Pilocarpus spp.: a survey of its chemical constituents and biological activities

Pilocarpus spp.: revisão sobre sua constituição química e atividades biológicas

REVIEW

Pilocarpus spp.: a survey of its chemical constituents and biological activities

Pilocarpus spp.: revisão sobre sua constituição química e atividades biológicas

Ana Paula Santos; Paulo Roberto Hrihorowitsch Moreno^*

Laboratório de Química de Produtos Naturais, Departamento de Química Orgânica, Instituto de Química, Universidade de São Paulo

ABSTRACT

Pilocarpus species have been exploited as the only source of the imidazole alkaloid pilocarpine (used in glaucoma treatment), since its isolation up to the present. Almost all Pilocarpusspecies are native from Brazil. Because of the medicinal importance of pilocarpine, several of them are in the path of extinction. Other secondary metabolites, such as coumarins, flavonoids and terpenes, were described for Pilocarpusspecies. In this review the secondary metabolites, other than pilocarpine, isolated from Pilocarpusspecies and their biological activities were compiled. Although the variety of structures and the importance of the biological activities described in literature for Pilocarpusspecies this is an unexploited field of research in Natural Products and Pharmacology.

Uniterms:Rutaceae. Pilocarpus spp. Secundary metabolites. Biological activities

RESUMO

Espécies de Pilocarpus têm sido exploradas como única fonte do alcalóide imidazólico pilocarpina (utilizado no tratamento do glaucoma) desde o isolamento dessa substância até os dias atuais. A maioria das espécies de Pilocarpus conhecida é nativa do Brasil e, devido à importância medicinal que a pilocarpina possui e ao desmatamento, várias se encontram em risco de extinção. Outros metabólitos secundários entre os quais cumarinas, flavonóides e terpenos foram descritos em espécies desse gênero. Nesta revisão foram relacionados os metabólitos secundários isolados em diversas espécies de Pilocarpus bem como suas atividades biológicas. Apesar da variedade de estruturas e as importantes atividades biológicas já descritas na literatura para as outras classes de metabólitos secundários, ainda há um vasto campo de estudo para as espécies de Pilocarpus.

Unitermos: Rutaceae. Pilocarpus spp. Metabólitos secundários. Atividades biológicas.

INTRODUCTION

Pilocarpus Vahl is one of the 150 genus that compose the Rutaceae family and it was first known in Europe from the reports of the early scientific expeditions made to Brazil (Gabriel Soares de Souza, in 1570, Guilherme Piso, in 1637, and Georg Marcgrave, in 1638). Several Pilocarpus species are popularly known by the name of "jaborandi" which was derived from the tupi-Guarani language, ya-mbor-endi (the one who causes mouth-dripping) (Holmsted et al., 1975). Several Rutaceae species are important due to their economical value as food, ornamental and medicinal uses. Some of the most common examples are listed in Table I.

The Pilocarpus genus was defined in 1797 with the descriptions of the species P. racemosus, however the position of the new taxon was not indicated (Skorupa, 1996). The initial conflicts in the systematic studies of the Rutaceae family imposed difficulties to classify this genus (Pirani, 1999; Albuquerque, 1985).

The most complete study about this genus was performed by Kaastra (1982) that kept the classification of Pilocarpus accordingly to Engler and recognized the genus Raulinoa Cowan as part of the subtribe Pilocarpineae (Scheme 1).

The Pilocarpus species are distributed in a large region of the American continent from Southern Central-America (Mexico) until the Southern part of the South-American continent (Argentina, Paraguay). There are 16 species described for this genus accordingly to Skorupa (1996). From these 13 can be found in Brazil, and 11 occur exclusively in the Brazilian territory (Table II).

These plants started to be studied concerning their pharmacological properties only in 1873, when it was confirmed that "jaborandi" was a potent stimulant of the secretory system, showing sialagogue, diuretic and diaphoretic activities (Corrêa, 1969). Since then, infusions of "jaborandi" leaves have been used for the treatment of fevers, stomatitis, bronchitis, gout, psoriasis, kidney diseases and several others illnesses (Holmsted et al., 1975).

After the isolation of the imidazole alkaloid pilocarpine (Figure 1, compound 1), in 1875 (Gerrard, 1875; Hardy, 1875), and its employment in ophthalmology (Weber, 1876), the "jaborandi" reached the status of one of the most important plants in the Brazilian flora (Pinheiro, 1997).

Besides alkaloids, a number of secondary metabolites have been reported in Pilocarpus species such as coumarins (Amaro-Luis et al., 1990), flavonoids (Bertrand et, al 2001), hydrocarbons (Skorupa et al., 1998; Negri et al., 1998), triterpenes (Andrade Neto et al., 1994) and volatile oils (Craveiro et al., 1979).

The main goal of this review is to point out the importance of the Pilocarpus spp. as a source of secondary metabolites in Rutaceae with a potential pharmacological activity.

SECONDARY METABOLITES OF PILOCARPUS SPP.

Alkaloids

The "jaborandi" alkaloids are mainly of the imidazole group and it is thought that L-histidine is the biosynthetic precursor of the imidazole moiety (Battersby, Openshaw, 1953; Brochmann-Hanssen et al., 1975; Cordell, 1981; Dewick, 2000).

Pilocarpine and other related alkaloids were isolated from several Pilocarpus species (Table III). Although the structural resemblance, only pilocarpine posses CNS activity, as a direct cholinergic which stimulates the parasympathetic system (bladder, tear ducts, sudoriferous and salivary glands). This alkaloid is the elected drug in the glaucoma treatment (Korolkovas, 1996) and the sialagogue property of pilocarpine has been exploited to treat the xerostomy (dry mouth) caused by the radio- or chemotherapy of throat cancer or those in the head area (Miller, 1993; Valdez et al., 1993).

Others alkaloids derived from L-tryptophan were also isolated from Pilocarpus species. Some examples are N,N-dimethyl-5-methoxy-triptamine (10) and N,N-dimethyl-triptamine (11) (known as DMT) obtained from P. organensis leaves; both have a CNS activity causing hallucinations (Balsam, Voigtländer, 1978).

Dictamine (14) a quinoline alkaloid obtained from P. grandiflorus posses a structural relationship with coumarins and, probably because of this resemblance, this substance exhibited a photosensitizing activity (Ashwood et al., 1982).

Coumarins

Coumarins are secondary metabolites biosynthesized from p-coumaric acid (a phenylalanine derived). Besides the simple coumarins, like scopolentin (28), in Pilocarpus species are also found pyrano- or furanocoumarins either with linear - xantyletin (13), chalepin (32) and bergapten (20) - or with an angular structure - allo-xantoxilletol (17) and 3-methoxy-angelicin (24). Some coumarins found in Pilocarpus species may also be O-prenylated - donatin (18), imperatorin (23) - or C-prenylated - osthole (30).

Although studies on the isolation of secondary products from Pilocarpus sp. have been performed for a long time, the isolation of coumarins has only been reported just over a decade ago from the leaves of P. goudotianus (Amaro-Luis et al., 1990). The efficacy of the jaborandi infusions in the treatment of skin diseases such as psoriasis and vitiligo might be related with this class of natural products. Nowadays, several coumarins (particularly the 8-methoxy-psoralen (21)) have been used for skin repigmentation (Manderfeld et al., 1997).

Some coumarins also showed good results as germination inhibitors (MACÍAS et al., 1993), insecticide (Calcagno et al., 2002; Ngwedson et al., 2003; Manderfeld et al., 1997), antioxidant (Shaw et al., 2003; Hoult, Paya, 1996), and against Chagas' disease (Pavão et al., 2002; Mafezoli et al., 2000). Synthetic coumarins derived from seselin (35) exhibit potential activity against HIV (Huang et al., 1994).

The known coumarins isolated from Pilocarpus species and their respective structures are listed in Table IV and Figure 2.

Flavonoids

Flavonoids represent one of the most important groups of phenolic natural products and, like coumarins, they are also biosynthesized from L-phenylalanine. These metabolites are obtained from Citrus species (Rutaceae) from seeds, fruits, flowers and leaves (Middleton, 1984). Among others, the suggested activities of flavonoids are: analgesic (Thirugnanasambanthan et al., 1990), sedative (Medina et al., 1997; Marder & Paladini, 2002), anti-inflammatory (Pathak et al., 1991).

The antioxidant activity of these substances is due to the ability of reducing free radical formation and to scavenge free radicals. Accordingly to Makersby (1997), the neurodegenerative Alzheimer's disease manifestation is related to the production of these species in the organism. In this sense, flavonoids can be considered as promising drugs in the treatment of this disease (Kim et al., 2002).

Hesperidin (46) was isolated from P. trachyllophus (Bertrand et al., 2001). This substance is currently isolated from other Rutaceae, such as Citrus and Zanthoxylum species (Kanes et al., 1993; Horowitz, Gentili, 1963; Arthur et al., 1956). This flavonoid has various pharmacological activities and some of them are anti-inflammatory, bactericidal, fungicidal, antiviral, abortive, analgesic and antipyretic (Garg et al., 2001). Recently, hesperidin was obtained from Valeriana species ("the Valium of 19^th century") and also exhibited sedative and sleep-enhancer properties (Marder et al., 2003).

The following flavonoids, listed in Table V, were isolated from P. trachyllophus leaves.

Terpenes

Several reports dealt with the terpenes present in Pilocarpus species, mostly in volatile oils. Terpenes are biosynthesized from IPP (isopentenyl diphosphate), through the mevalonate pathway that gives rise to the mono- (C10), sesqui- (C15), di- (C20) and triterpenes (C30).

There are many references about the importance of terpenes in plant metabolism, mainly as essential oils. Although it is of general sense that terpenes represent a fundamental tool in pollinator's attraction, guaranteeing a species reproduction. They also displayed a variety of biologic activities such as insecticide, antimicrobial and antiseptic (Figueiredo, 1992). The essential oils of P. spicatus, P. gradiflorus and P. pauciflorus species exhibited bactericidal activity against Bacilus subtilis, Salmonella typhimurium, Escherichia coli and Pseudomonas aeruginosa (Santos et al., 1997).

Although the occurrence of triterpenes and steroids in plants is quite common, and these compounds were only reported in three Pilocarpus species (Table VI and Figure 4). For P. grandiflorus the triterpenes b-amyrin (109), occotilone (111) and germanicol (114) were described. The b-amyrin acetate (110) obtained from P. trachyllophus showed a high cytostatic activity against cells of HEp-2 (Gomez et al., 1997).

Additional pharmacological activities, such as angiogenic, antihelminthic, antimicrobial and antitumoral, were described only for the steroid β-sitosterol (86) (Moon et al., 1999; Villasenor et al., 2002; Singh, Singh, 2003; Awad et al., 2003).

Other secondary metabolites isolated fom Pilocarpus species

Besides alkaloids, coumarins, flavonoids and terpenes there are minor compounds that can occur in some Pilocarpus species. Among these compounds are lignans, hydrocarbons and its alcohols, amides, carboxilic acids, esters and ketones derivatives (Table VII and Figure 5).

Lignans (also L-phenylalanine derivatives) were obtained from two different Pilocarpus species (Table VII). Lignans play an important role in the plant sustentation as cell wall constituents. The lignan lirioresinol B (124), isolated from P. grandiflorus (De Souza et al., 2003), showed antichagasic activity (Sauvain et al., 1996).

The amide pellitorine (125) was found in P. trachyllophus (Andrade Neto et al., 1995). This substance is frequently isolated from Piper species and it is widely known as an insecticide (He et al., 2002).

The pattern of n-alkanes is considered an important taxonomic marker in plant classification accordingly to Eglinton et al. (1962). The n-alkanes identified in leaf epicuticular waxes of different Pilocarpus species with a carbon chain ranging from C₁₄ to C₃₃ (Skorupa et al., 1998). An aromatic hydrocarbon (C₂₀) was detected only in P. jaborandi and this substance was considered a marker for the species (Negri et al., 1998).

CONCLUDING REMARKS

In this review, information concerning the occurrence and pharmacological activities of secondary metabolites isolated from Pilocarpus spp were collected. Alkaloids, coumarins, flavonoids and terpenoids are current compounds to this genus (Guerreiro et al., 2001). Compounds derived from L-phenylalanine are predominant in this genus.

Although the medicinal value of pilocarpine is widely recognized, but the importance of other secondary metabolites obtained from Pilocarpus species was not yet well described. The summary of the main bioactive compounds, other than pilocarpine, described for Pilocarpus species are listed below:

1. From the 16 known

   Pilocarpus species, alkaloids have only been described in eight species (almost 1 alkaloid/species) (

   Table III), and for the majority of them the bioactivity was not yet determined;

2. There are a few reports over the presence of coumarins in

   Pilocarpus spp., however the pharmacological activities of this class o f compounds are numerous;

3. Flavonoids have been increasingly described as antioxidant drugs but these compounds were only found in

   P. trachyllophus (

   Table V);

4. Only two lignans were isolated from two

   Pilocarpus species and one of them has been described as an antichagasic agent (

   Table VII).

The use of plants in folk medicine has lead scientists to find a wide variety of active substances of invaluable importance to mankind. Considering the variety of metabolites isolated from Pilocarpus, these species represent a vast research field to be exploited.

Recebido para publicação em 01 de março de 2004.

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Publication Dates

• Publication in this collection
  23 Mar 2010
• Date of issue
  June 2004

History

• Received
  01 Mar 2004