Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction
Autor(a) principal: | |
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Data de Publicação: | 2013 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/37016 http://dx.doi.org/10.1371/journal.pntd.0002556 |
Resumo: | Chagas disease is caused by the parasitic protozoan Trypanosoma cruzi. It has high mortality as well as morbidity rates and usually affects the poorer sections of the population. the development of new, less harmful and more effective drugs is a promising research target, since current standard treatments are highly toxic and administered for long periods. Fractioning of methanol (MeOH) extract of the stem bark of Calophyllum brasiliense (Clusiaceae) resulted in the isolation of the coumarin soulamarin, which was characterized by one- and two-dimensional H-1- and C-13 NMR spectroscopy as well as ESI mass spectrometry. All data obtained were consistent with a structure of 6-hydroxy-4-propyl-5-(3-hydroxy-2-methyl-1-oxobutyl)-6,6-dimethylpyrane-[2,3:8,7]-benzopyran-2-one for soulamarin. Colorimetric MTT assays showed that soulamarin induces trypanocidal effects, and is also active against trypomastigotes. Hemolytic activity tests showed that soulamarin is unable to induce any observable damage to erythrocytes (c(max.)=1,300 mu M). the lethal action of soulamarin against T. cruzi was investigated by using amino(4-(6-(amino(iminio)methyl)-1H-indol-2-yl)phenyl)methaniminium chloride (SYTOX Green and 1H,5H,11H,15H-Xantheno[2,3,4-ij:5,6,7-ij]diquinolizin-18-ium, 9-[4-(chloromethyl)phenyl]-2,3,6,7,12,13,16,17-octahydro-chloride (MitoTracker Red) as fluorimetric probes. With the former, soulamarin showed dose-dependent permeability of the plasma membrane, relative to fully permeable Triton X-100-treated parasites. Spectrofluorimetric and fluorescence microscopy with the latter revealed that soulamarin also induced a strong depolarization (ca. 97%) of the mitochondrial membrane potential. These data demonstrate that the lethal action of soulamarin towards T. cruzi involves damages to the plasma membrane of the parasite and mitochondrial dysfunction without the additional generation of reactive oxygen species, which may have also contributed to the death of the parasites. Considering the unique mitochondrion of T. cruzi, secondary metabolites of plants affecting the bioenergetic system as soulamarin may contribute as scaffolds for the design of novel and selective drug candidates for neglected diseases, mainly Chagas disease.Author Summary Chagas disease is a parasitic protozoan that affects the poorest population in the world, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. Natural products isolated from plants are commonly used as drug prototypes or precursors to treat parasitic diseases. As part of our investigation of bioactive compounds from Brazilian flora, the present study was undertaken in order to determine the antitrypanosomal effects of the soulamarin, a coumarin isolated from the stem bark of Callophyllum brasiliense (Clusiaceae), against Trypanossoma cruzi. This study moreover investigated the lethal action of soulamarin towards the parasite. Considering the obtained results, secondary metabolites of plants affecting the bioenergetic system as soulamarin may contribute as scaffolds for the design of novel and selective drug candidates for neglected diseases, mainly Chagas disease. |
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Rea, Alexandre [UNIFESP]Tempone, Andre G.Pinto, Erika G.Mesquita, Juliana T.Rodrigues, Eliana [UNIFESP]Silva, Luciana Grus M. [UNIFESP]Sartorelli, Patricia [UNIFESP]Lago, Joao Henrique G. [UNIFESP]Universidade Federal de São Paulo (UNIFESP)Adolfo Lutz InstUniversidade de São Paulo (USP)2016-01-24T14:34:46Z2016-01-24T14:34:46Z2013-12-01Plos Neglected Tropical Diseases. San Francisco: Public Library Science, v. 7, n. 12, 8 p., 2013.1935-2735http://repositorio.unifesp.br/handle/11600/37016http://dx.doi.org/10.1371/journal.pntd.0002556WOS000329168100028.pdf10.1371/journal.pntd.0002556WOS:000329168100028Chagas disease is caused by the parasitic protozoan Trypanosoma cruzi. It has high mortality as well as morbidity rates and usually affects the poorer sections of the population. the development of new, less harmful and more effective drugs is a promising research target, since current standard treatments are highly toxic and administered for long periods. Fractioning of methanol (MeOH) extract of the stem bark of Calophyllum brasiliense (Clusiaceae) resulted in the isolation of the coumarin soulamarin, which was characterized by one- and two-dimensional H-1- and C-13 NMR spectroscopy as well as ESI mass spectrometry. All data obtained were consistent with a structure of 6-hydroxy-4-propyl-5-(3-hydroxy-2-methyl-1-oxobutyl)-6,6-dimethylpyrane-[2,3:8,7]-benzopyran-2-one for soulamarin. Colorimetric MTT assays showed that soulamarin induces trypanocidal effects, and is also active against trypomastigotes. Hemolytic activity tests showed that soulamarin is unable to induce any observable damage to erythrocytes (c(max.)=1,300 mu M). the lethal action of soulamarin against T. cruzi was investigated by using amino(4-(6-(amino(iminio)methyl)-1H-indol-2-yl)phenyl)methaniminium chloride (SYTOX Green and 1H,5H,11H,15H-Xantheno[2,3,4-ij:5,6,7-ij]diquinolizin-18-ium, 9-[4-(chloromethyl)phenyl]-2,3,6,7,12,13,16,17-octahydro-chloride (MitoTracker Red) as fluorimetric probes. With the former, soulamarin showed dose-dependent permeability of the plasma membrane, relative to fully permeable Triton X-100-treated parasites. Spectrofluorimetric and fluorescence microscopy with the latter revealed that soulamarin also induced a strong depolarization (ca. 97%) of the mitochondrial membrane potential. These data demonstrate that the lethal action of soulamarin towards T. cruzi involves damages to the plasma membrane of the parasite and mitochondrial dysfunction without the additional generation of reactive oxygen species, which may have also contributed to the death of the parasites. Considering the unique mitochondrion of T. cruzi, secondary metabolites of plants affecting the bioenergetic system as soulamarin may contribute as scaffolds for the design of novel and selective drug candidates for neglected diseases, mainly Chagas disease.Author Summary Chagas disease is a parasitic protozoan that affects the poorest population in the world, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. Natural products isolated from plants are commonly used as drug prototypes or precursors to treat parasitic diseases. As part of our investigation of bioactive compounds from Brazilian flora, the present study was undertaken in order to determine the antitrypanosomal effects of the soulamarin, a coumarin isolated from the stem bark of Callophyllum brasiliense (Clusiaceae), against Trypanossoma cruzi. This study moreover investigated the lethal action of soulamarin towards the parasite. Considering the obtained results, secondary metabolites of plants affecting the bioenergetic system as soulamarin may contribute as scaffolds for the design of novel and selective drug candidates for neglected diseases, mainly Chagas disease.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Inst Ciencias Ambientais Quim & Farmaceut, São Paulo, BrazilAdolfo Lutz Inst, Dept Parasitol, São Paulo, BrazilUniv São Paulo, Inst Trop Med, São Paulo, BrazilUniversidade Federal de São Paulo, Inst Ciencias Ambientais Quim & Farmaceut, São Paulo, BrazilFAPESP: 2011/51739-0CNPq: 470853/2012-3CNPq: 471458/2012-0Web of Science8engPublic Library SciencePlos Neglected Tropical DiseasesSoulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunctioninfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000329168100028.pdfapplication/pdf742056${dspace.ui.url}/bitstream/11600/37016/1/WOS000329168100028.pdfaf5a8215b96127823e561b8aa5fc8716MD51open accessTEXTWOS000329168100028.pdf.txtWOS000329168100028.pdf.txtExtracted texttext/plain45795${dspace.ui.url}/bitstream/11600/37016/9/WOS000329168100028.pdf.txt2df011e73e0d29c26eec76dfb62e7636MD59open accessTHUMBNAILWOS000329168100028.pdf.jpgWOS000329168100028.pdf.jpgIM Thumbnailimage/jpeg8165${dspace.ui.url}/bitstream/11600/37016/11/WOS000329168100028.pdf.jpgeed07ff6f13381428686a3884c895d40MD511open access11600/370162023-06-05 19:25:00.068open accessoai:repositorio.unifesp.br:11600/37016Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-06-05T22:25Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction |
title |
Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction |
spellingShingle |
Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction Rea, Alexandre [UNIFESP] |
title_short |
Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction |
title_full |
Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction |
title_fullStr |
Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction |
title_full_unstemmed |
Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction |
title_sort |
Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction |
author |
Rea, Alexandre [UNIFESP] |
author_facet |
Rea, Alexandre [UNIFESP] Tempone, Andre G. Pinto, Erika G. Mesquita, Juliana T. Rodrigues, Eliana [UNIFESP] Silva, Luciana Grus M. [UNIFESP] Sartorelli, Patricia [UNIFESP] Lago, Joao Henrique G. [UNIFESP] |
author_role |
author |
author2 |
Tempone, Andre G. Pinto, Erika G. Mesquita, Juliana T. Rodrigues, Eliana [UNIFESP] Silva, Luciana Grus M. [UNIFESP] Sartorelli, Patricia [UNIFESP] Lago, Joao Henrique G. [UNIFESP] |
author2_role |
author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Universidade Federal de São Paulo (UNIFESP) Adolfo Lutz Inst Universidade de São Paulo (USP) |
dc.contributor.author.fl_str_mv |
Rea, Alexandre [UNIFESP] Tempone, Andre G. Pinto, Erika G. Mesquita, Juliana T. Rodrigues, Eliana [UNIFESP] Silva, Luciana Grus M. [UNIFESP] Sartorelli, Patricia [UNIFESP] Lago, Joao Henrique G. [UNIFESP] |
description |
Chagas disease is caused by the parasitic protozoan Trypanosoma cruzi. It has high mortality as well as morbidity rates and usually affects the poorer sections of the population. the development of new, less harmful and more effective drugs is a promising research target, since current standard treatments are highly toxic and administered for long periods. Fractioning of methanol (MeOH) extract of the stem bark of Calophyllum brasiliense (Clusiaceae) resulted in the isolation of the coumarin soulamarin, which was characterized by one- and two-dimensional H-1- and C-13 NMR spectroscopy as well as ESI mass spectrometry. All data obtained were consistent with a structure of 6-hydroxy-4-propyl-5-(3-hydroxy-2-methyl-1-oxobutyl)-6,6-dimethylpyrane-[2,3:8,7]-benzopyran-2-one for soulamarin. Colorimetric MTT assays showed that soulamarin induces trypanocidal effects, and is also active against trypomastigotes. Hemolytic activity tests showed that soulamarin is unable to induce any observable damage to erythrocytes (c(max.)=1,300 mu M). the lethal action of soulamarin against T. cruzi was investigated by using amino(4-(6-(amino(iminio)methyl)-1H-indol-2-yl)phenyl)methaniminium chloride (SYTOX Green and 1H,5H,11H,15H-Xantheno[2,3,4-ij:5,6,7-ij]diquinolizin-18-ium, 9-[4-(chloromethyl)phenyl]-2,3,6,7,12,13,16,17-octahydro-chloride (MitoTracker Red) as fluorimetric probes. With the former, soulamarin showed dose-dependent permeability of the plasma membrane, relative to fully permeable Triton X-100-treated parasites. Spectrofluorimetric and fluorescence microscopy with the latter revealed that soulamarin also induced a strong depolarization (ca. 97%) of the mitochondrial membrane potential. These data demonstrate that the lethal action of soulamarin towards T. cruzi involves damages to the plasma membrane of the parasite and mitochondrial dysfunction without the additional generation of reactive oxygen species, which may have also contributed to the death of the parasites. Considering the unique mitochondrion of T. cruzi, secondary metabolites of plants affecting the bioenergetic system as soulamarin may contribute as scaffolds for the design of novel and selective drug candidates for neglected diseases, mainly Chagas disease.Author Summary Chagas disease is a parasitic protozoan that affects the poorest population in the world, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. Natural products isolated from plants are commonly used as drug prototypes or precursors to treat parasitic diseases. As part of our investigation of bioactive compounds from Brazilian flora, the present study was undertaken in order to determine the antitrypanosomal effects of the soulamarin, a coumarin isolated from the stem bark of Callophyllum brasiliense (Clusiaceae), against Trypanossoma cruzi. This study moreover investigated the lethal action of soulamarin towards the parasite. Considering the obtained results, secondary metabolites of plants affecting the bioenergetic system as soulamarin may contribute as scaffolds for the design of novel and selective drug candidates for neglected diseases, mainly Chagas disease. |
publishDate |
2013 |
dc.date.issued.fl_str_mv |
2013-12-01 |
dc.date.accessioned.fl_str_mv |
2016-01-24T14:34:46Z |
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2016-01-24T14:34:46Z |
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Plos Neglected Tropical Diseases. San Francisco: Public Library Science, v. 7, n. 12, 8 p., 2013. |
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http://repositorio.unifesp.br/handle/11600/37016 http://dx.doi.org/10.1371/journal.pntd.0002556 |
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1935-2735 |
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WOS000329168100028.pdf |
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10.1371/journal.pntd.0002556 |
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Plos Neglected Tropical Diseases. San Francisco: Public Library Science, v. 7, n. 12, 8 p., 2013. 1935-2735 WOS000329168100028.pdf 10.1371/journal.pntd.0002556 WOS:000329168100028 |
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http://repositorio.unifesp.br/handle/11600/37016 http://dx.doi.org/10.1371/journal.pntd.0002556 |
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