Avaliação da atividade biológica in vitro de triazenos, sertralina e metildopa como alternativas no reaproveitamento de medicamentos
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional Manancial UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/22200 |
Resumo: | Currently, countless efforts to discover effective, selective and innovative antineoplastic and antimicrobial therapies have led to the synthesis and investigation of the biological activity of different molecules. Triazenes (TZCs) have established themselves as a promising class for drug discovery due to the wide pharmacological versatility demonstrated. Another approach is the reuse of medications, that is, investigating new uses for drugs already clinically approved in the treatment of other diseases. This practice has proven to be a good alternative, since it reduces risks, time and costs associated with the clinical development process, due to the availability of known pharmacokinetic and toxicological data. Our research group has evaluated the pharmacological potential of a series of triazene compounds and different drugs used in clinical practice, as alternatives in redirecting. We report the in vitro biological activity evaluation of three N-óxide triazene molecules: M1 (3- (4-chlorophenyl) -1-phenyltriazene N1-óxide), M2 (3- (4-bromophenyl) -1-phenyltriazene N1-óxido ) and M3 (3- (4-iodophenyl) -1-phenyltriazene N1-óxide), three N-óxide triazenide complexes of Cu(II): C1 ({Bis [3- (4-chlorophenyl) -1-phenyltriazenide N1- óxide-κ2N1, O4] copper (II)}), C2 ({Bis [3- (4-bromophenyl) -1-phenyltriazenide N1-oxido-κ2N1,O4]copper(II)}) and C3 ({Bis [3 - (4-iodophenyl) -1-phenyltriazenide N1-óxido-κ2N1, O4]copper (II)}) and their respective precursors, P1 (4-Chlorophenyl-amine), P2 (4-Bromophenyl-amine) and P3 (4-Iodophenyl-amine), as well as the candidate drugs for redirection, sertraline and methyldopa. The antibacterial activity was determined by the broth microdilution method, through the evaluation of minimal inhibitory concentration (MIC), against strains of the American Type Culture Collection and multidrug-resistant clinical isolates (MDR). Cytotoxicity was investigated using cell line cultures (tumor: murine melanoma - B16F10, human hepatocarcinoma - HepG2, glioblastoma multiforme - U87MG and T98G; normal: 292T - embryonic kidney fibroblast) using the colorimetric assay with the bromide reagent 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium (MTT). The chemical nuclease activity was verified using the agarose gel electrophoresis technique. The tested compounds showed variable cytotoxic activity. The C3 complex showed a greater cytotoxic effect compared to the HepG2 (IC50 = 2.672 μM) and B16F10 (IC50 = 3.950 μM) lines, being more active than the standard sorafenib tosylate (nexavar® - Bayer) (IC50 = 7,133 μM) and temozolomide (temodal® - Schering-Plow) (IC50 = 8,402 μM), respectively. In the strains of glioblastoma multiforme, the free N-óxide molecules were more cytotoxic compared to U87MG, with M1 (IC50 = 1.488 μM) with greater activity, which was approximately three times more active than standard temozolimide chemotherapy (IC50 = 4.369 μM). In relation to T98G, the N-óxide triazenide complexes showed a greater cytotoxic effect, highlighting the activity of the C2 complex (IC50 = 9.211 μM), whose values were close to that presented by the temozolomide standard (IC50 = 7.326 μM). The TZCs showed antibacterial activity, being more active compared to Gram positive. These did not show nuclease activity, as they were not able to cleave plasmid DNA. Among the drugs, sertraline showed greater antibacterial activity than methyldopa, both against Gram positive and Gram negative strains. However, additional studies are needed to evaluate the mechanisms of action involved to make its use safe in the treatment of infectious diseases of bacterial origin. Synergistic events (FICI <0.5) occurred between sertraline and methyldopa and in their associations with sulfamethoxazole/ trimethoprim. Methyldopa has chemical nuclease activity because it was able to cleave plasmid DNA, by a probable mechanism of hydrolytic action, similar to that promoted by natural nucleases. We conclude that the tested TZCs, M1 and C3, as well as the redirected drugs sertraline and methyldopa demonstrate an alternative for the design of new drugs with antitumor and antibacterial properties. |
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2021-09-13T17:31:05Z2021-09-13T17:31:05Z2021-04-19http://repositorio.ufsm.br/handle/1/22200Currently, countless efforts to discover effective, selective and innovative antineoplastic and antimicrobial therapies have led to the synthesis and investigation of the biological activity of different molecules. Triazenes (TZCs) have established themselves as a promising class for drug discovery due to the wide pharmacological versatility demonstrated. Another approach is the reuse of medications, that is, investigating new uses for drugs already clinically approved in the treatment of other diseases. This practice has proven to be a good alternative, since it reduces risks, time and costs associated with the clinical development process, due to the availability of known pharmacokinetic and toxicological data. Our research group has evaluated the pharmacological potential of a series of triazene compounds and different drugs used in clinical practice, as alternatives in redirecting. We report the in vitro biological activity evaluation of three N-óxide triazene molecules: M1 (3- (4-chlorophenyl) -1-phenyltriazene N1-óxide), M2 (3- (4-bromophenyl) -1-phenyltriazene N1-óxido ) and M3 (3- (4-iodophenyl) -1-phenyltriazene N1-óxide), three N-óxide triazenide complexes of Cu(II): C1 ({Bis [3- (4-chlorophenyl) -1-phenyltriazenide N1- óxide-κ2N1, O4] copper (II)}), C2 ({Bis [3- (4-bromophenyl) -1-phenyltriazenide N1-oxido-κ2N1,O4]copper(II)}) and C3 ({Bis [3 - (4-iodophenyl) -1-phenyltriazenide N1-óxido-κ2N1, O4]copper (II)}) and their respective precursors, P1 (4-Chlorophenyl-amine), P2 (4-Bromophenyl-amine) and P3 (4-Iodophenyl-amine), as well as the candidate drugs for redirection, sertraline and methyldopa. The antibacterial activity was determined by the broth microdilution method, through the evaluation of minimal inhibitory concentration (MIC), against strains of the American Type Culture Collection and multidrug-resistant clinical isolates (MDR). Cytotoxicity was investigated using cell line cultures (tumor: murine melanoma - B16F10, human hepatocarcinoma - HepG2, glioblastoma multiforme - U87MG and T98G; normal: 292T - embryonic kidney fibroblast) using the colorimetric assay with the bromide reagent 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium (MTT). The chemical nuclease activity was verified using the agarose gel electrophoresis technique. The tested compounds showed variable cytotoxic activity. The C3 complex showed a greater cytotoxic effect compared to the HepG2 (IC50 = 2.672 μM) and B16F10 (IC50 = 3.950 μM) lines, being more active than the standard sorafenib tosylate (nexavar® - Bayer) (IC50 = 7,133 μM) and temozolomide (temodal® - Schering-Plow) (IC50 = 8,402 μM), respectively. In the strains of glioblastoma multiforme, the free N-óxide molecules were more cytotoxic compared to U87MG, with M1 (IC50 = 1.488 μM) with greater activity, which was approximately three times more active than standard temozolimide chemotherapy (IC50 = 4.369 μM). In relation to T98G, the N-óxide triazenide complexes showed a greater cytotoxic effect, highlighting the activity of the C2 complex (IC50 = 9.211 μM), whose values were close to that presented by the temozolomide standard (IC50 = 7.326 μM). The TZCs showed antibacterial activity, being more active compared to Gram positive. These did not show nuclease activity, as they were not able to cleave plasmid DNA. Among the drugs, sertraline showed greater antibacterial activity than methyldopa, both against Gram positive and Gram negative strains. However, additional studies are needed to evaluate the mechanisms of action involved to make its use safe in the treatment of infectious diseases of bacterial origin. Synergistic events (FICI <0.5) occurred between sertraline and methyldopa and in their associations with sulfamethoxazole/ trimethoprim. Methyldopa has chemical nuclease activity because it was able to cleave plasmid DNA, by a probable mechanism of hydrolytic action, similar to that promoted by natural nucleases. We conclude that the tested TZCs, M1 and C3, as well as the redirected drugs sertraline and methyldopa demonstrate an alternative for the design of new drugs with antitumor and antibacterial properties.Atualmente, inúmeros esforços para descobrir terapias antineoplásicas e antimicrobianas eficazes, seletivas e inovadoras têm conduzido à síntese e investigação da atividade biológica de diferentes moléculas. Os Triazenos (TZCs) têm se firmado como uma classe promissora para a descoberta de fármacos pela ampla versatilidade farmacológica demonstrada. Outra abordagem é o reaproveitamento de medicamentos, ou seja, investigar novos usos para fármacos já aprovados clinicamente no tratamento de outras doenças. Essa prática tem provado ser uma boa alternativa, uma vez que reduz riscos, tempo e custos associados ao processo de desenvolvimento clínico, pela disponibilidade de dados farmacocinéticos e toxicológicos já conhecidos. Nosso grupo de pesquisa tem avaliado o potencial farmacológico de uma série de compostos triazenos e de diferentes medicamentos utilizados na prática clínica, como alternativas no redirecionamento. Reportamos a avaliação da atividade biológica in vitro de três moléculas triazenos N-óxidos: M1 (3-(4-clorofenil)-1-feniltriazeno N1-óxido), M2 (3-(4-bromofenil)-1-feniltriazeno N1-óxido) e M3 (3-(4-iodofenil)-1-feniltriazeno N1-óxido), três complexos triazenidos N-óxidos de Cu(II): C1 ({Bis[3-(4-chlorofenil)-1-feniltriazenido N1-óxido-κ2N1, O4]cobre(II)}), C2 ({Bis[3-(4-bromofenil)-1-feniltriazenido N1-óxido-κ2N1, O4]cobre(II)}) e C3({Bis[3-(4-iodofenil)-1-feniltriazenido N1-óxido-κ2N1, O4]cobre(II)}) e seus respectivos precursores, P1 (4-Clorofenil-amina), P2 (4-Bromofeni-amina) e P3 (4-Iodofenil-amina), bem como dos medicamentos candidatos ao redirecionamento, sertralina e metildopa. A atividade antibacteriana foi determinada pelo método da microdiluição em caldo, através da avaliação da concetração inibitória mínima (CIM), frente a cepas da coleção American Type Culture Collection e isolados clínicos multirresistentes (MDR). A citotoxicidade foi investigada utilizando-se culturas de linhagens celulares (tumorais: melanoma murino - B16F10, hepatocarcinoma humano – HepG2, glioblastoma multiforme - U87MG e T98G; não neoplásica: 292T - fibroblasto de rim embrionário) por meio do ensaio colorimétrico com o reagente brometo de 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazólio (MTT). A atividade de nuclease química foi verificada por meio da técnica de eletroforese em gel de agarose. Os compostos avaliados apresentaram atividade citotóxica variável. O complexo C3 apresentou maior efeito citotóxico frente às linhagens HepG2 (IC50 = 2.672 μM) e B16F10 (IC50=3.950 μM), sendo mais ativo que os quimioterápicos padrões tosilato de sorafenibe (nexavar® - Bayer) (IC50 = 7.133 μM) e temozolomida(temodal® - Schering-Plough) (IC50 = 8.402 μM), respectivamente. Nas linhagens do glioblastoma multiforme, as molélulas N-óxidos livres foram mais citotóxicas frente a U87MG, sendo M1 (IC50 = 1.488 μM) com maior atividade, o qual foi aproximadamente três vezes mais ativo que quimioterápico padrão temozolimida (IC50 = 4.369 μM). Frente a T98G, os complexos triazenidos N-óxidos apresentaram maior efeito citotóxico, destacando-se a atividade do complexo C2 (IC50 = 9.211 μM), cujos valores foram próximos ao apresentado pelo padrão temozolomida (IC50 = 7.326 μM). Os TZCs apresentaram atividade antibacteriana, sendo mais ativos frente à Gram positivos. Estes, não apresentaram atividade de nuclease, pois não foram aptos a clivar o DNA plasmidial. Entre os medicamentos, sertralina apresentou maior atividade antibacteriana que metildopa, tanto frente cepas Gram positivas como Gram negativas. Entretanto, estudos adicionais são necessários para avaliar os mecanismos de ação envolvidos para tornar seu uso seguro no tratamento de doenças infecciosas de origem bacteriana. Ocorreram eventos sinérgicos (FICI <0,5) entre sertralina e metildopa e em suas associações com sulfametoxazol/trimetoprima. Metildopa possui atividade de nuclease química, pois foi apto a clivar o DNA plasmidial, por provável mecanismo de ação hidrolítico, similar ao promovido pelas nucleases naturais. Concluímos que os TZCs ensaiados, M1 e C3, bem como os medicamentos redirecionados sertralina e metildopa demonstram uma alternativa para a concepção de novos medicamentos com propriedades antitumoral e antibacteriana.porUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em Ciências FarmacêuticasUFSMBrasilAnálises Clínicas e ToxicológicasAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessTriazenosClivagem do DNACitotoxicidadeReaproveitamento de medicamentosSertralinaMetildopaTriazenesDNA cleavageCytotoxicityDrug repositioningSertralineMethyldopaCNPQ::CIENCIAS DA SAUDE::FARMACIAAvaliação da atividade biológica in vitro de triazenos, sertralina e metildopa como alternativas no reaproveitamento de medicamentosEvaluation of in vitro biological activity of triazenes, sertralin and methildopa as alternatives in drugs repurposinginfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisHorner, Rosmarihttp://lattes.cnpq.br/5907084134183708Motta, Amanda de SouzaSantos, Aline Joana R. 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dc.title.por.fl_str_mv |
Avaliação da atividade biológica in vitro de triazenos, sertralina e metildopa como alternativas no reaproveitamento de medicamentos |
dc.title.alternative.eng.fl_str_mv |
Evaluation of in vitro biological activity of triazenes, sertralin and methildopa as alternatives in drugs repurposing |
title |
Avaliação da atividade biológica in vitro de triazenos, sertralina e metildopa como alternativas no reaproveitamento de medicamentos |
spellingShingle |
Avaliação da atividade biológica in vitro de triazenos, sertralina e metildopa como alternativas no reaproveitamento de medicamentos Bottega, Angelita Triazenos Clivagem do DNA Citotoxicidade Reaproveitamento de medicamentos Sertralina Metildopa Triazenes DNA cleavage Cytotoxicity Drug repositioning Sertraline Methyldopa CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Avaliação da atividade biológica in vitro de triazenos, sertralina e metildopa como alternativas no reaproveitamento de medicamentos |
title_full |
Avaliação da atividade biológica in vitro de triazenos, sertralina e metildopa como alternativas no reaproveitamento de medicamentos |
title_fullStr |
Avaliação da atividade biológica in vitro de triazenos, sertralina e metildopa como alternativas no reaproveitamento de medicamentos |
title_full_unstemmed |
Avaliação da atividade biológica in vitro de triazenos, sertralina e metildopa como alternativas no reaproveitamento de medicamentos |
title_sort |
Avaliação da atividade biológica in vitro de triazenos, sertralina e metildopa como alternativas no reaproveitamento de medicamentos |
author |
Bottega, Angelita |
author_facet |
Bottega, Angelita |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Horner, Rosmari |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/5907084134183708 |
dc.contributor.referee1.fl_str_mv |
Motta, Amanda de Souza |
dc.contributor.referee2.fl_str_mv |
Santos, Aline Joana R. Wohlmuth Alves dos |
dc.contributor.referee3.fl_str_mv |
Ramos, Daniela Fernandes |
dc.contributor.referee4.fl_str_mv |
Krause, Luciana Maria Fontanari |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/5938466840557613 |
dc.contributor.author.fl_str_mv |
Bottega, Angelita |
contributor_str_mv |
Horner, Rosmari Motta, Amanda de Souza Santos, Aline Joana R. Wohlmuth Alves dos Ramos, Daniela Fernandes Krause, Luciana Maria Fontanari |
dc.subject.por.fl_str_mv |
Triazenos Clivagem do DNA Citotoxicidade Reaproveitamento de medicamentos Sertralina Metildopa |
topic |
Triazenos Clivagem do DNA Citotoxicidade Reaproveitamento de medicamentos Sertralina Metildopa Triazenes DNA cleavage Cytotoxicity Drug repositioning Sertraline Methyldopa CNPQ::CIENCIAS DA SAUDE::FARMACIA |
dc.subject.eng.fl_str_mv |
Triazenes DNA cleavage Cytotoxicity Drug repositioning Sertraline Methyldopa |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
Currently, countless efforts to discover effective, selective and innovative antineoplastic and antimicrobial therapies have led to the synthesis and investigation of the biological activity of different molecules. Triazenes (TZCs) have established themselves as a promising class for drug discovery due to the wide pharmacological versatility demonstrated. Another approach is the reuse of medications, that is, investigating new uses for drugs already clinically approved in the treatment of other diseases. This practice has proven to be a good alternative, since it reduces risks, time and costs associated with the clinical development process, due to the availability of known pharmacokinetic and toxicological data. Our research group has evaluated the pharmacological potential of a series of triazene compounds and different drugs used in clinical practice, as alternatives in redirecting. We report the in vitro biological activity evaluation of three N-óxide triazene molecules: M1 (3- (4-chlorophenyl) -1-phenyltriazene N1-óxide), M2 (3- (4-bromophenyl) -1-phenyltriazene N1-óxido ) and M3 (3- (4-iodophenyl) -1-phenyltriazene N1-óxide), three N-óxide triazenide complexes of Cu(II): C1 ({Bis [3- (4-chlorophenyl) -1-phenyltriazenide N1- óxide-κ2N1, O4] copper (II)}), C2 ({Bis [3- (4-bromophenyl) -1-phenyltriazenide N1-oxido-κ2N1,O4]copper(II)}) and C3 ({Bis [3 - (4-iodophenyl) -1-phenyltriazenide N1-óxido-κ2N1, O4]copper (II)}) and their respective precursors, P1 (4-Chlorophenyl-amine), P2 (4-Bromophenyl-amine) and P3 (4-Iodophenyl-amine), as well as the candidate drugs for redirection, sertraline and methyldopa. The antibacterial activity was determined by the broth microdilution method, through the evaluation of minimal inhibitory concentration (MIC), against strains of the American Type Culture Collection and multidrug-resistant clinical isolates (MDR). Cytotoxicity was investigated using cell line cultures (tumor: murine melanoma - B16F10, human hepatocarcinoma - HepG2, glioblastoma multiforme - U87MG and T98G; normal: 292T - embryonic kidney fibroblast) using the colorimetric assay with the bromide reagent 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium (MTT). The chemical nuclease activity was verified using the agarose gel electrophoresis technique. The tested compounds showed variable cytotoxic activity. The C3 complex showed a greater cytotoxic effect compared to the HepG2 (IC50 = 2.672 μM) and B16F10 (IC50 = 3.950 μM) lines, being more active than the standard sorafenib tosylate (nexavar® - Bayer) (IC50 = 7,133 μM) and temozolomide (temodal® - Schering-Plow) (IC50 = 8,402 μM), respectively. In the strains of glioblastoma multiforme, the free N-óxide molecules were more cytotoxic compared to U87MG, with M1 (IC50 = 1.488 μM) with greater activity, which was approximately three times more active than standard temozolimide chemotherapy (IC50 = 4.369 μM). In relation to T98G, the N-óxide triazenide complexes showed a greater cytotoxic effect, highlighting the activity of the C2 complex (IC50 = 9.211 μM), whose values were close to that presented by the temozolomide standard (IC50 = 7.326 μM). The TZCs showed antibacterial activity, being more active compared to Gram positive. These did not show nuclease activity, as they were not able to cleave plasmid DNA. Among the drugs, sertraline showed greater antibacterial activity than methyldopa, both against Gram positive and Gram negative strains. However, additional studies are needed to evaluate the mechanisms of action involved to make its use safe in the treatment of infectious diseases of bacterial origin. Synergistic events (FICI <0.5) occurred between sertraline and methyldopa and in their associations with sulfamethoxazole/ trimethoprim. Methyldopa has chemical nuclease activity because it was able to cleave plasmid DNA, by a probable mechanism of hydrolytic action, similar to that promoted by natural nucleases. We conclude that the tested TZCs, M1 and C3, as well as the redirected drugs sertraline and methyldopa demonstrate an alternative for the design of new drugs with antitumor and antibacterial properties. |
publishDate |
2021 |
dc.date.accessioned.fl_str_mv |
2021-09-13T17:31:05Z |
dc.date.available.fl_str_mv |
2021-09-13T17:31:05Z |
dc.date.issued.fl_str_mv |
2021-04-19 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/22200 |
url |
http://repositorio.ufsm.br/handle/1/22200 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
400300000005 |
dc.relation.confidence.fl_str_mv |
600 600 600 600 600 600 |
dc.relation.authority.fl_str_mv |
71ad1279-3ed8-4b45-b319-57e5e774dd14 4b7d6f71-9a26-4d62-b5a1-bf6f1193adf6 901d69c0-961a-4a78-8686-3c19e2ba38eb 4a8f4ee9-8151-4f71-98fa-bec13871182b 0323bbab-0eb4-4282-bc76-e17f6d640930 a45db657-fbef-4efc-a2e6-1b1ebab5c203 |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Ciências Farmacêuticas |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Análises Clínicas e Toxicológicas |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional Manancial UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Repositório Institucional Manancial UFSM |
collection |
Repositório Institucional Manancial UFSM |
bitstream.url.fl_str_mv |
http://repositorio.ufsm.br/bitstream/1/22200/1/TES_PPGCF_2021_BOTTEGA_ANGELITA.pdf http://repositorio.ufsm.br/bitstream/1/22200/2/license_rdf http://repositorio.ufsm.br/bitstream/1/22200/3/license.txt http://repositorio.ufsm.br/bitstream/1/22200/4/TES_PPGCF_2021_BOTTEGA_ANGELITA.pdf.txt http://repositorio.ufsm.br/bitstream/1/22200/5/TES_PPGCF_2021_BOTTEGA_ANGELITA.pdf.jpg |
bitstream.checksum.fl_str_mv |
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bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional Manancial UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
ouvidoria@ufsm.br |
_version_ |
1808854711891132416 |