Send Orders for Reprints to [email protected] 290 The Natural Products Journal, 2014, 4, 290-298 Chemical Constituents and Biological Activities of Simira Genus: A Contribution to the Chemotaxonomic of Rubiaceae Family
Vinicius F. Moreira*, Ivo J. C. Vieira and Raimundo Braz-Filho
Sector of Natural Products Chemistry, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes-28013-602, RJ, Brazil
Abstract: The Simira genus belongs to the Rubiaceae family. Studies of this genus have attracted interest, mainly due to phototoxic activities, antifebrile, tonic and purgative presented by some secondary metabolites isolated from drug value of species of this genus. This study is a review of the Simira genus, through the acquisition of data from studies of phytochemicals and evaluation of biological activities of the species that compose it, in order to contribute their chemotaxonomic classification within the family. Keywords: Biological activities, chemical constituents, chemotaxom, phytochemicals, Rubiaceae, Simira.
1. INTRODUCTION genus was reordered into the subfamily Ixoroideae with the tribe Condamineeae by using molecular phylogenetic data Rubiaceae family includes approximately 660 genera and reconstruction [10]. about 11,150 species [1]. In molecular phylogenetic studies, this family is divided into three subfamilies: Cinchonoideae, Facing these changes in the classification of the genus Ixoroideae and Rubioideae [2, 3]. within subfamilies and tribes, it is necessary to gather data from various fields of study in order to confirm the position Occupying the fourth place in diversity among the of this genus within the family. In this review we sought, Angiosperms, behind only the Asteraceae, Orchidaceae primarily, chemical data collection and the main evaluations and Leguminosae [4], the Rubiaceae family has a wide of biological activities. distribution, mainly in tropical and subtropical regions, also reaching temperate and cold regions of Europe and Northern 2. METHODOLOGY Canada [5]. In America, the family is represented by approximately 229 genera and 5,200 species [6]. In Brazil, Data collection was conducted through websites and there are about 118 genera and 1,347 species, corresponding portals of academic research and databases: www.ibict.br, to one of the main families of our flora, even though a large www.scielo.org, www.sciencedirect.com, https://scifinder. number of species are still without any biological or cas.org, www.scirus.com and www.periodicos.capes.gov.br. phytochemicals studies [7]. The terms used in the strategy for scientific publications This vast family has a great range of chemical structures search were outlined by genus, species and family. With the goal of giving greater scope to the bibliographical study, which vary little, but with very significant pharmacological some specific terms related to phytochemical studies and potential. Among the classes of secondary metabolites biological activities were also selected. presented by the family, one can highlight iridoids, anthraquinones, triterpenes and indole alkaloids, the latter The academic papers and scientific publications obtained being considered as a chemotaxonomic marker of the family for the genre are sorted and presented in this study on [8]. Numerous chemical constituents such as flavonoids and four items: phytochemical studies, biological activities, other phenolic derivatives and Terpenoids (Diterpenes), are ethnopharmacological activities and other studies, according also found in this family [9]. to the information presented. From the Rubiaceae family, Simira genus was classified 3. THE Simira GENUS in the subfamily Cinchonoideae and in the tribe Rondeletieae based on morphological data. However, phylogenetic studies The Simira genus includes 45 species distributed in the based on molecular data places Simira in the tribe Simireae Neotropics, from Mexico to Bolivia, Paraguay and Brazil, within the subfamily Ixoroideae [3]. Recently, the Simira with reported species in the flora of Colombia, Venezuela, Costa Rica, Panama, Belize, Ecuador, Peru, Guyana and
Argentina. It is represented in Brazil by approximately 19 *Address correspondence to this author at the Sector of Natural Products species distributed among the States of Amazonas, Pará, Chemistry, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Goiás, Espírito Santo, Rio de Janeiro, São Paulo, Paraná and 28013-602 Campos dos Goytacazes-RJ, Brazil; Tel: +55 22 2748 6504; E-mail: [email protected] Santa Catarina, inserted in the Atlantic forest. Eight species
2210-3163/14 $58.00+.00 © 2014 Bentham Science Publishers Chemical Constituents and Biological Activities of Simira The Natural Products Journal, 2014, Vol. 4, No. 4 291
Table 1. Substances isolated from the genus Simira.
Substances Species References
Alkaloids
Harman (1) S. mexicana, S. glaziovii, S. rubra, S. salvadorensis, [19, 22, 23, 25, 30] S. eliezeriana, S. grazielae
Ophiorine A (2) S. glaziovii, S. tinctoria, S. williamsii, S. grazielae [21, 24, 30]
Ophiorine B (3) S. glaziovii, S. tinctoria, S. williamsii [21, 24]
Sickingine (4) S. tinctoria, S. williamsii [24]
5α-Carboxystrictosidine (5) S. tinctoria, S. williamsii [24]
Lyalosidic acid (6) S. tinctoria, S. williamsii [24]
Maxonine (7) S. maxonii [26-28]
Methyl lyalosilate (8) S. glaziovii [21]
Pentaacetyllyalosidic acid (9), S. glaziovii [21]
1,22-Lactamlyalosíde (10) S. glaziovii [21]
Harmine (11) S. tinctoria, S. williamsii [24]
Strictosamide (12) S. mexicana [25]
N-acetyl-serotonin (13) S. grazielae [30]
Coumarins
Isofraxidine (14) S. glaziovii, S. grazielae [22, 30]
Scopoletine (15) S. glaziovii, S. tinctoria, S. williamsii, S. grazielae [22, 24, 30]
Dimethylfratexine (16) S. glaziovii, S. grazielae [22, 30]
7-Hydroxy-8-methoxycoumarin (17) S. grazielae [30]
5,7-Dimethoxycoumarin (18) S. grazielae [30]
Terpenoids
Simirane A (19) S. eliezeriana [23]
Simirane B (20) S. glaziovii, S. eliezeriana [22, 23]
Lupeol (21), S. glaziovii [22]
Lupenone (22) S. glaziovii [22]
1β,3β-Dihydroxyolean-12-en (23) S. glaziovii [21]
Oleanoic ácid (24) S. tinctoria, S. williamsii [24]
Eufol (25), S. glaziovii [29]
Butirospermol (26), S. glaziovii [29]
Steroids
Sitosterol (27) S. glaziovii, S. eliezeriana, S. grazielae [21-23, 29, 30]
Stigmasterol (28) S. glaziovii, S. eliezeriana, S. grazielae [22, 23, 30]
Campesterol (29) S. glaziovii, S. eliezeriana [22, 23]
3β-O-β-D-Glicopyranosylsitosterol (30) S. glaziovii, S. grazielae [21, 30]
β-Sitostenone (31), S. glaziovii [22]
Stigmastenone (32) S. glaziovii [22]
3-O-Glicopyranosyl-(6,1)-acil-sitosterol (33) S. glaziovii [22] 292 The Natural Products Journal, 2014, Vol. 4, No. 4 Moreira et al.
Table 1. contd….
Substances Species References
Iridoids
Loganin (34) S. tinctoria, S. williamsii [24]
Sweroside (35) S. tinctoria, S. williamsii [24]
Secoxyloganin (36) S. tinctoria, S. williamsii [24]
Lignans
Pinoresinol (37) S. eliezeriana, S. grazielae [23, 30]
Pinocebrine (38) S. glaziovii [22]
Other substances
Methyl hexadecanoate (39) S. glaziovii [21]
Hexadecanoic acid (40) S. glaziovii [21]
Octadecanoic acid (41) S. glaziovii [21]
Eicosanoic acid (42) S. glaziovii [21]
Inositol (43) S. glaziovii [29]
Methyl trans-4-hydroxy-3-methoxycinnamate (44) S. glaziovii [21]
Coniferyl aldehyde (45) S. eliezeriana [23]
Syrigaldehyde (46) S. eliezeriana, S. grazielae [23, 30]
3,4,5-Trimethoxyphenol (47) S. grazielae [30]
6’-O-Vaniloilchioside (48) S. grazielae [30]
are found in the Southeast region, five of which occur in the photo-dermatitis in humans and predators, conferring an State of Rio de Janeiro [7, 11-14]. evolutionary advantage to the plants that have these The name Simira is popular in Guyana. In Brazil, species substances [19]. of this genus are known as araribá, araribá-vermelha, araribá- Simira species with reports in the literature of chemical rosa, araribá-branca, quina-rosa, canela-samambaia, maiate e studies until now are presented in Table 1, where the isolated marfim [11]. substances are listed, and where the names of the species from which we isolated the substances, and the original The genus is represented by small to large trees with bibliographic references of the citations referring to the species of economic interest, known for their tinctorial, substances are. The structures for these substances are timber, craft and landscape values for the planting of streets. represented in Fig. 1, and the biosynthetic pathway for these It is characterized by presenting brown or greyish heartwood, structures is in Torssell 1997 [20]. yellowish or greyish sapwood when freshly cut, and generally acquiring reddish, purplish or pink color when 3.1. Biological Activities of Simira Genus exposed to air and/or brightness which disappears a few months after collection [15-17]. The bibliographic survey highlighted studies on assessment of biological activities from extracts of the species Simira The interest on the chemical study of Simira species is glaziovii and S. sampaioana against Mycobacterium fortuitum based mainly on activities and substances of phar- and M. malmoense. We conducted a susceptibility screening macological value that were already identified in this genus, to determine the activity of extracts and partitioned plant with many of these species being used by the local extracts at fixed concentrations of 100 µg/mL, where the species community as producers of coloring, antifebrile, tonic and of Simira genus were not effective against mycobacteria purgative substances [17]. under study at this concentration [31]. The Simira genus presents as its striking feature; the Methanolic extracts from bark, flowers, fruits, leaves and presence of β-carbolinic alkaloids, which are found in plants stems of the species S. glaziovii and S. sampaioana were known to affect the central nervous system [18]. Another also assessed against anthracnose, caused by the fungus characteristic of this genus is the incidence of phototoxic Colletotrichum lindemuthianum in beans. The test was substances, presented by some of their chemical constituents, performed in microtiter plates. Each extract was dissolved in that function as a defense mechanism for the plant, causing 500 µl of 0.01 g/mL Tween-80 and 20 µL was added to Chemical Constituents and Biological Activities of Simira The Natural Products Journal, 2014, Vol. 4, No. 4 293
A COOH R1 N+ R N 2 N N N O N H CH H H H 3 H GluO O
H OGlu
(1) (2) R1 = COO- ; R2 = H (3) R1 = H ; R2 = COO- (4)
COOH H CH3 N COOH N NH H COOCH3 N N N H H H O O N H O H OGlu H OGlu
(7) (5) (6)
OR
OR N N O H O OR N N OR H O H R2 H O O H AcO O H OR1 O O AcO AcO OAc
(8) R1= CH3; R=R2=H (10) (9) R1= H; R=R2=Ac
H O O HO N N N H3CO N N CH H 3 H O H H N
OGlu
(11) (13) (12)
294 The Natural Products Journal, 2014, Vol. 4, No. 4 Moreira et al.
Fig. (1). contd.... B
OCH3 H3CO O O HO O O H3CO O O
HO H CO H3CO 3 OCH 3 (16) (14) (15)
HO OCH3 O OCH3 O O HO O O
H3CO OH (18) (17) (19)
HO O
HO (20) (21) O
(22)
H R
H HO HO H (23) R = CH3 (24) R = COOH (25)
R1
HO R2O
(27) R1 = Et; 22,23-dihydro; R2 = H (26) 22 (28) R1 = Et; ! ; R2 = H (29) R1 = CH3; 22,23-dihydro; R2 = H (30) R1 = Et; 22,23-dihydro; R2 = Glu
Chemical Constituents and Biological Activities of Simira The Natural Products Journal, 2014, Vol. 4, No. 4 295
Fig. (1). contd.... C
(31) 22-23 - dihydro (32) !22
O
O
n O O O
HO OH (33) HO
O OCH3 COOCH3 H H OGlu COOH
HO O O O O H O OGlu H3C OGlu (36) (35) (34)
R
OH OH HO O OH OCH3 HO OH
H3CO O O (43)
RO O HO n H3CO R (39) R = CH3; n= 13 R1 (40) R = H;n =13 (37) R = H (41) R = H;n =15 R2 (38) R = OCH 3 (42) R = H;n =17 (44) R1=R2 = OCH3 (45) R1 = H; R2 = OH
O H3CO OH H3CO H O OH
HO H3CO O OCH3 OCH3 OCH3 HO O (46) (47) HO O (48) OH
Fig. (1). (A). Substances isolated from the genus Simira. Biosynthetic route in Torssell, 1997 - alkaloids: p. 382-391. (B). Substances isolated from the genus Simira (continued). Biosynthetic route in Torssell, 1997 - coumarins: p. 153-156; diterpenes: p. 275-282; triterpenes: p. 283- 292; steroids: p. 293-300. (C). Substances isolated from the genus Simira (continued). Biosynthetic route in Torssell, 1997 - steroids: p. 293- 300; other substances: p.156-166. 296 The Natural Products Journal, 2014, Vol. 4, No. 4 Moreira et al. a conidial suspension of C. lindemuthianum at a The isolated substances from the species S. williamsii concentration of 1.2 x 106 conidia/m and the plates were and S. tinctoria, were tested under the same experimental incubated at 22°C for 72 hours. The extracts were considered conditions at concentrations of 500, 250 and 100 µg/ml in an inactive because they did not present visual inhibition of organ bath, dissolved in distilled water, with a contact time -4 fungal growth, according to the parameters adopted for this of 15 min. The substances (4) with IC50 = 1.0 x 10 mol/L, -4 -5 evaluation [32]. (5) with IC50 = 1.3 x 10 mol/L, (3) with IC50 = 5.3 x 10 -4 Yet for extracts of S. glaziovii and S. sampaioana, an mol/L, (6) with IC50 = 1.3 x 10 mol/L, (34) with IC50 = 1.0 x 10-4 mol/L and (35) with IC = 4.0 x 10-4 mol/L, showed evaluation of activity against Mycobacterium tuberculosis 50 significant inhibitory effect on EIC. The results suggest and Mycobacterium kansasii was performed, showing minimal that these extracts have neurosedative properties (neuro- inhibitory concentrations (MIC) higher than 100µg/ml. The pharmacological effect). The other isolated substances from results were not considered significant in a susceptibility these two species showed no activity [18, 36]. screening, which was performed to determine the activity of extracts and plant extract partitions [33]. Harman alkaloid (1) isolated from Mexican Simira species was tested and presented toxicity against Artemia The assessment of antioxidant potential, by using the salina (LC 25µg/ml), and exhibited moderate activity in DPPH method, showed the highest activity to the 50 vitro against Plasmodium falsiparum (IC 0.97µg/ml) [25]. hidromethanolic partition of the stems of S. glaziovii (EC 50 50 The same alkaloid isolated from S. salvadorensis, was tested 21.50 ± 0,30 ppm), to the partition of ethyl acetate of the stems of S. eliezeriana (EC 12.03 ± 0.07 ppm) and the for phototoxicity, showing growth inhibition of Sacharomyces 50 cereviceae, with inhibition zone of 4 mm (50µg/disc), a hydromethanolic (EC 1.200 ± 0.003 ppm) of the branches 50 result that indicates phototoxic activity [19]. of S. grazielae, when compared with rutin positive control (EC 27.00 ± 0.19 ppm) [34]. 50 3.2. Ethnopharmacological Activity In this same study, the degree of toxicity against larvae of The flowers of the species S. rubescens are used in skin Artemia salina was evaluated. Partitions in CH2Cl2 of stems of S. eliezeriana (DL 169.70±3.20 ppm) and in CH Cl of infection treatment, by maceration and application on the 50 2 2 infected area, and fresh bark is applied in the treatment of stems of S. grazielae (DL50148.80±2.35 ppm) [34] presented activity. Extracts or partitions are considered active when dental and oral cavity blemishes [37, 38]. they present DL50≤1000 ppm [35]. Studies on S. williamsii and S. tinctoria have shown that Moreover, assessment of antifungal potential, by using these species are applied in popular medicine of Peru for agar diffusion technique, showed that the partitions in their analgesic and anti-inflammatory activity. CH2Cl2 (17±0.06 mm) and ethyl acetate (20±0.1 mm) of the branches of S. glaziovii presented inhibition against Candida 3.3. Other Studies on Simira inconspicua, when compared with the control miconazole We have found botanical studies on Simira glaziovii and nitrate (37±0.3 mm) [34]. S. sampaioana with taxonomic and floristic composition Wood extracts of S. grazielae, were tested for anti- purposes [39-45]. We have also found works on regional nociceptive activity, by injecting 0.02ml of 2.5% formalin forest conservation and restoration of agroforestry systems of solution in mice paws and the results expressed an average Mesoamerica with Simira salvadorensis [46]. of±E.P.M. (n = 6) of licking time. The methanolic extract Only studies on Botany morphology and classification with an approximate time of 25s (p<0.01) and the partition involving the species S. pikia were found [15, 43], not of ethyl acetate with an approximate time of 25s (p<0.05) presenting any phytochemical work published at the showed better results in neurogenic phase, compared with moment. the data for morphine with an approximate time of 38s (p<0.05). And in the inflammatory stage, the methanolic We have also found studies on anti-corrosive properties extract, partition of ethyl acetate and the partition of of extracts rich in alkaloids of S. tinctoria in low-carbon dichloromethane with an approximate time of 75s (p<0.05) steel, showing promising results for corrosion inhibitors showed better results compared with the data for morphine [47]. with an approximate time of 75s (p<0.05). In this same study, we evaluated the antioxidant potential, by using the CONCLUSION DPPH method, and those were lower than Ascorbic acid It is concluded that a survey of phytochemical studies (EC50 7.1 µg/ml) used as references [30]. identified many secondary metabolites that are found in In studies of S. williamsii and S. tinctoria, the phar- many species in the genus Simira. Many of them have well- macological profiles of petroleum ether, chloroform, known biological activity. The biological activities of some chloroform-methanol and methanol extracts of these species of the purified substances are being investigated. The studies were assessed in vitro with electrically induced contractions in this direction are only performed with extracts of plants (EIC), at concentrations from 300 to 30 µg/ml dissolved in and partitions of these extracts. DMSO with a contact time of 15 minutes in isolated organ This review paper shows the alkaloid Harman (1) Table bath. Chloroform-methanol extract was the most active; (1), Fig. (1), an indole alkaloid β -carbolinic as a taxonomic (IC50 = 116.1µg) chloroform extract (IC50 = 400.9 µg), marker of Simira genus, however, this statement should be extracts of petroleum ether and methanol showed no activity reinforced by studies of other species of this genus. [18, 36]. Chemical Constituents and Biological Activities of Simira The Natural Products Journal, 2014, Vol. 4, No. 4 297
CONFLICT OF INTEREST [19] Arnason, T.; Morand, P.; Salvador, J.; Reyes, I.; Lanbert, J.; Towers, G.H.N. Phytochemistry, 1983, 22, 594. The authors confirm that this article content has no [20] Torssell, K.B.G. Natural product chemistry: A mechanistic, bio- conflict of interest. synthetic and ecological approach, 2nd edn. Apotekarsocieteten- Swedish Pharmaceutical Society, Stockholm, 1997. [21] Bastos, A.B.F. D'O.; Carvalho, M.G.; Velandia, J.R.; Braz-Filho, ACKNOWLEDGEMENTS R. Chemical Constituents from Simira glaziovii (K. Schum) Steyerm. And 1H and 13C NMR Assignments of Ophiorine and its The authors thank CNPq and FAPERJ for the financial Derivates, Quím. Nova, 2002, 25(2), 241-245. support. [22] Araújo, M.F.; Braz-Filho, R.; Carvalho, M.G.; Vieira, I.J.C. Other compounds isolated from Simira glaziovii and the 1H and 13C NMR REFERENCES chemical shift assignments of new 1-epi-castanopsol. Quím. Nova, 2012, 35(11), 2202-2204. [1] Robbrecht, E.; Manen, J. Major Lineages of Rubiaceae. Syst. Geog. [23] Araújo, M.F.; Vieira, I.J.C.; Braz-Filho, R.; Carvalho, M.G. Pl., 2006, 76, 85-146. Simiranes A and B: erythroxylanes diterpenes and other compounds [2] Bremer, B.; Jansen, R.K.; Oxelman, B.; Backlund, M.; Lantz, H.; from Simira eliezeriana (Rubiaceae). Nat. Prod. Res., 2011, 25(18), Kim, K.J. More characters or more taxa for a robust phylogeny-- 1713-1719. case study from the coffee family (Rubiaceae). Syst. Biol., 1999, [24] Aquino, R.; Garofalo, l.; Tommasi, N.; Ugaz, O.L.; Pizza, C. 48, 413-435. Phytochemistry, 1994, 37(5), 1471-1475. [3] Rova, J.H.E.; Delprete, P.G.; Andersson, L.; Albert, V.A. A trnL-F [25] Castaneda, P.; Albor, C.; Matar, R.; Bye, R.; Linares, E. Alkaloids cpDNA sequence study of the Condamineeae-Rondeletieae- from Simira mexicana. Fitoterapia, 1991, 62(4), 366. Sipaneeae complex with implications on the phylogeny of the [26] Castro, O.; Lopes, V.J. Harman, the principal alkaloid in roots of Rubiaceae. Am. J. Bot., 2002, 89, 145-159. Simira maxonii Standley (Rubiaceae). Ingenheria Ciencia Quimica, [4] Delprete, P.G. Rubiaceae. In Flowering Plant Families of the 1986, 10, 3-4, 56-57. American Tropics, Smith, N.P.; Heald, S.V.; Henderson, Mori, [27] Hasbun, C.P.; Calseron, M.; Castro, O; Gacs-Baitz, E.; Delle S.A.; Stevenson, D.W. Eds.; New York: Princeton University Monache, G.; Delle Monache, F. Maxonine, a novel alkaloid from Press/New York Botanical Garden Press, 2004; pp. 328-333. Simira-maxonii. Tetrahedron Lett., 1989, 30(45), 6199-6202. [5] Judd, W.S.; Campbell, C.S.; Kellogg, E.A.; Stevens, P.F.; [28] Kelly, T.R.; Xu, W.; Sundaresan, J. Maxonine - structure correction Donoghue, M.J. Plant systematics: a phylogenetic approach. and synthesis. Tetrahedron Lett., 1993, 34(39), 6173-6176. Ecologia Mediterranea, 1999, 25(2), 215. [29] Alves, C.C.F.; Cranchi, D.C.; Carvalho, M.G.; Silva, S.J. [6] Delprete, P.G. Rondeletieae (Rubiaceae) – Part I (Rustia, Tresanthera, Triterpenes, glucosyl steroid and alkaloid isolated from Simira Condaminea, Picardaea, Pogonopus, Chimarrhis, Dioicodendron, glaziovii. Floresta e Ambient., 2001, 8(1), 174-179. Molopanthera, Dolichodelphys, and Parachimarrhis). Fl. Neotrop. [30] Sanches, M.N.G. Phytochemical study of Simira grazielae 1999, Monogr. 77, pp.; 1-226. (Rubiaceae), and biological activities, dissertation master’s degree [7] Barbosa, M.R. Simira in List of Species of Flora of Brazil. Botanical post-graduate in chemistry, Rio de Janeiro, UFRRJ, 2013. Garden of Rio de Janeiro. Available in:
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Received: November 20, 2014 Revised: December 09, 2014 Accepted: December 12, 2014