Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction

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dc.contributor Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.author REA, Alexandre
TEMPONE, Andre G.
PINTO, Erika G. FMUSP-HC
MESQUITA, Juliana T.
RODRIGUES, Eliana
SILVA, Luciana Grus M.
SARTORELLI, Patricia
LAGO, Joao Henrique G.
dc.date.issued 2013
dc.identifier.citation PLOS NEGLECTED TROPICAL DISEASES, v.7, n.12, article ID e2556, 8p, 2013
dc.identifier.issn 1935-2735
dc.identifier.uri http://observatorio.fm.usp.br/handle/OPI/5321
dc.description.abstract 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.
dc.description.sponsorship · Research Foundation of Sao Paulo (FAPESP) [2011/51739-0]
· National Council for Technological and Scientific Development (CNPq) [470853/2012-3, 471458/2012-0]
dc.language.iso eng
dc.publisher PUBLIC LIBRARY SCIENCE
dc.relation.ispartof Plos Neglected Tropical Diseases
dc.rights openAccess
dc.subject.other chagas-disease; antitrypanosomal activities; mitochondrial dysfunction; american trypanosomiasis; leishmania-amazonensis; trypanocidal activity; derivatives; drugs; cells; trypomastigotes
dc.title Soulamarin Isolated from Calophyllum brasiliense (Clusiaceae) Induces Plasma Membrane Permeabilization of Trypanosoma cruzi and Mytochondrial Dysfunction
dc.type article
dc.rights.holder Copyright PUBLIC LIBRARY SCIENCE
dc.identifier.doi 10.1371/journal.pntd.0002556
dc.identifier.pmid 24340110
dc.type.category original article
dc.type.version publishedVersion
hcfmusp.author PINTO, Erika G.:IMT:
hcfmusp.author.external · REA, Alexandre:Univ Fed Sao Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Sao Paulo, Brazil
· TEMPONE, Andre G.:Adolfo Lutz Inst, Dept Parasitol, Sao Paulo, Brazil
· MESQUITA, Juliana T.:Adolfo Lutz Inst, Dept Parasitol, Sao Paulo, Brazil
· RODRIGUES, Eliana:Univ Fed Sao Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Sao Paulo, Brazil
· SILVA, Luciana Grus M.:Univ Fed Sao Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Sao Paulo, Brazil
· SARTORELLI, Patricia:Univ Fed Sao Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Sao Paulo, Brazil
· LAGO, Joao Henrique G.:Univ Fed Sao Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Sao Paulo, Brazil
hcfmusp.origem.id 2-s2.0-84892719802
hcfmusp.origem.id WOS:000329168100028
hcfmusp.publisher.city SAN FRANCISCO
hcfmusp.publisher.country USA
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dc.description.index MEDLINE
hcfmusp.citation.scopus 27
hcfmusp.citation.wos 24
hcfmusp.affiliation.country Brasil


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