Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFG |
Texto Completo: | http://repositorio.bc.ufg.br/tede/handle/tede/6756 |
Resumo: | Although the efforts employed by scientific community to discover new anticancer therapies suitable to the increasing cancer incidence and multidrug resistance, its necessary to develop more selective and target driven drugs. Therefore, in this work we have done a screening with LQFM030 analogues, which is a Nutlin-1 analogue, aiming to evaluate their cytotoxic potential. Furthermore, we have evaluated the cytotoxicity, the morphological alterations and the cell death induction mechanisms of the compound LQFM166 in leukemia cell line K562. In parallel, we have investigated the security profile of the compound upon 3T3 basal cell line to estimate its LD50 and the Selectivity Index. The cytotoxicity assays included the tetrazolium salt (MTT) reduction and the Neutral Red Uptake assays, to assess the cytotoxicity of LQFM166 in K562 and 3T3 cell lines, respectively. The investigation of cell death induction mechanisms was carried out using flow cytometry, whereby we have evaluated the cells biochemistry parameters, including cell cycle progression, phosphatidylserine externalization, caspases 3/7, 8 and 9 activity, cytochrome c release from mitochondria, p21, p27, Bax, Bcl-2, cyclin-B1 and NFkB expression, using specific labeling for each assay. Data were analyzed by t test and the difference between control and treated groups averages was considered statistically significant when p<0,05. Regarding leukemia cell line K562, the compound LQFM166 was cytotoxic, showing a dose-time-dependent profile. Morphological alterations were observed after treatment with the compound at cellular and nuclear levels, which corroborate with apoptotic cell death. Additionally, treatment with the IC50 for 48 hours has promoted cellular and molecular changes that characterize this process, including phosphatidylserine externalization, increase of caspases 3/7, 8 and 9 activity, expression of pro-apoptotic proteins Bax, p21and p27, as well as diminution of Bcl-2 and cyclin-B1. We have also observed increase of cytochrome-c release and NFkB expression. Concerning the security profile, the compound was considered relatively selective, once the IC50 found to basal cell line (185,3 µM) was the double of the obtained to leukemia cell line regarding the same time of exposure (56,76 µM). The outcomes allow us to conclude that LQFM166 was cytotoxic upon leukemia cells K562, promoting morphological and biochemical alterations that indicate apoptotic cell death induction. |
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Valadares, Marize Camposhttp://lattes.cnpq.br/6157755243167018Cortez, Alane Pereirahttp://lattes.cnpq.br/2956692199865146Valadares, Marize CamposDiniz, Danielle Guimarães AlmeidaOliveira, Gisele Augusto Rodrigues dehttp://lattes.cnpq.br/2928160816821426Santos, Thaís Rosa Marques dos2017-01-17T14:43:57Z2016-05-20SANTOS, Thaís Rosa Marques dos. Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562. 2016. 72 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2016.http://repositorio.bc.ufg.br/tede/handle/tede/6756Although the efforts employed by scientific community to discover new anticancer therapies suitable to the increasing cancer incidence and multidrug resistance, its necessary to develop more selective and target driven drugs. Therefore, in this work we have done a screening with LQFM030 analogues, which is a Nutlin-1 analogue, aiming to evaluate their cytotoxic potential. Furthermore, we have evaluated the cytotoxicity, the morphological alterations and the cell death induction mechanisms of the compound LQFM166 in leukemia cell line K562. In parallel, we have investigated the security profile of the compound upon 3T3 basal cell line to estimate its LD50 and the Selectivity Index. The cytotoxicity assays included the tetrazolium salt (MTT) reduction and the Neutral Red Uptake assays, to assess the cytotoxicity of LQFM166 in K562 and 3T3 cell lines, respectively. The investigation of cell death induction mechanisms was carried out using flow cytometry, whereby we have evaluated the cells biochemistry parameters, including cell cycle progression, phosphatidylserine externalization, caspases 3/7, 8 and 9 activity, cytochrome c release from mitochondria, p21, p27, Bax, Bcl-2, cyclin-B1 and NFkB expression, using specific labeling for each assay. Data were analyzed by t test and the difference between control and treated groups averages was considered statistically significant when p<0,05. Regarding leukemia cell line K562, the compound LQFM166 was cytotoxic, showing a dose-time-dependent profile. Morphological alterations were observed after treatment with the compound at cellular and nuclear levels, which corroborate with apoptotic cell death. Additionally, treatment with the IC50 for 48 hours has promoted cellular and molecular changes that characterize this process, including phosphatidylserine externalization, increase of caspases 3/7, 8 and 9 activity, expression of pro-apoptotic proteins Bax, p21and p27, as well as diminution of Bcl-2 and cyclin-B1. We have also observed increase of cytochrome-c release and NFkB expression. Concerning the security profile, the compound was considered relatively selective, once the IC50 found to basal cell line (185,3 µM) was the double of the obtained to leukemia cell line regarding the same time of exposure (56,76 µM). The outcomes allow us to conclude that LQFM166 was cytotoxic upon leukemia cells K562, promoting morphological and biochemical alterations that indicate apoptotic cell death induction.Mesmo com os esforços da comunidade científica em descobrir ou desenvolver medicamentos adequados a crescente incidência do câncer e ainda adequados à suas formas multirresistentes, é necessário o desenvolvimento de medicamentos que sejam seletivos e alvo-dirigidos. Assim, no trabalho proposto, foi realizada uma triagem com compostos análogos ao LQFM030, análogo estrutural do Nutlin-1, visando determinar o potencial citotóxico dos mesmos. Além disso, foram investigados a citotoxicidade, as alterações morfológicas e os mecanismos de indução de morte celular do composto escolhido LQFM166 em linhagem de células leucêmicas K562. Paralelamente, foi investigado o perfil de segurança do composto sobre a linhagem basal 3T3, a fim de estimar a DL50 e o Índice de Seletividade do mesmo. Os ensaios de citotoxicidade incluíram o método de redução do sal de tetrazólio (MTT) e o método de incorporação do corante vermelho neutro, para a avaliação do potencial citotóxico sobre as linhagens K562 e 3T3, respectivamente. Para a investigação dos mecanismos de indução de morte celular foi utilizada a técnica de citometria de fluxo, por meio da qual foi realizada a avaliação de parâmetros bioquímicos incluindo progressão ciclo celular, externalização da fosfatidilserina, atividade das caspases 3/7, 8 e 9, liberação do citocromo c, expressão das proteínas p21, p27, Bax, Bcl-2, ciclina-B1 e NFkB, empregando-se técnicas de marcação específicas para cada ensaio. Os dados foram analisados pelo teste t e a diferença entre as médias dos grupos controle e tratado foram consideradas estatisticamente significativas quando p<0,05. Em relação à linhagem leucêmica K562, o composto LQFM166 foi citotóxico apresentando um perfil dose e tempo dependentes. Foram observadas alterações morfológicas a níveis celular e nuclear, após o tratamento com composto, condizentes com o processo de morte celular por apoptose. Adicionalmente, externalização da fosfatidilserina, aumento da atividade das caspases 3/7, 8 e 9, aumento da expressão das proteínas pró-apoptóticas Bax, p21 e p27, bem como diminuição da expressão das proteínas Bcl-2 e ciclina-B1, após tratamento com a CI50 por 48 horas, desencadeou alterações celulares e moleculares que reforçam a sugestão de processo de morte celular por apoptose. Observouse ainda aumento da liberação do citocromo-c e da expressão da proteína NFkB. Já em relação ao perfil de segurança, o composto mostrou-se relativamente seletivo e com menor toxicidade, uma vez que a CI50 encontrada para a linhagem basal (185,3 μM) foi cerca de duas vezes maior ao encontrado para a linhagem tumoral para o mesmo tempo de exposição (56,76 μM). Considerando os resultados obtidos, pode-se concluir que o composto LQFM166 foi citotóxico sobre a linhagem leucêmica K562, desencadeando alterações morfológicas e bioquímicas características de morte celular por apoptose.Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2017-01-17T14:43:31Z No. of bitstreams: 2 Dissertação - Thaís Rosa Marques dos Santos - 2016.pdf: 1811805 bytes, checksum: 381d90956275aee309bb1d2948f724de (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-01-17T14:43:57Z (GMT) No. of bitstreams: 2 Dissertação - Thaís Rosa Marques dos Santos - 2016.pdf: 1811805 bytes, checksum: 381d90956275aee309bb1d2948f724de (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Made available in DSpace on 2017-01-17T14:43:57Z (GMT). No. of bitstreams: 2 Dissertação - Thaís Rosa Marques dos Santos - 2016.pdf: 1811805 bytes, checksum: 381d90956275aee309bb1d2948f724de (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-05-20Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqapplication/pdfporUniversidade Federal de GoiásPrograma de Pós-graduação em Ciências Farmacêuticas (FF)UFGBrasilFaculdade Farmácia - FF (RG)http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessLQFM166TrifluormetilApoptoseK562Morte CelularLQFM166TrifluoromethylApoptosisK562Cell deathFARMACIA::FARMACOTECNIAAvaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562Evaluation of the antitumor activity of n-phenyl-piperazine compounds in K562 cell lineinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesis8249369881961524126006006006006010281161524209375-1498234366838932019-2555911436985713659reponame:Repositório Institucional da UFGinstname:Universidade Federal de Goiás (UFG)instacron:UFGLICENSElicense.txtlicense.txttext/plain; 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dc.title.por.fl_str_mv |
Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562 |
dc.title.alternative.eng.fl_str_mv |
Evaluation of the antitumor activity of n-phenyl-piperazine compounds in K562 cell line |
title |
Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562 |
spellingShingle |
Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562 Santos, Thaís Rosa Marques dos LQFM166 Trifluormetil Apoptose K562 Morte Celular LQFM166 Trifluoromethyl Apoptosis K562 Cell death FARMACIA::FARMACOTECNIA |
title_short |
Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562 |
title_full |
Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562 |
title_fullStr |
Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562 |
title_full_unstemmed |
Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562 |
title_sort |
Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562 |
author |
Santos, Thaís Rosa Marques dos |
author_facet |
Santos, Thaís Rosa Marques dos |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Valadares, Marize Campos |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/6157755243167018 |
dc.contributor.advisor-co1.fl_str_mv |
Cortez, Alane Pereira |
dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/2956692199865146 |
dc.contributor.referee1.fl_str_mv |
Valadares, Marize Campos |
dc.contributor.referee2.fl_str_mv |
Diniz, Danielle Guimarães Almeida |
dc.contributor.referee3.fl_str_mv |
Oliveira, Gisele Augusto Rodrigues de |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/2928160816821426 |
dc.contributor.author.fl_str_mv |
Santos, Thaís Rosa Marques dos |
contributor_str_mv |
Valadares, Marize Campos Cortez, Alane Pereira Valadares, Marize Campos Diniz, Danielle Guimarães Almeida Oliveira, Gisele Augusto Rodrigues de |
dc.subject.por.fl_str_mv |
LQFM166 Trifluormetil Apoptose K562 Morte Celular |
topic |
LQFM166 Trifluormetil Apoptose K562 Morte Celular LQFM166 Trifluoromethyl Apoptosis K562 Cell death FARMACIA::FARMACOTECNIA |
dc.subject.eng.fl_str_mv |
LQFM166 Trifluoromethyl Apoptosis K562 Cell death |
dc.subject.cnpq.fl_str_mv |
FARMACIA::FARMACOTECNIA |
description |
Although the efforts employed by scientific community to discover new anticancer therapies suitable to the increasing cancer incidence and multidrug resistance, its necessary to develop more selective and target driven drugs. Therefore, in this work we have done a screening with LQFM030 analogues, which is a Nutlin-1 analogue, aiming to evaluate their cytotoxic potential. Furthermore, we have evaluated the cytotoxicity, the morphological alterations and the cell death induction mechanisms of the compound LQFM166 in leukemia cell line K562. In parallel, we have investigated the security profile of the compound upon 3T3 basal cell line to estimate its LD50 and the Selectivity Index. The cytotoxicity assays included the tetrazolium salt (MTT) reduction and the Neutral Red Uptake assays, to assess the cytotoxicity of LQFM166 in K562 and 3T3 cell lines, respectively. The investigation of cell death induction mechanisms was carried out using flow cytometry, whereby we have evaluated the cells biochemistry parameters, including cell cycle progression, phosphatidylserine externalization, caspases 3/7, 8 and 9 activity, cytochrome c release from mitochondria, p21, p27, Bax, Bcl-2, cyclin-B1 and NFkB expression, using specific labeling for each assay. Data were analyzed by t test and the difference between control and treated groups averages was considered statistically significant when p<0,05. Regarding leukemia cell line K562, the compound LQFM166 was cytotoxic, showing a dose-time-dependent profile. Morphological alterations were observed after treatment with the compound at cellular and nuclear levels, which corroborate with apoptotic cell death. Additionally, treatment with the IC50 for 48 hours has promoted cellular and molecular changes that characterize this process, including phosphatidylserine externalization, increase of caspases 3/7, 8 and 9 activity, expression of pro-apoptotic proteins Bax, p21and p27, as well as diminution of Bcl-2 and cyclin-B1. We have also observed increase of cytochrome-c release and NFkB expression. Concerning the security profile, the compound was considered relatively selective, once the IC50 found to basal cell line (185,3 µM) was the double of the obtained to leukemia cell line regarding the same time of exposure (56,76 µM). The outcomes allow us to conclude that LQFM166 was cytotoxic upon leukemia cells K562, promoting morphological and biochemical alterations that indicate apoptotic cell death induction. |
publishDate |
2016 |
dc.date.issued.fl_str_mv |
2016-05-20 |
dc.date.accessioned.fl_str_mv |
2017-01-17T14:43:57Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
SANTOS, Thaís Rosa Marques dos. Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562. 2016. 72 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2016. |
dc.identifier.uri.fl_str_mv |
http://repositorio.bc.ufg.br/tede/handle/tede/6756 |
identifier_str_mv |
SANTOS, Thaís Rosa Marques dos. Avaliação da atividade antitumoral de compostos n-fenilpiperazínicos em linhagem tumoral K562. 2016. 72 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2016. |
url |
http://repositorio.bc.ufg.br/tede/handle/tede/6756 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.program.fl_str_mv |
824936988196152412 |
dc.relation.confidence.fl_str_mv |
600 600 600 600 |
dc.relation.department.fl_str_mv |
6010281161524209375 |
dc.relation.cnpq.fl_str_mv |
-1498234366838932019 |
dc.relation.sponsorship.fl_str_mv |
-2555911436985713659 |
dc.rights.driver.fl_str_mv |
http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Goiás |
dc.publisher.program.fl_str_mv |
Programa de Pós-graduação em Ciências Farmacêuticas (FF) |
dc.publisher.initials.fl_str_mv |
UFG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Faculdade Farmácia - FF (RG) |
publisher.none.fl_str_mv |
Universidade Federal de Goiás |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFG instname:Universidade Federal de Goiás (UFG) instacron:UFG |
instname_str |
Universidade Federal de Goiás (UFG) |
instacron_str |
UFG |
institution |
UFG |
reponame_str |
Repositório Institucional da UFG |
collection |
Repositório Institucional da UFG |
bitstream.url.fl_str_mv |
http://repositorio.bc.ufg.br/tede/bitstreams/0d69f39d-cb23-4c3c-ade0-e0f1e4ff9834/download http://repositorio.bc.ufg.br/tede/bitstreams/b76b9b35-96a6-4b60-85d1-b6dbb0bc10e0/download http://repositorio.bc.ufg.br/tede/bitstreams/f117f55d-1a74-4b00-8cf2-5e1555c5c547/download http://repositorio.bc.ufg.br/tede/bitstreams/a97ccc36-2f44-4d9e-8e13-988d323a11b6/download http://repositorio.bc.ufg.br/tede/bitstreams/704b96b9-d138-4992-89ad-a9c19ea79bb8/download |
bitstream.checksum.fl_str_mv |
bd3efa91386c1718a7f26a329fdcb468 4afdbb8c545fd630ea7db775da747b2f d41d8cd98f00b204e9800998ecf8427e d41d8cd98f00b204e9800998ecf8427e 381d90956275aee309bb1d2948f724de |
bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional da UFG - Universidade Federal de Goiás (UFG) |
repository.mail.fl_str_mv |
tasesdissertacoes.bc@ufg.br |
_version_ |
1798044375062675456 |