Borreria and Spermacoce species (Rubiaceae): A review of their ethnomedicinal properties, chemical constituents, and biological activities.

Borreira and Spermacoce are genera of Rubiaceae widespread in tropical and subtropical America, Africa, Asia, and Europe. Based on its fruits morphology they are considered by many authors to be distinct genera and most others, however, prefer to combine the two taxa under the generic name Spermacoce. Whereas the discussion is still unclear, in this work they were considered as synonyms. Some species of these genera play an important role in traditional medicine in Africa, Asia, Europe, and South America. Some of these uses include the treatment of malaria, diarrheal and other digestive problems, skin diseases, fever, hemorrhage, urinary and respiratory infections, headache, inflammation of eye, and gums. To date, more than 60 compounds have been reported from Borreria and Spermacoce species including alkaloids, iridoids, flavonoids, terpenoids, and other compounds. Studies have confirmed that extracts from Borreria and Spermacoce species as well as their isolated compounds possess diverse biological activities, including anti-inflammatory, antitumor, antimicrobial, larvicidal, antioxidant, gastrointestinal, anti-ulcer, and hepatoprotective, with alkaloids and iridoids as the major active principles. This paper briefly reviews the ethnomedicinal uses, phytochemistry, and biological activities of some isolated compounds and extracts of both genera.

INTRODUCTION

The Rubiaceae family comprises one of the largest angiosperm families, with 650 genera[1] and approximately 13,000 species,[2] distributed mainly not only in tropical and subtropical regions, but also reaching the temperate and cold regions of Europe and Northern Canada.[3] In Brazil, this family comprises about 130 genera and 1500 species distributed across different vegetation formations, with a great occurrence in the Atlantic Forest.[3-5] This family is currently classified in three subfamilies and over 43 tribes.[2] The tribe Spermacoceae (subfamily Rubioideae), which belongs to the genera Borreria G.F.W. Mey. and Spermacoce L., is characterized by a herbaceous habitat, with over 1000 species have a mainly pantropical distribution, but a few genera extend into temperate regions, excluding New Zealand.[67]

The genera Borreria and Spermacoce, the largest of the tribe Spermacoceae, comprises about 280 species distributed in tropical and subtropical America, Africa, Asia, and Europe.[8] In Brazil, 36 Borreria species were recorded, of which 22 are endemics.[910] Based on its fruits morphology, they are considered by many authors to be distinct genera and most others, however, prefer to combine the two taxa under the generic name Spermacoce.[611] In this work, they were considered as synonyms. This review reports an account of the species used in traditional medicine, their phytochemical profile, and biological activities of isolated compounds, mainly alkaloids and iridoids, and extracts. The data collected are based on the papers published up to September 2011 and the data bases assessed include Chemical Abstracts, Napralert, and ISI Web of Science.

Ethnomedicinal properties

Borreria and Spermacoce species are used medicinally in various manners and are reputed in traditional medicine of Latin America, Asia, Africa, and West Indies. The species most used as medicinal are described below:

B. alata (Aubl.) DC. [Syn.: S. alata Aubl., S. latifolia Aubl., B. latifolia (Aubl.) K. Schum.] is a herbaceous species native to South America.[1213] In Nepal, the roots juice this plant is used to treat malaria.[14]

B. articularis (L. f.) F. N. Williams [Syn.: S. articularis L.f., S. scabra Willd. and B. hispida (L.) K. Schum.)], commonly known in Brazil as “poaia”, is originally native to the temperate and tropical Asia regions and naturalized in Africa and Australia.[15] The leaves of this plant are used as ophthalmic, inflammation of eye and gums, blindness, carache, fever, spleen complaints, sore, conjunctivitis, hemorrhage, gallstones, dysentery, and diarrhoea,[1516] and the decoction of the leaves, roots, and seeds is used in India for dropsy.[17]

B. centranthoides Cham. and Schltdl. (Syn.: B. centranthoides f. glabrior Chodat and Hassl.), known in Brazil as “sabugueirinho do campo”, is a perennial herb originating from fields in southern Brazil, and possibly Uruguay and Argentina. In Brazil, these plants have been used for the treatment of liver ailments,[1819] kidneys disorders,[20] and in Argentina as an abortifacient.[21]

B. eupatorioides Cham. and Schltdl. (Syn.: B. polyana DC, S. eupatorioides (Cham. and Schltdl.) Kuntze, and Galianthe eupatorioides (Cham. and Schltdl.) E.L. Cabral) is an herb which decoction of the leaves is used in Argentina with Petroselinum crispum (Mill.) Nyman ex. AW Hill. or Gymnopteris tomentosa (Lam.) as emmenagogue and the roots as a contraceptive,[22] and for diarrhea, and urinary and respiratory infections.[23]

B. hispida (Linn.) K. Schum. (Syn.: S. hispida L.) is being used as an alternative therapy for diabetes.[24] In India, decoction of the plant is used for headache[25] and the seeds as stimulant[26] and for the treatment of internal injuries of nerves and kidney.[27]

B. laevis (Lam.) Griseb. (Syn.: S. laevis Roxb. and S. assurgens Ruiz and Pavon) is a small herb found in the tropical regions of Asia.[28] Also occurs in Mexico, where decoction of the leaves is used to treat kidney pain and prevent menstruation[29] while the entire plant in admixture with Cuscuta L. and Zebrina pendula Schum is used for amenorrhea in Jamaica[30] and West India.[31] In Jamaica, the tea of the entire plant boiled with Desmodium Desv. and Iresine paniculata Kuntze also is used as diuretic.[30]

B. latifolia (Aubl.) K. Schum. (Syn.: S. latifolia Aubl.), known in Brazil as “poaia-do-campo”, is an annual erect herb that occur in the Americas.[332]

B. ocymoides (Burm. f.) DC. (Syn.: S. ocymoides Burm. f.) is common in all America, also occurs in eastern Africa and East India.[9] In Nigeria, the juice of the leaves is applied for ring worm and eczema and the sap is squeezed on to the wound or lesion.[33]

B. princeae K. Schum. [Syn.: S. princeae (K. Schum.) Verdec.] is a scrambling or decumbent perennial herb, native to Africa, where is used for the treatment of skin diseases.[34]

B. pusilla (Wall.) DC. [Syn.: B. stricta (Linn. f.) K. Schum., S. pusilla Wall.] is an annual erect herb native to tropical Africa and Asia. In India, the fresh buds associated with flowers are used for cuts and wounds[35] and crushed of leaves are applied to the affected areas for bone fracture and scabies, and for snake and scorpion bites.[36]

B. verticillata (L.) G. F. W. Mey. (Syn.: S. verticillata L.), known in Brazil as “poaia”, “poaia preta”, “poaia miúda”, “coroa-de-frade”, and “vassourinha”, is a small perene and erect herb, originating from South and Central Americas and distributed by the Old World, Southern United States to South America.[937] In Brazil, the infusion of the flowers is used as antipyretic and analgesic,[3839] the roots as emetic and leaves as antidiarrheal, and for treat erysipelas and hemorrhoids.[40] In West India, the decoction of this plant is used for diabetes and dysmenorrhea, and when prepared with Cuscuta and Zebrina Schnizlein is used for amenorrhea;[31] while in Senegal it is used to treat bacterial skin infections and leprosy.[41] In Nigeria, fresh aerial part juice is applied for eczema[34] and in Jamaica the decoction of the endocarp, prepared jointly with Iresine P. Browne. and Desmodium, is used as a diuretic and as a remedy for amenorrhea mixed with Cuscuta and Zebrina.[30]

Spermacoce exilis (L.O. Williams) C.D. Adams [Syn.: B. exilis L.O. Williams, B. gracilis L.O. Williams, B. repens DC., S. repens (DC.) Fosberg and J. M. Powell, and S. mauritiana Gideon] is a weak erect, decumbent, or procumbent annual herb distributed in Africa and America and is used for headache.[42]

CHEMICAL CONSTITUENTS AND SOME OF THEIR BIOLOGICAL ACTIVITIES

The widespread uses of Borreria and Spermacoce species in traditional medicine have resulted in considerable chemical investigation of the plants and their active principles. The first phytochemical report was published in 1961, and revealed the detection of (-)-emetina (7) from roots of B. verticillata.[43] Today, over 60 compounds distributed in different classes have been isolated [Table 1]. Alkaloids, iridoids, flavonoids, and terpenoids are the main groups of constituents. Among them, alkaloids and iridoids displayed in vivo or in vitro some biological activities.

Table 1

Compounds isolated from Borreria and Spermacoce species

Alkaloids

A total of eleven alkaloids [Table 1 and Figure 1], containing indole [borrecapine (1), borrecoxine (2), borreline (3), borrerine (4), dehydroborrecapine (6), verticillatine A (10), and verticillatine B (11)], bis-indole [borreverine (5), isoborreverine (8) and spermacoceine (9)] and tetrahydroisoquinoline [(-)-emetine (7)] skeletons have been isolated from B. capitata,[44-46] Borreria spp.,[47] and B. verticillata.[39414348-52] Phytochemical screening indicated the presence of emetine in B. poaya DC., B. suaveolens var. platyphylla (K. Schum.) Standl., B. verbenoides Cham. and Schltdl., and B. verticillata.[48] Among isolated alkaloids, borreverine tartrate showed in vitro antibacterial activity against Sarcina lutea (MIC 3.0 μg/mL), Vibrio cholerae (MIC 12.5 μg/mL), and Staphyloccocus aureus (MIC 100 μg/mL).[41]

Figure 1

Alkaloids isolated from Borreria species

Emetine (7) is a tetrahydroisoquinoline alkaloid that occurs mainly in Psychotria ipecacuanha Stokes (Rubiaceae), also known as Cephaelis ipecacuanha A. Rich.[5354] The first use of emetine in medicine was as emetic and expectorant.[55] Later, other properties were being discovered and today several important biological activities are reported for this compound. Among which are anticancer,[56-58] antiparasitic,[59-61] antiviral,[6263] contraceptive,[6465] inhibition of protein, DNA and RNA synthesis, reduction of T-2 toxin toxicity association with cells, and inhibition of the nonsense-mediated MRNA decay (NMD) pathway.[63] However, its medicinal use has been discouraged due to its toxicity.[63]

Iridoids

Thirteen iridoids (12–24) have been isolated from B. latifolia,[66] B. verticillata,[383967] and S. laevis[27] [Table 1 and Figure 2]. Among these compounds, asperuloside (12) was claimed as muscle anabolic steroids,[68] inhibited TNF-α, decreased IL-1β prodution, reduced formation of PGE2, and treated rheumatoid arthritis in mice.[69] This compound, along with deacetylasperulosidic acid (18) and scandoside (24) exhibited in vitro activity against the Epstein-Barr virus.[70] Deacetylasperulosidic acid (18, 63.8 ± 1.5%) and scandoside (24, 62.2 ± 1.6%), inhibited LDL-oxidation, at 20 μg/ml.[71] Compounds 12, 18 and methyl deacetylasperulosidate (23) showed purgative effects in mice[72] and 23 lowered the blood glucose level in normal mice.[73]

Figure 2

Iridoids and flavonoids isolated from Borreria and Spermacoce species

Asperolosidic acid (13) showed weak inhibition against TPA-induced inflammation in mice (ID50 > 1.0 mg/ear) and exhibited moderate effects against the EBV-EA activation induced by TPA (IC50 578 mol).[74] It also was effective in suppressing TPA- or EGF-induced cell transformation and associated AP-1 activity. TPA- or EGF-induced phosphorylation of c-Jun was also blocked.[75] Compounds 12, 13, borreriagenin (15), deacetylasperuloside (17), and 6α-hydroxyadoxoside (21) were inactive as antioxidants (IC50 > 30 μmol)[7677] and compounds 13 and 18 did not exhibit hypoglycemic effects in STZ-induced diabetic mice.[78]

Compounds 12 and 13 suppressed germination of large crabgrass, alfalfa, and white clover to 52 and 56, 58 and 80, and 30 and 40%, respectively, at 400 ppm.[79] Compounds 12 and 23 also were tested for their inhibitory activities toward germination and seedling growth of several plant species. Compound 12 inhibited growth of rice and lettuce seedlings at 10-4 to 10-3 mol, while 23 had no inhibitory activity.[80] Iridoid 13 did not show any effect in vitro on the soybean lipoxygenase and bovine testis hyaluronidase.[81]

The insecticidal activity of 13, 18, 10-hydroxyloganin (22), and 24 against ants (Crematogaster scutellaris) and termites (Kalotermes flavicollis) was evaluated. Significant levels of toxicity was observed only for 22.[82]

Flavonoids

Only eight flavonoids (25–32) have been isolated from Borreria and Spermacoce species [Table 1 and Figure 2]. All are free or glycosides flavonols derivatives and their occurrence are restricting to B. stricta [astragalin (25), quercetin (29) and rutin (32)],[8384] B. hispida [isorhamnetin (26)][26] and S. laevis [kaempferol 3-O-β-D-glucopyranoside (27), kaempferol 3-O-rutinoside (28), quercetin 3-O-β-D-galactopyranoside (30), quercetin 3-O-a-L-rhamnopyranosyl-(1→6)-β-D-galactopyranoside (31), and rutin (32)].[28]

Terpenoids

The Borreria species also contains pentacyclic triterpenoids of oleanane- and ursane-types [Table 1 and Figure 3]. From the chloroform extract of the aerial parts and roots of B. auricularis, a plant used in traditional medicine for several purposes,[1516] seven triterpenes were isolated [3a-acetoxy-olean-12-en-29-oic acid (33), β-amyrin (34), 3-keto-olean-12-en-29-oic acid (41), epikatonic acid (38), ursolic acid (45), ursolic acid methyl ester (46), and uvaol (47)].[85-87] Furthermore, from the essential oil and aerial parts of B. verticillata two sesquiterpenes, caryophyllene (39) and guiaene (40), were isolated, respectively.[3488] From the seeds of B. stricta[84] and B. hispida,[89] β-sitosterol (43) and ursolic acid (45) were isolated; and from aerial parts of B. latifolia the diterpene phytol (42) was isolated.[66]

Figure 3

Terpenoids found in Borreria species

Other classes of compounds

Besides the above-mentioned groups of compounds, two benzyl (48-49), four (Z)-3-hexenyl (50-53), three phenylethyl glycosides derivatives (55-57), and a megastigmane glycoside (58) [Table 1 and Figure 4] were isolated from aerial parts of S. laevis[28] and from aerial parts of B. articularis 6-methyl-5-cyclodecen-1-ol (54) was also isolated.[16] This compound exhibited antibacterial (MIC 500–2000 μg/mL and MBC 1000–3000 μg/mL) and antifungal (MIC 750–1500 mg/mL and MFC 1500–3000 mg/mL) activities against Aspergillus niger, A. ustus, A. ochraceus, Bacillus cereus, B. megaterium, B. subtilis, C. albicans, E. coli, P. aeruginosa, S. aureus, S. dysenteriae, S. sonnei, S. typhi, S. paratyphi, and V. cholerae.[16]

Figure 4

Miscellaneous compounds found in Borreria and Spermacoce species

From B. stricta[8384] and B. articularis[85] two alcohols (59-60) and four carboxylic acids (61-64) were isolated [Table 1 and Figure 4]. In addition, seventeen amino acids, including a protein and three carbohydrates have been identified from the leaves and seeds of B. stricta.[8384] A recent study on B. verticillata roots has led to the isolation of mixtures of aliphatic acids, tri-O-acylglycerols and sucrose, and glucose and sucrose.[39]

Volatile components

Fatty acids, monoterpenoids, aromatic compound, and alcohol were identified by GC-MS from S. ocymoides[90] and some fatty acids and terpenoids, such as linalool, eugenol, β-bisabolene, E-β-farnesene, phytol and terpineol,[91] guaiene,[34] and phytol, 1,8-cineole, α-pinene, and p-cymene[92] were identified by GC-MS from the aerial parts of B. verticillata.

BIOLOGICAL ACTIVITIES OF CRUDE EXTRACTS

Borreria and Spermacoce species possess a wide variety of medicinal properties. So far, a few species have been screened for confirmation of their biological activities. Experimental results have shown some species as antimicrobial, antitumor, antioxidant, anti-inflammatory, hepatoprotective, larvicidal, etc. The various biological activities reported from different extracts of Borreria and Spermacoce species are summarized in Table 2.

Table 2

Biological activities for crude extracts and fractions of Borreria and Spermacoce species

CONCLUSIONS

Given the small of species chemically studied, no definite conclusions can be drawn about chemical relationships among Borreria and Spermacoce species. However, the classes of compounds found are suggestive of chemical patterns in the tribe Spermacoceae. The most representative classes of compounds found were mainly alkaloids (only Borreria species) and iridoids (in two genera) which have been found in species from America (e.g. B. capitata and B. verticillata), Europe and Africa (e.g. B. verticillata) and Asia (e.g. B. latifolia and S. laevis) as well as in species of other genera of Spermacoceae. Flavonoids were found only in species from Asia (B. hispida, B. stricta, and S. laevis). Thus, the common possession of alkaloids and iridoids by few groups of species should be viewed as retention of an ancient characteristic or as a mark of natural affinity. Therefore, a molecular phylogeny of Borreria and Spermacoce, including plants with known chemistry, would be extremely helpful to clarify trends in the chemical evolution of the genera.