Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450

Detalhes bibliográficos
Ano de defesa: 2017
Autor(a) principal: Melo, Francisco do Vale Chaves e lattes
Orientador(a): Felzenszwalb, Israel lattes
Banca de defesa: Paes, Márcia Cristina lattes, Leitão, álvaro Augusto da Costa lattes, Carvalho, Alcione Silva de lattes
Tipo de documento: Tese
Tipo de acesso: Acesso aberto
Idioma: por
Instituição de defesa: Universidade do Estado do Rio de Janeiro
Programa de Pós-Graduação: Programa de Pós-Graduação em Biociências
Departamento: Centro Biomédico::Instituto de Biologia Roberto Alcantara Gomes
País: BR
Palavras-chave em Português:
Palavras-chave em Inglês:
Área do conhecimento CNPq:
Link de acesso: http://www.bdtd.uerj.br/handle/1/16193
Resumo: Chagas disease is a tropical, infectious and neglected disease that affects mostly poor regions of developing countries, infecting thousands of people every year. The lack of a safe and effective pharmacological treatment also contributes to the maintenance of the Chagas disease. The Institute of Pharmaceutical Technology, Oswaldo Cruz Foundation, synthesized new bioactive substances in order to develop a safe and effective alternative to the available treatment. They are: PNING 43-14 (ethyl-1-(1-methyl-4-nitro-1H-imidazol-5-yl)-1H-1,2,3-triazole-4-carboxylate), PNING 47-13 (4-cyclopropyl-1-(1-methyl-4-nitro-1H-imidazol-5-yl)-1H-1,2,3-triazole) and PNING 39-14 (1-(1-methyl-4-nitro-1H-imidazol-5-yl)-4-(4-pentylphenyl)-1H-1,2,3-triazole). The aim of this study was to assess the trypanocidal, cytotoxic and genotoxic activities of new nitro-heterocyclic derivatives, and the cytochrome P450 genes expressed, through the treatment of in vitro cell cultures models. The nitro-heterocyclic derivatives showed trypanocidal activity in the treatment (from 5.0 g/mL) of axenic amastigote evolutive form of Trypanosoma cruzi Y strain cell culture, and in the treatment of peritoneal macrophages primary mice cells infected with Trypanosoma cruzi, Y strain cells. In the assessment of cell viability through the colorimetric tests WST-1 and LDH, the nitro-heterocyclic derivatives PNING 43-14 and PNING 47-14 induced damages on high concentrations (500 and 1000 g/mL) and exposure time (48 h), in the treatment of the human hepatocarcinoma cells HepG2, only. The derivative PNING 39-14 induced damage in HepG2 and macrophage RAW 264.7 cells, using low concentrations (5.0 to 100 g/mL) and exposure times (from 3 h), being the most cytotoxic derivative. In the cell death assessment, observed by the annexin V and propidium iodide binding, in the treatment (50 to 1000 g/mL) of RAW 264.7 cells, the derivative PNING 43-14 induced necrosis, while the derivative PNING 39-14 induced apoptosis. In the Salmonella/microsome test, the derivatives induced pair bases substitutions mutations in the treatment of Salmonella enterica TA100 and TA102 strains, and deletions mutations in the TA97 strain, with and without exogenous metabolic activation. In the treatment of strains that overexpress nitroredutases (YG1021) and acetyltransferases (YG1024) enzymes, the derivatives induced cell death, with or without exogenous metabolic activation, mostly by the treatment with the derivative PNING 43-14 (100 to 1000 g/mL). In addition, the derivatives induced (50 to 1000 g/mL; 3 and 24 h) the micronuclei formation in HepG2 and RAW 264.7 cells, in the micronucleus test. In the assessment of cytochrome P450 gene expression in HepG2 cells, the derivatives PNING 43-14 and PNING 47-13 induced the 3A4 gene expression and inhibit the 1A2, 2B6 and 2E1 gene expression, while the derivative PNING 39-14 induced the 1A2, 2B6 and 2E1 gene expression and inhibit the 3A4 gene expression. The gene expression induced by the treatment using the derivative PNING 39-14 is related to cytotoxic and genotoxic positive responses. Despite the toxic positive results, there are lower concentrations of the derivatives that are safe and still hold an important trypanocidal activity.
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spelling Felzenszwalb, Israelhttp://lattes.cnpq.br/8132847165466920Paes, Márcia Cristinahttp://lattes.cnpq.br/7463829190927034Leitão, álvaro Augusto da Costahttp://lattes.cnpq.br/1797697611370460Carvalho, Alcione Silva dehttp://lattes.cnpq.br/5148096669239336http://lattes.cnpq.br/3809738780445226Melo, Francisco do Vale Chaves e2021-04-26T01:12:00Z2018-04-252017-07-27MELO, Francisco do Vale Chaves e. Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450. 2017. 171 f. Tese (Doutorado em Biociências Nucleares; Ecologia) - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2017.http://www.bdtd.uerj.br/handle/1/16193Chagas disease is a tropical, infectious and neglected disease that affects mostly poor regions of developing countries, infecting thousands of people every year. The lack of a safe and effective pharmacological treatment also contributes to the maintenance of the Chagas disease. The Institute of Pharmaceutical Technology, Oswaldo Cruz Foundation, synthesized new bioactive substances in order to develop a safe and effective alternative to the available treatment. They are: PNING 43-14 (ethyl-1-(1-methyl-4-nitro-1H-imidazol-5-yl)-1H-1,2,3-triazole-4-carboxylate), PNING 47-13 (4-cyclopropyl-1-(1-methyl-4-nitro-1H-imidazol-5-yl)-1H-1,2,3-triazole) and PNING 39-14 (1-(1-methyl-4-nitro-1H-imidazol-5-yl)-4-(4-pentylphenyl)-1H-1,2,3-triazole). The aim of this study was to assess the trypanocidal, cytotoxic and genotoxic activities of new nitro-heterocyclic derivatives, and the cytochrome P450 genes expressed, through the treatment of in vitro cell cultures models. The nitro-heterocyclic derivatives showed trypanocidal activity in the treatment (from 5.0 g/mL) of axenic amastigote evolutive form of Trypanosoma cruzi Y strain cell culture, and in the treatment of peritoneal macrophages primary mice cells infected with Trypanosoma cruzi, Y strain cells. In the assessment of cell viability through the colorimetric tests WST-1 and LDH, the nitro-heterocyclic derivatives PNING 43-14 and PNING 47-14 induced damages on high concentrations (500 and 1000 g/mL) and exposure time (48 h), in the treatment of the human hepatocarcinoma cells HepG2, only. The derivative PNING 39-14 induced damage in HepG2 and macrophage RAW 264.7 cells, using low concentrations (5.0 to 100 g/mL) and exposure times (from 3 h), being the most cytotoxic derivative. In the cell death assessment, observed by the annexin V and propidium iodide binding, in the treatment (50 to 1000 g/mL) of RAW 264.7 cells, the derivative PNING 43-14 induced necrosis, while the derivative PNING 39-14 induced apoptosis. In the Salmonella/microsome test, the derivatives induced pair bases substitutions mutations in the treatment of Salmonella enterica TA100 and TA102 strains, and deletions mutations in the TA97 strain, with and without exogenous metabolic activation. In the treatment of strains that overexpress nitroredutases (YG1021) and acetyltransferases (YG1024) enzymes, the derivatives induced cell death, with or without exogenous metabolic activation, mostly by the treatment with the derivative PNING 43-14 (100 to 1000 g/mL). In addition, the derivatives induced (50 to 1000 g/mL; 3 and 24 h) the micronuclei formation in HepG2 and RAW 264.7 cells, in the micronucleus test. In the assessment of cytochrome P450 gene expression in HepG2 cells, the derivatives PNING 43-14 and PNING 47-13 induced the 3A4 gene expression and inhibit the 1A2, 2B6 and 2E1 gene expression, while the derivative PNING 39-14 induced the 1A2, 2B6 and 2E1 gene expression and inhibit the 3A4 gene expression. The gene expression induced by the treatment using the derivative PNING 39-14 is related to cytotoxic and genotoxic positive responses. Despite the toxic positive results, there are lower concentrations of the derivatives that are safe and still hold an important trypanocidal activity.A doença de Chagas é uma doença tropical, infecciosa e negligenciada que atinge principalmente regiões pobres de países em desenvolvimento, infectando milhares de pessoas todo ano. A ausência de um tratamento farmacológico eficaz e seguro contribui para a manutenção da doença. O Instituto de Tecnologia em Fármacos (Farmanguinhos), Fundação Oswaldo Cruz, sintetizou novas substâncias bioativas a fim de desenvolver uma alternativa segura e eficaz ao tratamento disponível. São eles: PNING 43-14 (etil-1-(1-metil-4-nitro-1H-imidazol-5-il)-1H-1,2,3-triazol-4-carboxilato), PNING 47-13 (4-ciclopropil-1-(1-metil-4-nitro-1H-imidazol-5-il)-1H-1,2,3-triazol) e PNING 39-14 (1-(1-metil-4-nitro-1H-imidazol-5-il)-4-(4-pentilfenil)-1H-1,2,3-triazol). O objetivo deste estudo foi avaliar a atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclicos, e os genes do citocromo P450 expressos, através do tratamento de modelos in vitro de cultura de células. Os derivados apresentaram atividade tripanocida no tratamento (a partir de 5,0 g/mL) de cultura axênica de Trypanosoma cruzi, cepa Y, forma amastigota, e de cultura primária de macrófagos peritoneais de camundongo Swiss Webster infectadas com Trypanosoma cruzi, cepa Y. Na análise da viabilidade celular pelos testes colorimétricos WST-1 e LDH, os derivados PNING 43-14 e PNING 47-13 induziram danos nas maiores concentrações (50 e 100 g/mL) e tempo de exposição (48 h), no tratamento de cultura de hepatocarcinoma humano HepG2, somente. O derivado PNING 39-14 induziu danos em células de HepG2 e de macrófagos RAW 264,7, a partir de concentrações (5,0 a 100 g/mL) e tempos de exposição (a partir de 3 h) menores, demonstrando ser mais citotóxico. Na análise da indução de morte celular, observada pela marcação por anexina V e iodeto de propídio, no tratamento (50 a 1000 g/mL) de células RAW 264,7, o derivado PNING 43-14 induziu necrose, enquanto o derivado PNING 39-14 induziu apoptose. No teste Salmonella/microssoma, os derivados induziram mutações de substituição de pares de bases nas linhagens de Salmonella enterica (TA100 e TA102), e deleção de pares de bases (TA97), independente de metabolização exógena, nas maiores concentrações (500 e 1000 g/mL). No tratamento de linhagens que superexpressam enzimas nitroredutases (YG1021) e acetiltransferases (YG1024), induziram morte celular, independente de metabolização exógena, principalmente no tratamento com PNING 43-14 (100 a 1000 g/mL). Os derivados também induziram a formação de células micronucleadas no tratamento (50 a 1000 g/mL; 3 a 24 h) de células HepG2 e RAW 264,7, no teste do micronúcleo. Na análise da expressão de genes do citocromo P450 em células HepG2, os derivados PNING 43-14 e PNING 47-13 induziram a expressão do gene 3A4 e a inibição dos genes 1A2, 2B6 e 2E1, enquanto o derivado PNING 39-14 induziu a expressão dos genes 1A2, 2B6 e 2E1, e a inibição do gene 3A4. A expressão dos genes induzidos pelo tratamento com o derivado PNING 39-14 está mais relacionada a geração de respostas citotóxicas e genotóxicas. Apesar dos resultados tóxicos positivos, existem concentrações menores e seguras que apresentam atividade tripanocida relevante.Submitted by Boris INFORMAT (boris@uerj.br) on 2021-04-26T01:12:00Z No. of bitstreams: 1 Francisco do Vale Chaves e Mello Tese completa.pdf: 4039718 bytes, checksum: 916228d220c6db3640e099055a1b5620 (MD5)Made available in DSpace on 2021-04-26T01:12:00Z (GMT). No. of bitstreams: 1 Francisco do Vale Chaves e Mello Tese completa.pdf: 4039718 bytes, checksum: 916228d220c6db3640e099055a1b5620 (MD5) Previous issue date: 2017-07-27Coordenação de Aperfeiçoamento de Pessoal de Nível Superiorapplication/pdfporUniversidade do Estado do Rio de JaneiroPrograma de Pós-Graduação em BiociênciasUERJBRCentro Biomédico::Instituto de Biologia Roberto Alcantara GomesChagas diseaseNitro-heterocyclic derivativesTrypanocidal activityToxicological studyCytochrome P450 genesChagas, Doença deAgentes antineoplásicosGenotoxicidadeDoença de ChagasDerivados nitro-heterocíclicostividade tripanocidaEstudo toxicológicoGenes do citocromo P450CitotoxinaAgentes tripanocidasCNPQ::CIENCIAS BIOLOGICAS::GENETICA::MUTAGENESEAtividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450Trypanocidal, cytotoxic and genotoxic activity of new nitro-heterocyclic derivatives and their effects on the cytochrome p450 genes expression.info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UERJinstname:Universidade do Estado do Rio de Janeiro (UERJ)instacron:UERJORIGINALFrancisco do Vale Chaves e Mello Tese completa.pdfapplication/pdf4039718http://www.bdtd.uerj.br/bitstream/1/16193/1/Francisco+do+Vale+Chaves+e+Mello+Tese+completa.pdf916228d220c6db3640e099055a1b5620MD511/161932024-02-26 11:25:01.409oai:www.bdtd.uerj.br:1/16193Biblioteca Digital de Teses e Dissertaçõeshttp://www.bdtd.uerj.br/PUBhttps://www.bdtd.uerj.br:8443/oai/requestbdtd.suporte@uerj.bropendoar:29032024-02-26T14:25:01Biblioteca Digital de Teses e Dissertações da UERJ - Universidade do Estado do Rio de Janeiro (UERJ)false
dc.title.por.fl_str_mv Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450
dc.title.alternative.eng.fl_str_mv Trypanocidal, cytotoxic and genotoxic activity of new nitro-heterocyclic derivatives and their effects on the cytochrome p450 genes expression.
title Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450
spellingShingle Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450
Melo, Francisco do Vale Chaves e
Chagas disease
Nitro-heterocyclic derivatives
Trypanocidal activity
Toxicological study
Cytochrome P450 genes
Chagas, Doença de
Agentes antineoplásicos
Genotoxicidade
Doença de Chagas
Derivados nitro-heterocíclicos
tividade tripanocida
Estudo toxicológico
Genes do citocromo P450
Citotoxina
Agentes tripanocidas
CNPQ::CIENCIAS BIOLOGICAS::GENETICA::MUTAGENESE
title_short Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450
title_full Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450
title_fullStr Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450
title_full_unstemmed Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450
title_sort Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450
author Melo, Francisco do Vale Chaves e
author_facet Melo, Francisco do Vale Chaves e
author_role author
dc.contributor.advisor1.fl_str_mv Felzenszwalb, Israel
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/8132847165466920
dc.contributor.referee1.fl_str_mv Paes, Márcia Cristina
dc.contributor.referee1Lattes.fl_str_mv http://lattes.cnpq.br/7463829190927034
dc.contributor.referee2.fl_str_mv Leitão, álvaro Augusto da Costa
dc.contributor.referee2Lattes.fl_str_mv http://lattes.cnpq.br/1797697611370460
dc.contributor.referee3.fl_str_mv Carvalho, Alcione Silva de
dc.contributor.referee3Lattes.fl_str_mv http://lattes.cnpq.br/5148096669239336
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/3809738780445226
dc.contributor.author.fl_str_mv Melo, Francisco do Vale Chaves e
contributor_str_mv Felzenszwalb, Israel
Paes, Márcia Cristina
Leitão, álvaro Augusto da Costa
Carvalho, Alcione Silva de
dc.subject.eng.fl_str_mv Chagas disease
Nitro-heterocyclic derivatives
Trypanocidal activity
Toxicological study
Cytochrome P450 genes
topic Chagas disease
Nitro-heterocyclic derivatives
Trypanocidal activity
Toxicological study
Cytochrome P450 genes
Chagas, Doença de
Agentes antineoplásicos
Genotoxicidade
Doença de Chagas
Derivados nitro-heterocíclicos
tividade tripanocida
Estudo toxicológico
Genes do citocromo P450
Citotoxina
Agentes tripanocidas
CNPQ::CIENCIAS BIOLOGICAS::GENETICA::MUTAGENESE
dc.subject.por.fl_str_mv Chagas, Doença de
Agentes antineoplásicos
Genotoxicidade
Doença de Chagas
Derivados nitro-heterocíclicos
tividade tripanocida
Estudo toxicológico
Genes do citocromo P450
Citotoxina
Agentes tripanocidas
dc.subject.cnpq.fl_str_mv CNPQ::CIENCIAS BIOLOGICAS::GENETICA::MUTAGENESE
description Chagas disease is a tropical, infectious and neglected disease that affects mostly poor regions of developing countries, infecting thousands of people every year. The lack of a safe and effective pharmacological treatment also contributes to the maintenance of the Chagas disease. The Institute of Pharmaceutical Technology, Oswaldo Cruz Foundation, synthesized new bioactive substances in order to develop a safe and effective alternative to the available treatment. They are: PNING 43-14 (ethyl-1-(1-methyl-4-nitro-1H-imidazol-5-yl)-1H-1,2,3-triazole-4-carboxylate), PNING 47-13 (4-cyclopropyl-1-(1-methyl-4-nitro-1H-imidazol-5-yl)-1H-1,2,3-triazole) and PNING 39-14 (1-(1-methyl-4-nitro-1H-imidazol-5-yl)-4-(4-pentylphenyl)-1H-1,2,3-triazole). The aim of this study was to assess the trypanocidal, cytotoxic and genotoxic activities of new nitro-heterocyclic derivatives, and the cytochrome P450 genes expressed, through the treatment of in vitro cell cultures models. The nitro-heterocyclic derivatives showed trypanocidal activity in the treatment (from 5.0 g/mL) of axenic amastigote evolutive form of Trypanosoma cruzi Y strain cell culture, and in the treatment of peritoneal macrophages primary mice cells infected with Trypanosoma cruzi, Y strain cells. In the assessment of cell viability through the colorimetric tests WST-1 and LDH, the nitro-heterocyclic derivatives PNING 43-14 and PNING 47-14 induced damages on high concentrations (500 and 1000 g/mL) and exposure time (48 h), in the treatment of the human hepatocarcinoma cells HepG2, only. The derivative PNING 39-14 induced damage in HepG2 and macrophage RAW 264.7 cells, using low concentrations (5.0 to 100 g/mL) and exposure times (from 3 h), being the most cytotoxic derivative. In the cell death assessment, observed by the annexin V and propidium iodide binding, in the treatment (50 to 1000 g/mL) of RAW 264.7 cells, the derivative PNING 43-14 induced necrosis, while the derivative PNING 39-14 induced apoptosis. In the Salmonella/microsome test, the derivatives induced pair bases substitutions mutations in the treatment of Salmonella enterica TA100 and TA102 strains, and deletions mutations in the TA97 strain, with and without exogenous metabolic activation. In the treatment of strains that overexpress nitroredutases (YG1021) and acetyltransferases (YG1024) enzymes, the derivatives induced cell death, with or without exogenous metabolic activation, mostly by the treatment with the derivative PNING 43-14 (100 to 1000 g/mL). In addition, the derivatives induced (50 to 1000 g/mL; 3 and 24 h) the micronuclei formation in HepG2 and RAW 264.7 cells, in the micronucleus test. In the assessment of cytochrome P450 gene expression in HepG2 cells, the derivatives PNING 43-14 and PNING 47-13 induced the 3A4 gene expression and inhibit the 1A2, 2B6 and 2E1 gene expression, while the derivative PNING 39-14 induced the 1A2, 2B6 and 2E1 gene expression and inhibit the 3A4 gene expression. The gene expression induced by the treatment using the derivative PNING 39-14 is related to cytotoxic and genotoxic positive responses. Despite the toxic positive results, there are lower concentrations of the derivatives that are safe and still hold an important trypanocidal activity.
publishDate 2017
dc.date.issued.fl_str_mv 2017-07-27
dc.date.available.fl_str_mv 2018-04-25
dc.date.accessioned.fl_str_mv 2021-04-26T01:12:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/doctoralThesis
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dc.identifier.citation.fl_str_mv MELO, Francisco do Vale Chaves e. Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450. 2017. 171 f. Tese (Doutorado em Biociências Nucleares; Ecologia) - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2017.
dc.identifier.uri.fl_str_mv http://www.bdtd.uerj.br/handle/1/16193
identifier_str_mv MELO, Francisco do Vale Chaves e. Atividade tripanocida, citotóxica e genotóxica de novos derivados nitro-heterocíclico e os efeitos na expressão de genes do citocromo P450. 2017. 171 f. Tese (Doutorado em Biociências Nucleares; Ecologia) - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2017.
url http://www.bdtd.uerj.br/handle/1/16193
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dc.publisher.none.fl_str_mv Universidade do Estado do Rio de Janeiro
dc.publisher.program.fl_str_mv Programa de Pós-Graduação em Biociências
dc.publisher.initials.fl_str_mv UERJ
dc.publisher.country.fl_str_mv BR
dc.publisher.department.fl_str_mv Centro Biomédico::Instituto de Biologia Roberto Alcantara Gomes
publisher.none.fl_str_mv Universidade do Estado do Rio de Janeiro
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