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Essential Oil from Flowers of Solanum stipulaceum: Composition, Effects of γ-Radiation, and Antileukemic Activity

Abstract

The composition of essential oils from flowers of Solanum stipulaceum Roem & Schult collected in May and September was studied for the first time. Effects of g-radiation on volatile constituents were investigated by gas chromatography (GC) with flame ionization detector (FID). In addition, the antileukemic activity was studied by a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) colorimetric assay against human cell lines HL-60 and THP-1. The main constituents of the essential oil of flowers collected in May were β-caryophyllene (25.8%), γ-gurjunene (11.9%), and β-gurjunene (8.2%), whereas the essential oil of flowers collected in September was mainly composed of β-caryophyllene (26.5%), caryophyllene oxide (11.0%), and γ-gurjunene (10.0%). The main components of essential oil from flowers collected in September were not significantly affected by γ-radiation at lower doses than 10.0 kGy. No cytotoxic activity in leukemic cell lines was observed for non-irradiated samples. However, irradiated samples exhibited slightly cytotoxic activity.

Keywords:
Solanum stipulaceum ; essential oil; β-caryophyllene; gamma-radiation; antileukemic activity


Introduction

Essential oils are mixtures of volatile natural organic compounds usually obtained from plant material, which usually consist of terpenoids, aromatic, and aliphatic compounds.11 Guimarães, R.; Sousa, M. J.; Ferreira, I. C. F. R.; Ind. Crops. Prod.2010, 32, 152. Essential oils exhibit a large spectrum of biological properties, such as antimicrobial, analgesic, and antiseptic.22 Raut, J. S.; Karuppayil, S. M.; Ind. Crops. Prod.2014, 62, 250. The pleasant fragrance of the essential oil components makes them a raw material widely employed by cosmetic, pharmaceutical, agricultural, and food industries. In nature, essential oils play an important role in the protection of plants in their ecosystem.33 Bakkali, F.; Averbeck, S.; Averbeck, D.; Idaomar, M.; Food Chem. Toxicol.2008, 46, 446.

The family Solanaceae includes about 3,000 species distributed in 96 genera, and 1,500 of them belong to the genus Solanum. Solanum species occur in different regions around the world, with the greatest diversity concentrated in Central and South America.44 Batista-Franklim, C. P. R.; Gonçalves-Esteves, V.; Acta Bot. Bras.2008, 22, 782.Solanum stipulaceum Roem & Schult (popularly known as "caiçarinha") is an endemic and native Brazilian plant, widely distributed in the Cerrado region of the state of Minas Gerais.55 http://floradobrasil.jbrj.gov.br/jabot/floradobrasil/FB14865 accessed in August 2015.
http://floradobrasil.jbrj.gov.br/jabot/f...
The polar extract of the stem of S. stipulaceum exhibits molluscicidal activity and cardiac-depressant properties.66 Silva, T. M. S.; Câmara, C. A.; Agra, M. D. F.; de Carvalho, M. G.; Frana, M. T.; Brandoline, S. V. P. B.; Paschoal, L. D. S.; Braz-Filho, R.; Fitoterapia2006, 77, 449.,77 Ribeiro, E. A. N.; Batitucci, M. C. P.; Lima, J. A. T.; Araújo, I. G. A.; Mauad, H.; Medeiros, I. A.; Rev. Bras. Farmacogn.2002, 12, 34. Alkaloids, such as solasodine, solaparnaine, and solamargin, were isolated from their fruits, stems and branches.88 Silva, T. M. S.; Agra, M. D. F.; Bhattacharyya, J.; Rev. Bras. Farmacogn. 2005, 15, 292.,99 Silva, T. M. S.; Agra, M. F.; Bhattacharyya, J.; Acta Hortic.2007, 745, 295. Although some studies have been reported for extracts of S. stipulaceum, the flowers have not been studied.

g-Radiation is an efficient method for microbial decontamination and insect disinfestation of vegetal materials. Moreover, radiosterilization is the most widely used method for commercial preparations of medicinal plants.1010 Thongphasuk, P.; Thongphasuk, J.; RJAS2012, 2, 57. However, chemical composition and biological activities of vegetal species can be changed when plant material is exposed to g-radiation.1111 Silva, T. M.; Dias, M. D.; Pereira, M. T.; Takahashi, J. A.; Ferraz, V. P.; Piló-Veloso, D.; Alcântara, A. F. C.; Radiat. Phys. Chem.2012, 81, 22. In the case of volatile compounds, some studies indicated that the γ-radiation effect is negligible,1212 Shim, S.-L.; Hwang, I.-M.; Ryu, K.-Y.; Jung, M.-S.; Seo, H.-Y.; Kim, H.-Y.; Song, H.-P.; Kim, J.-H.; Lee, J.-W.; Byun, M.-W.; Kwon, J.-H.; Kim, K.-S.; Radiat. Phys. Chem.2009, 78, 665.

13 Fatemi, F.; Dini, S.; Rezaei, M. B.; Dadkhah, A.; Dabbagh, R.; Naij, S.; J. Essent. Oil Res.2014, 26, 97.
-1414 Silva, T. M.; Miranda, R. R. S.; Ferraz, V. P.; Pereira, M. T.; de Siqueira, E. P.; Alcântara, A. F. C.; Rev. Bras. Farmacogn. 2013, 23, 600. however, significant changes in the essential oil composition have been observed for samples exposed at high doses of ionizing radiation.1515 Yalcin, H.; Ozturk, I.; Hayta, M.; Sagdic, O.; Gumus, T.; J.Med. Food2011, 14, 1223.

16 Onyenekwe, P. C.; Stahl, M.; Adejo, G.; Nat. Prod. Res.2012, 26, 2030.
-1717 Sádecká, J.; Czech J. Food. Sci.2010, 28, 44.

The present work describes for the first time the chemical composition of the essential oil from flowers of S. stipulaceum. Seasonal variations are also considered in the analysis of chemical oil composition, and the effects of γ-radiation on essential oil constituents are studied for flowers submitted at different radiation doses. Moreover, antileukemic activity and evaluation of g-radiation effects on cytotoxicity are investigated for the essential oil from flowers of S. stipulaceum.

Experimental

Plant material

Flowers of Solanum stipulaceum Roem & Schult were collected in Montes Claros (state of Minas Gerais, Brazil) in May and September 2014 (samples MS and SS, respectively). The botanical identification was made by Maria Olivia Mercadante-Simões (Universidade Estadual de Montes Claros, Minas Gerais, Brazil). The voucher specimen (BHCB 169873) has been deposited in the Herbarium of the Instituto de Ciências Biológicas of the Universidade Federal de Minas Gerais.

Ionizing radiation treatment

Flower samples collected in September 2014 (SS) were irradiated. Five samples (20.0 g) were placed in plastic packages and exposed to γ-radiation at 1.0, 2.5, 5.0, 10.0, and 20.0 kGy at room temperature (22 ºC) in the Centro de Desenvolvimento da Tecnologia Nuclear (CDTN, Belo Horizonte, Brazil). The samples were exposed to g-radiation using a GammaBeam-127 irradiator, model IR-214 (Nordion Inc.) equipped with a cobalt-60 source. The dose rate was 2.81 kGy h-1. The irradiator was calibrated with a Fricke standard dosimeter, and the absorbed doses were controlled by the exposure time of each sample to the source.

Essential oils isolation and analysis

Irradiated and non-irradiated flowers of S. stipulaceum were submitted to hydrodistillation for 5 h on a Clevenger-type apparatus. After distillation, the essential oils were extracted three times with dichloromethane, dried over anhydrous sodium sulfate and filtered. After solvent evaporation, volatile oils were stored at 4 ºC in the dark until analysis.1818 Guenther, E.; The Essential Oils, vol. I; D. Van Nostrand Co.: New York, 1948, p. 316. Solutions of essential oils at 1% in chloroform were prepared for gas chromatography (GC) analysis. All reagents and organic solvents were purchased from Sigma-Aldrich Co. GC with flame ionization detector (FID) analyses were carried out using an Agilent HP 7820A GC system. An Agilent HP5 column (30 m × 0.32 mm × 0.25 µm) was used with hydrogen as the carrier gas (3 mL min-1). The GC oven temperature was programmed from 70-250 ºC at 3 ºC min-1, with injector temperature at 250 ºC, injection volume 1 µL, split ratio adjusted at 30:1, and FID detector temperature at 250 ºC. Percentages of separated compounds were calculated from GC-FID peak areas using EZChrom Elite Compact software. GC/mass spectrometry (MS) analyses were performed using a Shimadzu QP2010 ULTRA GC/MS system. An Rxi-1MS column (30 m × 0.25 mm × 0.25 µm) was used with helium as carrier gas (1.5 mL min-1). GC oven temperature was kept at 70 ºC for 2 min and programmed to 250 ºC at 5 ºC min-1. The injector temperature was 250 ºC, and the injection volume was 1 µL. The split ratio was adjusted at 10:1. MS interface and the detector temperature was 250 ºC. Electron ionization (EI) MS were recorded at 70 eV. Data acquisition was performed and analyzed by GCMSsolution software. Identification of essential oil components was carried out after comparison with those available in the computer library (NIST11) and by comparison of their Kováts retention index with a series of n-alkanes.

Antileukemic activity

The cytotoxicity of essential oils was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma-Aldrich) colorimetric assay. The evaluation of the cytotoxic activity was performed with human acute promyelocytic leukemia cell line American Type Culture Collection (ATCC)# CCL-240 (HL-60), acute monocytic leukemia cells ATCC# TIB-202 (THP-1) and lung fibroblast ATCC# CCL-95.1 (Wi-26VA4) cell lines. Cells were plated in 96-well plates (2 × 1055 http://floradobrasil.jbrj.gov.br/jabot/floradobrasil/FB14865 accessed in August 2015.
http://floradobrasil.jbrj.gov.br/jabot/f...
cells per well) and incubated for 24 h at 37 ºC in a humidified atmosphere with 5% CO2. After 24 h, the wells were washed with culture medium (RPMI-1640 + 20% inactivated fetal bovine serum + 2 mmol L-1L-glutamine) and incubated with samples at concentrations from 0.10 to 100 µg mL-1. After 48 h of incubation, the plates were treated with MTT (5 mg mL-1). Colorimetric measurements were performed at 550 nm using the microplate reader Spectramax M5e. All experiments were performed in triplicate. Cytotoxicity was scored as the percent of reduction in absorbance vs. untreated control cultures. The results were expressed by the IC50 values (concentration of the drug that reduced cell viability by 50%). IC50 values were calculated using OriginPro 8.0 software.

Results and Discussion

Hydrodistillation of non-irradiated samples collected in May and September provided pale yellowish oils with a pleasant aroma, yielding 0.08 and 0.03% (m/m), respectively, from flower extracts. Figure 1 shows the GC-FID chromatograms of essential oils from samples MS and SS. Twenty-four constituents were identified in the essential oil from MS, corresponding to 88.2% of the overall oil composition. In turn, essential oil from SS provided only fourteen constituents with chemical structures identified, corresponding to 90.3% of the overall oil composition. The compound name, Kováts retention index, and percentage of the volatile constituents of both samples are given in Table 1.

Figure 1
GC-FID chromatograms of essential oils from flowers of Solanum stipulaceum for samples collected in (a) May (MS) and (b) September (SS).
Table 1
Chemical composition of essential oils from flowers of S. stipulaceum collected in May (MS) and September (SS)

Essential oil from MS provided a high content of sesquiterpene hydrocarbons (76.2%). The most abundant component was β-caryophyllene (25.8%), followed by γ-gurjunene (11.9%), β-gurjunene (8.2%), α-selinene (5.3%), D-germacrene (3.6%), δ-cadinene (3.6%), aromandendrene (3.5%), δ-elemene (2.8%), α-humulene (2.7%), β-copaene (2.4%) γ-muurolene (1.8%), α-copaene (1.2%), α-neoclovene (0.8%), and α-gurjunene (0.7%). Sesquiterpene epoxides (6.9%) and sesquiterpenols (3.8%) were found in relatively smaller amounts, specifically, caryophyllene oxide (3.6%), alloaromadendrene oxide-(2) (2.2%), isoaromadendrene epoxide (1.1%), β-spathulenol (2.4%), cubenol (1.0%), and viridiflorol (0.5%). Pentadecanoic acid (1.3%) was also detected in MS essential oil. On the other hand, essential oil from SS contains fewer volatile constituents than MS, exhibiting only fourteen constituents (Figure 1 and Table 1). Essential oil from SS contains a lower content of sesquiterpenes (65.9%) and a higher content of sesquiterpene epoxides (14.6%) in relation to oil from MS (76.2 and 6.9%, respectively). Sesquiterpenols were not detected in SS. The volatile compounds α-gurjunene, β-gurjunene, β-copaene, α-neoclovene, γ-muurolene, valencene, isoaromadendrene epoxide, and pentadecanoic acid were not detected in the essential oil of SS. On the other hand, essential oil of SS contains a high content of palmitic acid (9.9%). However, this carboxylic acid was not detected in the essential oil of MS.

Essential oils from flowers of other species of Solanum contain many sesquiterpenes, which were also identified in the present work. β-Caryophyllene, α-copaene, β-elemene, γ-muurolene, D-germacrene, and δ-cadinene were reported in the essential oil from flowers of S. stuckeflii,2020 Zygadlo, J. A.; Grosso, N. R.; J. Essent. Oil Res.1997, 9, 111. whereas β -caryophyllene and β-selinene were the predominant sesquiterpenes in the essential oil from flowers of S. incisurm.2020 Zygadlo, J. A.; Grosso, N. R.; J. Essent. Oil Res.1997, 9, 111.

The differences observed in the composition of essential oils from MS and SS may be related to environmental factors, such as variation in temperature, photoperiod, and humidity conditions and pollinators.2121 Gobbo-Neto, L.; Lopes, N. P.; Quim. Nova2007, 30, 374. These biotic and abiotic factors influence the production of secondary metabolites in plants which can explain the greater variety of constituents in the essential oil from MS in relation to SS.

The effects of γ-radiation on essential oils from flowers of S. stipulaceum were observed in the extraction yield and their chemical composition. The yield of volatile oil obtained from non-irradiated flowers collected in September (0.03%) was slightly increased by gamma radiation. Extraction yield was 0.04% for irradiated material at 1.0, 2.5, and 5.0 kGy. Additionally, the extraction yield was 0.05% for irradiated material at higher doses (10.0 and 20.0 kGy). This increase of the extraction yields is due to damage to plant tissues caused by radiation.2222 Dhanya, R.; Mishra, B. B.; Khaleel, K. M.; Radiat. Phys. Chem.2011, 80, 1247.

Figure 2 shows the GC-FID chromatograms of essential oils from irradiated flowers of S. stipulaceum collected in September, and their chemical composition is shown in Table 2. Essential oils from irradiated material exhibited a higher content of caryophyllene oxide, δ-cadinene, and alloaromadendrene oxide-(2) at all radiation doses than the corresponding non-irradiated sample. The content of some constituents increased at a dose of 1.0 kGy, mainly β-caryophyllene, aromadendrene, and caryophyllene oxide, probably as a result of the increase of their extractability.1616 Onyenekwe, P. C.; Stahl, M.; Adejo, G.; Nat. Prod. Res.2012, 26, 2030. On the other hand, the volatile compounds D-germacrene, γ-gurjunene, α-selinene, 7-epi-α-cadinene, and palmitic acid decreased after irradiation at 1.0 kGy, which could be due to their radiation sensitivity (Figure 3).2323 Seo, H.-Y.; Kim, J.-H.; Song, H.-P.; Kim, D.-H.; Byun, M.-W.; Kwon, J.-H.; Kim, K.-S.; Radiat. Phys. Chem.2007, 76, 1869. An increase of the content of α-copaene, β-elemene, β-caryophyllene, α-humulene, and aromadendrene was observed for essential oil from flowers exposed to g-radiation at doses below 10.0 kGy. However, the content of these compounds decreased for samples exposed at a dose of 20.0 kGy. On the other hand, the content of δ-elemene, D-germacreme, γ-gurjunene, 7-epi-α-cadinene, and α-selinene decreased when flowers were exposed to g-radiation at different doses. The content of palmitic acid decreased when flowers were irradiated at doses from 1.0 to 10.0 kGy and its content increased at a dose of 20.0 kGy. The content of δ-cadinene, caryophyllene oxide, and alloaromadendrene oxide-(2) also increased at 20.0 kGy (Table 2 and Figure 3). Four new peaks (between 27 and 33 min) were observed in the chromatogram for samples irradiated at 20.0 kGy (Figure 2). Compounds corresponding to these peaks were not identified. Therefore, they were attributed to radiolytic products and correspond to 8.1% of the total oil composition. As a result, g-radiation induces irregular changes in the composition of the essential oil from flowers of S. stipulaceum. However, a direct relation between radiation dose and changes in the essential oil composition was not observed. These results are in agreement with those reported in the literature for essential oils from Angelica gigas Nakai, in which the content of sesquiterpene hydrocarbons and oxygenated sesquiterpenes increased without any correlation with γ-radiation dose.2323 Seo, H.-Y.; Kim, J.-H.; Song, H.-P.; Kim, D.-H.; Byun, M.-W.; Kwon, J.-H.; Kim, K.-S.; Radiat. Phys. Chem.2007, 76, 1869. Yalcin et al.1515 Yalcin, H.; Ozturk, I.; Hayta, M.; Sagdic, O.; Gumus, T.; J.Med. Food2011, 14, 1223. also reported irregular changes in the volatile profile of linseed exposed to γ-radiation, in addition to significant decreases in the content of linseed volatile compounds induced by higher doses of γ-radiation.

Figure 2
GC-FID chromatograms of essential oils from non-irradiated and irradiated flowers of S. stipulaceum collected in September (*: new peaks detected).
Table 2
Composition of volatile oils from irradiated flowers of S. stipulaceum collected in September
Figure 3
Composition of major constituents of the essential oil from non-irradiated and irradiated flowers of S. stipulaceum collected in September.

Oxidation of β-caryophyllene promoted by g-radiation or action of free radicals generated in the ionization of water can explain the increase in the content of caryophyllene oxide when flower samples were irradiated at 20.0 kGy. Similar results were also observed for the essential oil from Piper nigrum L. after radiation at a dose of 30 kGy. An increase in the content of caryophyllene oxide is matched by a decrease of β-caryophyllene.1717 Sádecká, J.; Czech J. Food. Sci.2010, 28, 44. Hydroxyl radicals (HO•) are generated from water molecules by exposure to g-radiation. This radical can initiate oxidation of β-caryophyllene by radical addition to the double internal bond, followed by the addition of molecular oxygen to produce peroxyl radicals (RO2•). The reaction of the formed peroxyl radicals with another organic peroxyl radical (RO2•) formed in situ produces β-hydroxyalkoxyl (RO•) radicals which undergo a ring-retaining reaction to obtain caryophyllene oxide.2424 Jaoui, M.; Leungsakul, S.; Kamens, R. M.; J. Atmos. Chem.2003, 45, 261. This oxidation process can occur with other sesquiterpenes of the essential oil, justifying the decrease in the composition of major constituents of the essential oil (Figure 2).

The essential oil from flowers of S. stipulaceum contains some active components that have been reported to exhibit cytotoxic activity. β-Caryophyllene, the major constituent identified in this essential oil, has been reported as a cytotoxic agent against human breast and colorectal adenocarcinoma cells.2525 Hadri, A. E.; Gómez, M. á.; Sanz, J.; González, A.; Idaomar, M.; Ribas, B.; Benedí, J.; Sánchez, M. I.; An. R. Acad. Nac. Farm.2010, 76, 343. Moreover, the volatile compounds α-humulene, β-elemene, δ-elemene, and caryophyllene oxide exhibit cytotoxicity against different human cancer cells.2525 Hadri, A. E.; Gómez, M. á.; Sanz, J.; González, A.; Idaomar, M.; Ribas, B.; Benedí, J.; Sánchez, M. I.; An. R. Acad. Nac. Farm.2010, 76, 343.

26 Dai, Z.-J.; Tang, W.; Lu, W.-F.; Gao, J.; Kang, H.-F.; Ma, X.-B.; Min, W.-L.; Wang, X.-J.; Wu, W.-Y.; Cancer Cell Int.2013, 13, 27.

27 Xie, C.-Y.; Yang, W.; Li, M.; Ying, J.; Tao, S.-J.; Li, K.; Dong, J.-H.; Wang, X.-S.; J. Pharm. Soc. Jpn.2009, 129, 1403.
-2828 Jun, N. J.; Mosaddik, A.; Moon, J. Y.; Jang, K.-C.; Lee, D.-S.; Ahn, K. S.; Cho, S. K.; Rec. Nat. Prod.2011, 5, 242.

Some cytotoxicity studies on essential oils from Solanum sp. have been reported in the literature. The essential oil from leaves of S. erianthum exhibited 98.85 and 97.94% of cell lethality against breast and prostate cancer cells, respectively.2929 Essien, E. E.; Ogunwande, I. A.; Setzer, W. N.; Ekundayo, O.; Pharm. Biol.2012, 50, 474. Moreover, the essential oil from leaves of S. macranthum exhibited 2% lethality against breast cancer cells,2929 Essien, E. E.; Ogunwande, I. A.; Setzer, W. N.; Ekundayo, O.; Pharm. Biol.2012, 50, 474. whereas the essential oil from leaves of S. spirale exhibited significant citotoxicity against breast, oral and lung cancer cells (IC50 = 19.69, 26.42 and 24.02 µg mL-1, respectively).3030 Keawsa-Ard, S.; Liawruangrath, B.; Liawruangrath, S.; Teerawutgulrag, A.; Pyne, S. G.; Nat. Prod. Commun.2012, 7, 955.

Table 3 shows the results of the cytotoxicity of essential oils from flowers of S. stipulaceum collected in September and irradiated. Cytotoxic action of the non-irradiated sample was not observed for an acute myeloid leukemia (AML) model, specifically HL-60 and THP1 cell lines, when compared with the non-selective chemotherapy control etoposide. Cytotoxic activity was increased for essential oils from irradiated samples, exhibiting a direct relationship with the radiation dose. However, the increase of the cytotoxicity of the samples is not comparable to the corresponding action of etoposide. The essential oil from flowers irradiated at 20.0 kGy was not considered for the cytotoxic assay because the volatile oil composition was significantly affected by γ-radiation.

Table 3
Cytotoxic activity in vitro of essential oils from non-irradiated and irradiated flowers of S. stipulaceum and etoposide (control) for AML cell lines and control

Some factors may affect the cytotoxic activity of the essential oils from irradiated flowers of S. stipulaceum. Concentration of various essential oil constituents, such as caryophylene, a sesquiterpenoid reported as a potential candidate for prevention and treatment of cancer, increased with the g-irradiation dose.3131 Park, K.-R.; Nam, D.; Yun, H.-M.; Lee, S.-G.; Jang, H.-J.; Sethi, G.; Cho, S. K.; Ahn, K. S.; Cancer Lett.2011, 312, 178. However, since the essential oil is a mixture of volatile compounds, the biological properties can be the result of synergism.3232 Silva, C. E. L.; Minguzzi, S.; Silva, R. C. L.; Matos, M. F. C.; Tofoli, D.; Carvalho, J. E.; Ruiz, A. L. T. G.; Costa, W. F.; Simionatto, E.; J. Braz. Chem. Soc.2015, 26, 233.

Conclusions

The essential oil composition from flowers of S. stipulaceum was here reported for the first time. Twenty-four constituents of the oil were identified in flowers collected in May, and fourteen in the sample collected in September. The major components were β-caryophyllene, γ-gurjunene, and β-gurjunene in the May sample, whereas, in flowers collected in September, β-caryophyllene, caryophyllene oxide, γ-gurjunene, and palmitic acid were identified as the major volatile components.

Essential oils from flowers of S. stipulaceum exhibited a decrease in the content of the major volatile components when exposed to γ-radiation at 20.0 kGy, induced by oxidation of their constituents. However, a radiation dose at 10.0 kGy, which is the conventional dose for radiosterilization of plant material, did not significantly affect the content of volatile oil constituents.

The essential oil from non-irradiated flowers of S. stipulaceum did not show significant cytotoxic activity against HL-60 and THP-1 cell lines. However, an increase of the antileukemic activity was observed for essential oils from flowers exposed to γ-radiation.

Acknowledgments

The authors thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) for their financial support.

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Publication Dates

  • Publication in this collection
    Nov 2015

History

  • Received
    29 June 2015
  • Accepted
    21 Aug 2015
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