Abstract

REVISÃO

Lychnophorinae (asteraceae): a survey of its chemical constituents and biological activities^# # This paper is dedicated to Prof. Hans Viertler

Larissa Costa Keles^I; Nathalya Isabel de Melo^I; Gabriela de Paula Aguiar^I; Kamila Akemi Lima Wakabayashi^I; Carlos Eduardo de Carvalho^I; Wilson Roberto Cunha^I; Antônio Eduardo Miller Crotti^I; João Luis Callegari Lopes^II; Norberto Peporine LopesII, ^* * e-mail: npelopes@fcfrp.usp.br

^INúcleo de Pesquisas em Ciências Exatas e Tecnológicas, Universidade de Franca, 14404-600 Franca - SP, Brasil

^IIDepartamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, 14040-903 Ribeirão Preto - SP, Brasil

ABSTRACT

This work reviews the current literature about the chemical constituents and the biological activities of the subtribe Lychnophorinae (Vernonieae, Asteraceae). The notable secondary metabolites are sesquiterpene lactones of furanoheliangolide (goyazensolide and eremantholide types) and flavonoids. Some of its most investigated activities include its anti-inflammatory, analgesic, antimicrobial and cytotoxic activities, specially for the Lychnophora and Eremanthus species. The data presented on this paper not only displayed the role played by the Lychnophorinae species as a source of bioactive compounds, but also reinforced the need of further studies involving the species of such subtribe.

Keywords: Lychnophorinae; Lychnophora; sesquiterpene lactones.

INTRODUCTION

The subtribe Lychnophorinae belongs to the tribe Vernonieae of Asteraceae (Compositae). Most of its genera is found on the Brazilian's rupestrian vegetation (Table 1), which is present on the top of mountain chains on the Central and Southeastern regions of Brazil, especially in Minas Gerais, Bahia and Goiás, all presenting many species¹ with a high degree of endemism.

Due to the taxonomic complexity of the Lychnophorinae, the genera of this subtribe have received considerable attention and several previous classification had to be changed.^2-4 In the most recent literature review of Lychnophorinae, Robinson³ considered the following ten genera: Anteremanthus H. Robinson, Chronopappus DC, Eremanthus Less. (syn. Sphaerophora Schultz-Bip = Paralychnophora MacLeish), Vanillosmopsis Schultz-Bip, Lychnophora Mart. (syn. Haplostephium Mart.), Lychnophoriopsis Schultz-Bip. (syn Episcothamnus H. Robinson), Minasia H. Robinson, Piptolepis Schultz-Bip, Pithecoseris Mart., and Proteopsis Mart & Zucc. ex Schultz-Bip.

The terpenoid chemistry of this subtribe is mainly formed by furanoheliangolide sesquiterpene lactones (STL).⁴ The biological activities of these compounds were extensively investigated in the literature. Some species of the subtribe Lychnophorinae have also been employed in Brazilian traditional medicine. For example, the Lychnophora species, popularly known as "arnica da serra" or "falsa arnica" are used as analgesic and anti-inflammatory agents.⁵ Some species also have an economic importance, such as Eremanthus erythropappa, popularly known as "candeia" in Portuguese, whose essential oil is rich in α-bisabolol and it is used in several cosmetic preparations.⁶

Based on the economical and social importance of the subtribe Lychnophorinae, the goal of this work is to present a current literature review on the secondary metabolites and biological activities of the species of such subtribe in order to provide a basis for several different research areas such as botanic, pharmaceutical, medical and chemical fields.

SECONDARY METABOLITES OF LYCHNOPHORINAE

The chemical composition of Eremanthus and Lychnophora, the two most numerous genera of Lychnophorinae have been extensively investigated, as clearly seen by the number of papers dealing with this matter. On the other hand, some genera of this subtribe (i.e., Anteremanthus, Chronopappus and Pithecoseris) have not been submitted to phytochemical studies yet. Previous studies have been mostly focused on the investigation of extracts from the aerial parts or leaves of this subtribe, although a number of studies on roots have also been reported.^7-16 The secondary metabolites mentioned earlier were usually identified and/or isolated from extracts obtained by maceration with non-polar (n-hexane or petroleum ether) or moderately polar solvents (i.e., dichloromethane, chloroform, and ethyl acetate). Nevertheless, more recent studies have focused on the chemical composition of alcoholic and hydroalcoholic extracts.^11,12,17,18 Alternative extraction methods, such as glandular trichomes microsampling¹⁹ and sonication-assisted extraction²⁰ have also been investigated.

Figure 1 shows the main groups of secondary metabolites that have been described for the Lychnophorinae species, and theirs structures are shown in Figures 5-21. Terpenoids (70.2%) and flavonoids (16.9%) are the notable secondary metabolites of Lychnophorinae, although acetylene derivatives (2.6%), quinic acid derivatives (5.0%), benzoic acid derivatives (0.4%), phenylpropanoids (1.4%), and lignans (1.2%) have also been reported. It must be mentioned that the lack of data on the chemical composition of polar fractions and hydroalcoholic and aqueous extracts have direct influence on the number of occurrences of such metabolite groups in literature.

Among the terpenoids, there is a predominance of sesquiterpenes (65.8%), which are reported to be present in each species of the subtribe, as shown in Figure 2. Triterpenes (26.9%), steroids (2.9%), saponins (0.3%) and monoterpenes (3.7%) have also been noted, whereas diterpenes (0.2%) were found only in Lychnophora selowii.²¹ Regarding the sesquiterpenes, sesquiterpene lactones (STL) are reported to be isolated and/or identified in 90% of the species investigated. This class of secondary metabolites is divided into groups (i.e., germacranolides, eudesmanolides, guaianolides, furanoheliangolides, among others) according to their structural diversity, which results of enzyme-catalyzed and eventually selective oxidations, cyclizations, condensations and rearrangements of their common biosynthetic precursor (farnesylpyrophosphate, FPP).²² Because of their number of occurrence and structural diversity, STLs have been used as chemotaxonomic markers of various taxa of Asteraceae,²³ including the subtribe Lychnophorinae.^4,22

Furanoheliangolides from the goyazensolide and eremantholide types are the most common STLs in Lychnophorinae, as shown in Figure 3. They have been reported to be the major STL of all the investigated species, except for Lychnophoriopsis candelabrum, Lychnophora pseudovillosissima and L. reticulata, in which the predominance of guaianolides and eudesmanolides were observed. Furanoheliangolides of the eremantholide type has been proposed to be biosynthesized from a goyazensolide type of STL by means of a Michael-type addition to the exocyclic double bond conjugated with the lactone carbonyl (Figure 3).^22,24 The conversion of goyazensolide-type into eremantholide in laboratory was recently achieved by making use of Striker's reagent.²⁵ Most of the furanoheliangolides from goyazensolide type occurring in Lychnophorinae have the same structural core, but they differ on the degree of oxidation and substituents at C-8. The majority mostly exhibit exocyclic double bond between C-11 and C-13 (94.8%) and an oxygenated group (a hydroxyl or an acyloxy group) bounded at C-8 (100%), followed by common methacryloxy (52.2%), angeloxy (36.5%), tigloxy (11.3%) or their derivatives. In contrast, oxygenated groups at C-15 (26.9%) and double bonds between C-4 and C-5 (74.8%) are less common. The oxygenated groups at C-8 from mostly of the STL of Lychnophorinae are usually α-orientated in relation to the mean plane of the ring, as reported for other subtribes of Vernonieae.²² Differently, the furanoheliangolides of the eremantholide type mostly shows double bond between C-4 and C-5 (72.7%) and hydroxyl at C-1' (93.5%), whereas oxygenated groups at C-15 are rarely found (20.8%).

Flavonoids also have a widespread occurrence in the subtribe Lychnophorinae. Flavonols (37.4%) and flavones (38.7%) have higher percentages of occurrence than dihydroflavones (12.9%), dihydroflavonols (9.7%) and chalcones (1.3%). Methoxyl (53.3%) and glycosyl (25.0%) are the most common substituent groups in flavones. The glycosyl groups are often bounded at C-6 and C-8 or at C-8 solely. In the case of flavonols, only 37.9% exhibit free hydroxyl group at C-3 (B ring), once this group is the precursor of methoxyl (32.8%), glycosyl (8.6%) and heteroside groups (20.7%). Chalcones have been identified only in Lychnophora ericoides.²⁶

Opposed to terpenoids and flavonoids, whose occurrence is widespread in Lychnophorinae, some classes of secondary metabolites have been restricted to some species. Lignans were isolated only from roots of Lychnophora ericoides,¹¹ and quinic acid derivatives have been found only in some Lychnophora species (L. ericoides,^12,27L. pinaster,²⁸L. pohli²⁸ and L. vilosissima²⁸) and Lychnophoriopsis candelabrum.²⁸

BIOLOGICAL ACTIVITIES OF LYCHNOPHORINAE

Although fifty species of Lychnophorinae have been submitted to phytochemical studies, up to now only twenty-eight species were investigated regarding their biological activities, as shown in Table 2. Several biological activities from the species of the Lychnophorinae subtribe have been evaluated, and their mostly common reported activities are antimicrobial, anti-inflammatory, tripanocidal, toxicity, analgesic and antinociceptive (Figure 4).

Extracts from the Lychnophora species have been used in the Brazilian folk medicine as analgesic and anti-inflammatory. For this reason, a number of studies have focused on the evaluation of crude extracts and pure compounds for their analgesic and anti-inflammatory potential. Guzzo and co-workers²⁹ investigated the antinociceptive activity of the ethanol aerial parts extracts of five Lychnophora species using hot-plate and writhing tests. They reported that the Lychnophora pinaster (0.75 g/kg) and Lychnophora ericoides (1.50 g/kg) extracts significantly increased the time for paw licking in mice. By using the dose of 0.75g/kg for Lychnophora passerina, Lychnophoriopsis candelabrum and Lychnophora pinaster, and doses of 0.75 and 1.50 g/kg for both Lychnophora ericoides and Lychnophora trichocarpha it was observed a significant reduction on the number of writhes induced by acetic acid. This activity was initially proposed due to the presence of sesquiterpene lactones.³⁰ However, Grael and co-workers³¹ reported that extracts of the aerial parts of Lychnophora granmongolense showed no analgesic activity in the writhing model of pain, even though the STLs goyazensolide (84) and centratherin (92) were isolated from those extracts. These results, in combination with those obtained for the L. salicifolia extracts,³² suggested that not all the Lychnophora species could exhibit analgesic activity correlated to the accumulation of sesquiterpene lactones. Differently, lignans¹¹ and di-caffeoylquinic acid derivatives,¹² isolated from roots of Lychnophora ericoides exhibited interesting analgesic activity. More recently, di-caffeoylquinic acid derivatives were also identified in the leaves of L. ericoides,²⁶ thus indicating that these compounds can be responsible for the analgesic activity of the hydroalcoholic extracts used by the Brazilian population.

Rungeler and co-workers³³ investigated the anti-inflammatory activity of 28 sesquiterpene lactones (STL), which are commonly found in leaves and aerial parts of extracts of Lychnophora and other species from the subtribe Lychnophorinae. These compounds are known to inhibit the transcription factor NF-κB by selectively alkylating its p65 sub-unit probably by reacting with cysteine residues.³⁰ The authors proposed that the α-methylene-γ-lactone and α,β-unsaturated carbonyl can alkylate the cysteine residue (Cys 38) in the DNA binding loop 1 (L1) and a further cysteine (Cys 120) in the nearby E' region. This cross link alters the position of tyrosine 36 and additional amino acids in such a way that their specific interactions with the DNA become impossible.³³ However, Gobbo-Neto and co-wokers¹⁸ recently reported that vicenin-2 (258), isolated from the methanol extract of the leaves of Lychnophora ericoides showed significant anti-inflammatory activity in the carrageenan-induced rat paw edema, thus indicating that this compound is responsible for the anti-inflammatory activity. More recently, Dos Santos and co-workers³⁴ demonstrated that vicenin-2 (257) exhibits no effect on tumor necrosis factor (TNF)-α production, but inhibits, in a dose-dependent manner, the production of prostaglandin (PG) E2 without altering the expression of cyclooxygenase (COX)-2 protein. Also, the authors reported that 3,5-dicaffeoylquinic acid (333) and 4,5-dicaffeoylquinic acid (332), at lower concentrations, had small but significant effects on reducing PGE2 levels; at higher doses these compounds stimulated PGE2 and also TNF-α production by the cells. Both compounds 333 and 332, in a dose-dependent manner, were able to inhibit monocyte chemoattractant protein-3 synthesis/release, with compound 332 being the most potent at the highest tested concentration. These results strongly suggested that the anti-inflammatory effect of hydroalcoholic extracts of L. ericoides are due to the presence of compounds 332 and 333, rather than sesquiterpene lactones. In addition, Guzzo and co-workers²⁹ investigated the ethanolic extracts of the aerial parts of five Lychnophora species for their anti-inflammatory and antinociceptive activities. They reported that administration of Lychnophora pinaster and Lychnophora trichocarpha ointments, in both evaluated concentrations (5 and 10%, w/w), and Lychnophora passerina and Lychnophoriopsis candelabrum, in the concentration of 10%, significantly reduced the paw edema measured 3 h after carrageenan administration, suggesting, for the first time, an anti-inflammatory activity upon topical administration of these species. However, the authors did not report the chemical composition of those extracts.

Despite the fact that sesquiterpene lactones have a widespread occurrence in the Eremanthus species, most of the biological activities of this genus are due to their essential oils from the leaves and stems. Nascimento and co-workers³⁵ investigated the activity of Eremanthus erythropappus oil and some of its compounds and their potential synergistic interaction with ampicillin against different strains of Staphylococcus aureus. They identified β-bisabolene as the main active constituent and reported its potential to restore the effectiveness of ampicilin against the resistant S. aureus.

Recently, the antimicrobial activity of this oil against Candida albicans and Salmonella ssp was also reported, but the major constituents were β-pinene and β-caryophyllene instead of β-bisabolene.⁶ More recently, the essential oil of E. erythropappus was also investigated for its antinociceptive and anti-inflammatory activities.³⁶ The authors found that doses of 200 and 400 mg/kg inhibited 10.69% and 27.06% of acetic-acid-induced writhing in mice, respectively. In the formalin-induced nociception test in mice, the essential oil inhibited the first phase of paw licking by 29.13% (400 mg/kg) and the second phase by 32.74% (200 mg/kg) and 37.55% (400 mg/kg). In the hot-plate test in mice, doses of 200 and 400 mg/kg significantly increased the reaction time after 30, 60 and 90 min of treatment. Doses of 200 and 400 mg/kg inhibited carrageenan-induced paw edema in rats by 15.18 and 36.61%, respectively. Doses of 200 and 400 mg/kg administered 4 h before intra-pleural injection of carrageenan significantly reduced exudation volume (by 20.20 and 48.70%, respectively) and leucocyte mobilization (by 5.88 and 17.29%, respectively).

The trypanocidal activity of the Lychnophora species has been extensively investigated in the literature. In this case, however, these studies are part of an intensive search for active compounds against Trypanosoma cruzi, the etiology agent of Chaga's disease, therefore, they are not correlated with the use of species from the subtribe Lychnophorinae in traditional medicine. The bioguided fractionation of the crude extracts of L. passerina, L. pinaster and L. trichocarpha resulted in the isolation of the bioactive sesquiterpene lactones goyazensolide (84), eremantholide C (116), lychnopholide (91), and lychnophoic acid (57).³⁷ Goyazensolide and eremantholide C were 100% active at concentrations of 240 and 3600 μg/mL, whereas lychnopholide inhibited 50% of the grown of trypomastigote forms at concentration of 150 μg/mL.³⁸ Besides goyazensolide, centratherin (92) and the flavonoid eridictyol (303), isolated from L. granmongolense were also found to be active against T. cruzi.³¹ Quercetin 3-methyl ether (291), isolated from L. staavioides showed also significant trypanocidal activity.³⁹

Flavonoids and sesquiterpene lactones have also been investigated for their citotoxicity^40-42 and genotoxicity.⁴³ Recent studies performed by Vasconcellos and co-workers⁴³ demonstrated that 15-deoxygoyazensolide (83) is mutagenic in Saccharomyces cerevisae due to the possible intercalation effect, in addition to the pro-oxidant status that exacerbates oxidative DNA damage. Studies on the toxicity of the essential oil of Eremanthus erythropappus have also been reported.^44,45

CONCLUDING REMARKS

In this literature review, information concerning the occurrence and pharmacological activities of secondary metabolites isolated from species of the subtribe Lychnophorinae were collected. Sesquiterpene lactones of furanoheliangolide (goyazensolide and eremantholide types) and flavonoids are the distinguished secondary metabolites. Anti-inflammatory, analgesic, antimicrobial and cytotoxic properties are amongst the most investigated activities in the literature, mainly for the Lychnophora and Eremanthus species. However, a number of species of Lychnophorinae has not been submitted to phytochemical or pharmacological studies yet. Furthermore, although vicenin-2 and di-caffeoylquinic acids have been reported responsible for the anti-inflammatory and analgesic activities of the hydroalcoholic extracts of Lychnophora ericoides used in the medicine folk, a number of other species of Lychnophorinae used by the Brazilian population for medicinal purposes remains unknown until now. In this context, data presented herein demonstrated not only the role played by species of Lychnophorinae as source of bioactive compounds, but also reinforce the need of further studies involving species of such subtribe.

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Recebido em 1/7/10; aceito em 21/9/10; publicado na web em 27/10/10

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