estafiatin 6-8 Arteglasin A

R=AC Angeloylajadin

"=a4 Ca ni n (B.p-diepoxy)

T. indicum

T. indicum

Mladenova et a/ . , 1985

Mladenova et al., 1985

T. parthenium Bohlmann and Zdero, 1982 Groenewegen eta/ . , 1986 Begley eta/ . , 1989 Todorova and Ognyanov, 1985 Groenewegen et al., 1986

Artecanin (cl,u-diepoxy) T. macrophyllum T. parthenium

Tannunolide A

Tannunolide B R=Me; R '=H

R = H : R '=Me

T. annum Barrero et al., 1987

T. annum Barrero et a/.. 1987

on Tu nefuli n T. indicum var tuneful

Mladenova eta / . 1988

Tanaphartolide A (u-OH)

Tanaphartolide B ( F O H )

T. parthenium

T. parthenium

Bohlmann and Zdero, 1982 Groenewegen eta/ . , 1986 Bohlrnann and Zdero, 1982

Tanaphillin T. macrophyllum Todorova and Ognyanov, 1985

T. parthenium Wagner et al., 1988

REVIEW OF TANACETUM xs

presence of a cyclooctane system fused to a tetrahydro- pyrane and a y-lactone ring (Appendino et al., 1988).

There are also reports in the literature of several chemotypes of T. uufgare containing eudesmanolides as main sesquiterpene lactones, not the usual compounds in the genus Tanacetum. Several specimens growing in different geographical locations, yielded the eudesmanolides tanacetin (Samek er al., 1973), reynosin, lp-hydroxyarbusculin A (Grabarczyk et af., 1973; Ognyanov and Todorova, 1983), erivanin (Samek et a f . , 1975), dentatin A (Yusunov et a/., 1980), santamarin (Appendino et af., 1982b; Ognyanov and Todorova, 1983), 1-epi-ludovicin C, armefolin and magnolialide (Sanz and Marco, 1991).

The occurrence of sesquiterpene lactones in other species of Tanaceturn also has biogenetic importance, and reports of their phytochemical composition are recorded in the literature.

Some germacranolides present in different chemo-

types of T. uufgare have also been identified in other species of the genus. Parthenolide, for example, has been observed in European feverfew (T. partheniurn), a crude drug traditionally used as a herbal remedy in the treatment of migraine and arthritis, and reported as its main active principle (Bohlmann and Zdero, 1982; Berry, 1984; Johnson et a f . , 1985; Murphy et af., 1988). Furthermore, parthenolide exhibits a wide spectrum of biological activities, which we discuss later.

The germacranolide sesquiterpene lactone dihydro- ridentin was isolated from Tanacetum santofinoides (DC.) Feinbr. & Fertig, together with an isomer of this compound, a heliangolide with a la-hydroxy group (El Sebakhy et af., 1986; El Sebakhy and El Ghazouly, 1986). Ridentin and isoridentin were previously reported from Tanacetum santolina L. (Abduazimov et a f . , 1980b).

New germacranolides, the glaucolide-like sesquiterpene lactones named tanalbin A and B, were found in

Table 4. Eudesmanolides in Tunaceturn L. reported between 1973-1993

Structure OH

Name

Santarnarin

Erivanin

1P-Hyd roxya rbu scu I i n A

Reynosin R=H; R ' = H

Tanacetin

Dentatin A R=OH; R'=H

R=H; R'=OH

1-€pi-ludovicin C

Di hydro-B-cyclopyreth rosin

Ta narna n i n

Tanarnarin

Plant species References T. vulgare Appendino et a/., 1982b

Ognyanov and Todorova, 1983 Sanz and Marco, 1991 Abduazimov et a/., 1980b T. santolina

T. balsamita T. santolinoides

Samek et al., 1975 El Sebakhy and E l Ghazouly, 1986

T. vulgare Sarnek et a/., 1973 Sanz and Marco, 1991

T. vulgare

T. parthenium T. vulgare

Sarnek et al., 1973 Sanz and Marco, 1991 Bohlrnann and Zdero, 1982 Grabarczyk et a/., 1973

T. vulgare T. argyrophyllum

Yusunov et al., 1980 Goren et a/., 1990

T. vulgare Ognyanov and Todorova, 1983 Sanz and Marco, 1991

T. cinerariifolium Sashida et a/. 1983

T. densum Goren et al., 1992 subsp. amani

T. densurn

T. sinaicum

Goren et a/., 1992

Abdel-Mogib et a/., 1989 subsp. amani

86 M. J . ABAD E T A L .

Tanaceturn albipannosum. Hub.-Mor. et Grierson. These compounds have been isolated almost exclusively from members of the tribe Vernonieae in Compositae (Goren and Jakupovic, 1990).

Costunolide diepoxide and artemorin were also identified in T . parthenium (Bohlmann and Zdero, 1982). tatridin A and B in T. cinerariifofium (Sashida et a f . , 1983), tansanin in T . santolina (Abduazimov et a f . , 1980a; Yusunov et al., 1981), and tanachin and tavulin in Tanacetum argyrophyflurn (C. Koch) Tzvel. var. argyrophyffum, endemic species of Turkey (Goren et al., 1990). This last taxon, together with other species of Tanacetum, yielded eudesmanolides characteristic of T . uulgare: santamarin in T . santofina (Abduazimov et a f . , 1980b), reynosin in T. parthenium (Bohlmann and Zdero, 1982), and erivanin in T . santofinoides (El Sebakhy and El Ghazouly, 1986) and Tanacetum balsamita L. (Samek et al., 1975).

More recently, new eudesmanolides were isolated from Tanacetum densum (Lab.) Schultz Bip., subsp. amani Heywood, which is an endemic species to Turkey (Goren et al., 1992).

In spite of new germacranolides and eudesmanolides having been reported in several genera of Tanaceturn, they yielded mainly compounds representing the biogenetic derivatives of most of the other lactones found in T . vufgare, typical constituents in Compositae.

The guaianolides of the matricarin group, such as matricarin, desacetylmatricarin, desacetoxymatricarin, dehydroleucodin, arbiglovin, and achillin, are the most widespread lactones in the tribe. Their biosynthesis may be explained by a series of dehydration and epoxidation processes, starting from cumambrins. Cumambrins have been isolated in large amounts from several species of this tribe, but in the genus Tanaceturn, they have only been reported in T . santolina (Yusunov et al. 1978), and Chrysanthemum coronarium L. (= T . coronarium) (El Masry et al. , 1984).

As products of the biogenetic processes of these lactones, several guaianolides have been reported in Tanacetum: 11,13-dehydrodesacetylmatricarin in T . vufgare (Ognyanov and Todorova, 1983), hydroxyachillin in T . macrophyflum (Todorova and Ognyanov, 1985), and T . microphyffum (Abad ef al., 1994), and estafiatin. canin and artecanin in T . parthenium (Bohl- mann and Zdero, 1982; Begley et al., 1989). The two last guaianolides, canin and artecanin, were also isolated from T . macrophyflum (Todorova and Ognyanov, 1985). The guaianolides angeloylcumambrin B and arteglasin A, together with a new compound named angeloylajadin, were reported in T. indicurn (Mlade- nova et a f . , 1985).

Recent studies show the presence of new biogenetically closely related sesquiterpene lactones, named according to the species in which they have been isolated. Thus, macrotanacin was reported in T . macro- phylfum (Todorova and Ognyanov, 1985), tunefulin in T. indicum var. tuneful (Mladenova et a f . , 1988), and tannunolides A and B, two new guaianolides with a fulvene arrangement, in Tanaceturn aniturn L. (Barrero et al., 1987).

Sesquiterpene lactones with seco-guaianolide skeleton have also been reported in Tanaceturn. The first 1,lO-seco-guaianolides, called tanaphartolide A and B, were isolated, only in traces, from T . parthenium (Bohlmann and Zdero, 1982). A new secolactone.

tanaphillin, was found in a relatively larger amount in T. rnacrophylfurn growing in Bulgaria (Todorova and Ognyanov, 1985).

Finally, a review of the literature showed the interest of several research groups to study the contribution of terpenoid patterns to a better understanding of systematic relationships in the Tanaceturn species, and nowadays new detailed studies are currently being undertaken in this way (Wagner et a f . , 1988; Abdel-Mogib et al., 1989; Rustaiyan et al., 1990).

Sterols and other sesquiterpenic compounds. u p to now only a few reports of sterols and triterpenes occurring in the genus Tanacetum are available.

In 1982, Chandler et al. reported the wide range of pharmacological activities exhibited by plant sterols and triterpenes, and determined the nature of these compounds in T . uufgare. They identified 6-sitosterol as the major sterol, and a-amyrin as the major triterpene. They also identified the sterols stigmasterol, campesterol and colesterol, and the triterpenes 6- amyrin and taraxasterol. A fourth triterpene was tenta- tively identified as pseudo-taraxasterol, together with stearic acid (Chandra et a f . , 1987b).

Recently, some of these compounds have been reported in other species of Tanacetum, such as Tanacetum nubiginum Wallich ex DC. (Khetwall and Harbola, 1989), and Pyrethrum santofinoides DC. (= Tanacetum sinaicum Del. ex DC.) (Abdel-Mogib et al., 1989). The roots of this last species afforded rare and unusual triterpenes, specifically two further representatives of the rare type of malabaricane- triterpenes (Jakupovic et al., 1987).

The aerial parts of Tunucetunt heterotomum Bornm., which is an endemic plant in Turkey, afforded taraxasterol and epifriedenol, also identified in T . afbipanno- sum (Goren et al., 1988; Goren and Jakupovic, 1990).

Phenolic compounds

Flavonoids. Flavonoids comprise a large number of naturally occurring substances, widespread in the plant kingdom, and found practically in all parts of the plants. These compounds are chemically characterized by a C,-C& carbon skeleton, where the C, components are aromatic rings. Flavonoid patterns are syste- matically important within the Anthemideae, and they are particularly valuable in the study of intergeneric relationships.

A survey of the present available chemical data suggests that methylated flavones and flavonols, mainly aglycones, are the main classes of phenolic compounds in Tanacetum (Harborne et a f . , 1975; Emerenciano et a f . , 1987). Their occurrence is of special systematic interest in T . vufgare, a species which presents different chemotypes according to its chemical composition.

A chemosystematic investigation of several chemotypes of T . uulgare, the most widespread in the South of Piedmont, led to the isolation of a cytotoxic flavone, eupatilin (Nano et al., 1979, 1980; Appendino et a f . , 1982a, 1982b). However, the occurrence of this flavonoid is unusual in specimens collected in this area, and investigated by these authors. It is noteworthy that the chemotype containing tanacetols, found only in the Vermenagma valley, differed from the other so far

REVIEW OF TANACETUM

Name

FLAVONES Apigenin

Luteolin

Chrysoeriol Diosrnetin Jaceidin

Jaceosidin E u pati I i n

Hispidulin

Centaureidin Artemetin

FLAVONOLS Quercetin

lsorharnnetin

Axi I lari n

FLAVANON ES Naringenin Hornoeriodictyol lsosa kurarnetin

Substitution

5,7,4’-(OH),-6-MeO- 4‘,7’-dirnethylether

5,7,4‘-(OH),-7-glucuroc. 5,7,4’-(OH),-7-galacturoc.

methyl ester 5,7,3’,4‘-(OH),

3,6,3’-(MeO),

Plant species

T. vulgare

T. cinerariifolium

T. albipannosum T. cinerariifolium

T. cinerariifolium T. vulgare T. boreale

T. cinerariifolium T. vulgare T. vulgare T. cinerariifolium T. vulgare T. vulgare T. vulgare

T. sibiricum T. sibiricum T. albipannosum T. vulgare T. chilioph yllum T. santolinoides T. chilioph yllum T. santolinoides T. microph yllum T. dolichophyllum T. gracile

T. vulgare T. boreale

T. boreale

T. vulgare T. boreale

T. sibiricum T. microph yllum

T. sibiricum T. sibiricum T. sibiricum

~

Table 5. Flavones and flavonols in Tanaceturn L. reported between 1973-1993 References

Adikhodzhaeva et al., 1977 Appendino et al., 1983 Chandra et al., 1987b Sashida et al., 1983

Goren and Jakupovic, 1990 Sashida et al.. 1983

Sashida et al., 1983 Adikhodzhaeva et al., 1977 Stepanov et al., 1980; Stepanov and Glyzin, 1980 Sashida et al., 1983 Adikhodzhaeva et al., 1977 Adikhodzhaeva et al., 1977 Sashida et al., 1983 Ognyanov and Todorova, 1983 Ognyanov and Todorova, 1983 Nan0 et a/., 1980 Appendino et al., 1982a. b Stefanovic et al., 1985 Stepanov et al., 1981a Stepanov et al., 1981a Goren and Jakupovic, 1990 Wollenweber et al., 1989 Wollenweber et al., 1989 Wollenweber et al., 1989 Wollenweber et al., 1989 Wollenweber et al., 1989 Abad et al., 1993 Shawl, 1993 Shawl, 1993

Adikhadzhoeva et al., 1977 Stepanov et a/., 1980; Stepanov and Glyzin, 1980 Stepanov et al., 1980; Stepanov and Glyzin, 1980 Adikhadzhoeva et al., 1977 Stepanov et al., 1980; Stepanov and Glyzin, 1980 Stepanov et al., 1981 a Abad et al., 1993

Stepanov et al., 1981b Stepanov et al., 1981 b Stepanov et al., 1981 b

investigated in its content of flavonoids. It lacked eupatilin, present in fairly large amounts in all chemotypes studied in this geographical location, and instead contained large amounts of apigenin, which was not detected in the other chemotypes (Appendino et af., 1983).

Apigenin and luteolin, the most widespread flavonoids in the tribe, together with several flavonoid glycosides, were also identified in the preparation ‘tanacin’, a chemotype produced from flowers of T . uufgare growing in Russia (Adikhodzhaeva et af., 1977; Ban’Kovskii et af., 1978). These compounds, as well as new flavonoids such as jaceidin and jaceosidin, were also isolated from specimens collected in Bulgaria

(Ognyanov and Todorova, 1983), and India (Chandra et a[ . , 1987b).

Reports on the occurrence of flavonoids in other species of Tanaceturn, are also recorded in the literature. In Table 5, we indicate the characteristic flavonoids isolated from the genus Tanaceturn in the past two decades.

The aerial parts of T . boreale yielded the flavonoids aglycones, axillarin, luteolin, quercetin, and isorham- netin, as well as several glycosides (Stepanov and Glyzin, 1980; Stepanov et a f . , 1980). From Tanaceturn sibiricum L., these authors isolated the aglycons hispidulin, axillarin, and 5,7,3’-trihydroxy-3,4’-dimethoxy- flavone. Several flavanones were also identified


(Stepanov et al., 1981a, 1981b). Known flavones and 6-methoxy flavonols were also reported in T. cinerariifolium, Tanacetum chiliophyllum L., T . uulgare, and T . santolinoides (Sashida et al., 1983; Wollenweber et al., 1989).

The flavone artemetin, typical compound of Artemisia species, was also identified in Tanacetum dolichophyllum Kitam., and Tanacetum gracile Hook. P. and Thomas (Shawl, 1993).

More recently, our laboratory reported the isolation of two flavonoids from T . microphyllum, endemic species of the Iberian Peninsula: centaureidin, isolated for the first time in the genus Tanacetum, and 5,3'- dihydroxy-4'-methoxy-7-carbomethoxyflavonol (Abad et al., 1993). Regarding the presence of the carbometh- oxy group in this last compound, references have been found only in some models of isoflavones (Mabry et a!. , 1970).

Coumarins. Hydroxycoumarins are common constituents in the Anthemideae tribe, but have been isolated so far mainly from Artemisia and Achillea species. In the genus Tanacetum, we have only found reports of the coumarin derivatives in T . hererotomum, endemic species of Sivas (Turkey). During a chemosystematic investigation of the terpenic composition in this plant, Goren et al. (1988) identified the coumarins isofraxidin, 6,7,8-trimethoxycoumarin, and 6' ,7'-dimethoxyfeselol, together with an acetylenic compound.

More recently, Banthorpe and Brown (1989) established callus lines of two members of this genus, T . uulgare and T . parthenium, that produced significant amounts of secondary metabolites, such as coumarin derivatives. These tissue cultures, under a wide variety of conditions, produced scopoletin and isofraxidin in a relatively large amount, but did not accumulate detec- table quantities of characteristic components of the parent plant, e.g. terpenoids. The two coumarins pre- dominant in culture were either absent from, or were very minor components of the parent plant.

Tannins. They are not typical compounds in the Compositae family, but we have found reports in the literature of their occurrence in Tanacetum species, e.g. T . argyrophyllum, T . balsamita and T . chiliophyllum (Musaelyan et al., 1983).

Other chemical compounds

Finally, a few reports of the occurrence of other different constituents in Tanacetum species are available. Yakovlev and Sysoeva (1983) and Sysoeva et al. (1979) reported the polysaccharide composition in T . uulgare, and its relationships with geographical location and flowering period.

Alkaloids, not common constituents of aromatic plants, were, however, reported in some genera of Compositae, as Achillea and Artemisia (Hofer, 1987). In Tanacetum species, we have found reports of the alkaloid content in T . balsamita and T . boreale (Vasil'- Kevich, 1985).

Recently, in a research programme to investigate high altitude herbs growing in the Himalayan region of India, a chemical investigation of T . nubiginum afforded two new aliphatic hydroxy ketones: 22-

hydroxyoctacosan-25-one and 24-hydroxytricontan-27- one (Khetwall and Harbola, 1989). This is the first report of the finding of these compounds in nature.

PHARMACOLOGICAL ACTIVITIES

Compositae plants have been used for medicinal purposes for many centuries, showing several different biological activities. Plant belonging to the genus Tanacetum are reputed to have excellent medicinal values, and a large number of sesquiterpenoids and sesquiterpene lactones, which are typical constituents of these drugs, were isolated from Tanacetum species. These compounds might be partly or wholly responsible for the effect exhibited by the plants.

Sesquiterpenoids in general are known to have a wide range of biological and chemical properties. They are believed to possess antitumour and antihyperlipide- mic activities, and are also used clinically as analeptics, antibiotics, and antihelmintics (Wagner and Wolff, 1977; Woerdenbag et al., 1987). In recent times, sesquiterpenoids have attracted much attention as possible antiinflammatory and antiarthritic agents (Johnson et al. , 1985). Some reports of the biological activity of sesquiterpene lactones have described them as antiinflammatory, cytoprotective, antitumour, antimicrobial, antifeedant, cytotoxic, allergenic contact dermati- tic, and plant growth regulatory compounds (Hall et al., 1979, 1980; Giordano et a l . , 1990; Dey and Harborne, 1991).

Reports of the chemical composition in Tanacetum species, and the biological relationships between them, have been recorded in the literature for several decades.

The plant T. parthenium, known by the common name of 'feverfew', has been used in folk medicine since the Middle Ages in the treatment of migraine, asthma, rheumatism and gynecological problems (Berry, 1984). Since the publication of two double- blind placebo-controlled clinical trials in England, the interest in feverfew has spectacularly increased, and the drug has again become very popular in the treatment of migraine and arthritis (Johnson et al., 1985; Murphy et al. , 1988). These studies clearly established the poten- tial of feverfew as a prophylactic against migraine, with a reduction in the frequency and severity of headache, and in the degree of vomiting.

A number of hypotheses have been advanced by several research groups to account for feverfew's activity in relieving migraine symptoms and related pharmacological activities, but the actual mechanism has not been unequivocally established.

Collier et al. (1980) reported for the first time that extracts of feverfew inhibit prostaglandin biosynthesis, and that this action may account for its effectiveness as a herbal remedy in arthritis, pain and migraine. Subsequently, several authors strengthen this hypothesis, and have reported that feverfew inhibits arachido- nate products of the cycloxygenase and lipoxygenase pathways by a mechanism involving cellular phospholipase inhibition (Thakkar et al., 1983; Jain and Jahagirdar, 1985; Capasso, 1986; Losche et al., 1988a; Pugh and Sambo, 1988).

Moreover, in uitro studies with extracts of feverfew

REVIEW OF TANACETUM XY

showed inhibition of platelet aggregation from human platelet and granule secretion from polymorphonuclear leucocytes, as well as an inhibition of histamine release from rat peritoneal mast cells (Makheja and Bailey, 1981; Heptinstall et al., 1987; Hayes and Foreman, 1987; Losche et al . , 1988b). All these studies suggest that the inhibitory activity of feverfew may relate to its medicinal properties. However, it is thought that the ability of feverfew to inhibit release of serotonin (5- hydroxytryptamine) from blood platelets may be rele- vant to its effects in migraine (Heptinstall et al., 1985).

Fractionation and analysis of extracts of feverfew indicated that the components responsible for its activity are sesquiterpene lactones, typical compounds in all genus Tanaceturn (Groenewegen et al . , 1986). Examples of sesquiterpene lactones found in feverfew are canin, artecanin, santamarin and reynosin, but the component regarded as mainly responsible for the activity is the germacranolide sesquiterpene lactone parthenolide (Groenewegen and Heptinstall, 1990). In the clinical trials that have been performed, only feverfew that contained defined amounts of parthenolide was used.

All of the sesquiterpene lactones present in feverfew contain an a-methylenebutyrolactone unit as an integral part of their chemical structure. It is known that the activated methylene group in this unit renders it susceptible to nucleophilic attack, via Michael addition, with biological nucleophiles such as sulphydryl groups (Kupchan et al . , 1970). Sulphydryl groups are important constituents of the plasma membrane and cytoskeleton of various mammalian cells and may be involved in cell function. A perturbation of the sulphydryl/disulphide status by sulphydryl-affecting substances leads to functional alterations in different cells. It is possible then, that the antisecretory activity of such compounds is due to the blockage of molecules that contain sulphydryl groups (Groenewegen et al., 1986). Thus, it is important for the activity of feverfew that the a-methylenebutyrolactone unit in the compounds remains intact.

As well as having antisecretory and antiinflammatory activity, feverfew shows several properties that might be considered disadvantageous rather than advan- tageous, and that require an assessment of the benefits and safety of this plant in man. One of these disadvantageous properties is its capacity to induce contact dermatitis in some individuals, an effect that appears to be brought about by sesquiterpene lactones, such as parthenolide, present in the plant (Hausen and Osmundsen, 1983; Mensing et al., 1985).

At any rate, in the past few years the use of feverfew as a therapy, mainly for migraine and arthritis, has been popularized to such an extent that various types of commercial preparations are on sale in most pharmacy and health food shops, at least in England. For this reason, it became apparent that a sensitive and accur- ate assay method for the quantification of parthenolide and related sesquiterpene lactones, was required to provide evidence of source, purity and quality of the lactonic material, and to prevent adulterants.

This need for a simple assay in commercial feverfew preparations, which would be easily accessible to the herbal industry, led to the development of different procedures by several research groups (Kery et al . , 1988; Burford and Smith, 1989; Fontanel et al. , 1990; Awang et al . , 1991; Dolman et al . , 1992).

Other Tanacetum species, widely compiled from the flora of Europe, Turkey and Russia, have also been used traditionally as herbal remedies because of their pharmacological and microbiological properties.

T . oulgare is used in folk medicine in the treatment of gastroduodenal diseases, and because of its anthielmin- tic and antiseptic properties (Font-Quer, 1979; Sysoeva et al., 1984). Several authors have reported the microbiological and antibacterial activity of the essential oil from T . uulgare (Tetenyi et al., 1981; Schearer, 1984; Holopainen and Kauppinen, 1989), and its sesquiterpene lactones (Nawrof, 1983). The chemotype p- thujone, widely distributed in Europe, Asia and North America, is also employed as a vermifuge (Gallino, 1988).

Reports of the microbiological properties in other Tanaceturn species, are also recorded in the literature. This activity is due mainly to sesquiterpene lactones in T . indicum var. tuneful (Jawad et al . , 1985), and T . argyrophyllum (Goren et al . , 1990), and to terpenoid constituents of its essential oil in T . cilicium, T . corymbosum, and T . macrophyllum. These last species also reported anticoagulant and antifibrinolytic properties (Thomas, 1989a, 1989b, 1989~).

Finally, T. microphyllum, a drug widely used in Spanish traditional medicine, contains principles with antiinflammatory and antiulcerogenic properties, which make it possible to corroborate its use as a herbal remedy (Abad e t a l . , 1991, 1993, 1994).

Acknowledgements

This work was supported in part by Grant PB/870908C0201 CAICYT, and a Scientific Research Grant from Complutense University, Madrid, Spain.

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An approach to the genusTanacetum L. (Compositae): Phytochemical and pharmacological review

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