Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidade
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | http://hdl.handle.net/1843/41162 |
Resumo: | Platinum(II)-based drugs are well known and widely used in cancer chemotherapy since the serendipitous discovery of the antitumor properties of cisplatin. However, toxic side effects and intrinsic or acquired cell resistance by some patients under cisplatin treatment can compromise its efficacy and have been stimulating the search for analog compounds with a more promising effects profile. This work presents the synthesis and structural characterization of platinum complexes of general formula [PtII(Pz)2Cl2], where Pz are diphenyl-pyrazole derived ligands, aiming to obtain potential antitumor agents. Pyrazole heterocycle derivatives are biologically relevant for their wide range of bioactivities reported in the literature. The diphenyl-pyrazole ligands used in this work have structure modifications on aryl groups, one is a para-fluorophenyl and the other phenyl is para-substituted by R groups (-CH3, -F or -Cl), L1, L2 e L3 respectively, in order to investigate their structure-activity relationships. The complexes were characterized by elemental, conductivity and thermogravimetric analysis, FTIR, electronic, NMR and mass spectrometry, as well as single-crystal X-ray diffraction. The interaction of synthesized compounds with DNA and BSA through spectrophotometric assay was also evaluated, resulting in similar or superior binding ability compared to the free ligands. In addition, agarose gel electrophoresis with plasmid DNA revealed that complexes are capable of interaction with DNA and modify its electrophoretic mobility. Antiproliferative activities were assessed against tumor (B16F10 and 4T1) and non-tumor (BHK21) cell lines, and the cytotoxicity of the compounds was strongly increased after metal complexation displaying promising activity, especially complexes C1 and C3, despite its low selectivity. It was also assessed the ability of BSA and GSH biomolecules to decrease the cytotoxicity of the complexes against B16F10. It can be highlighted here that the C3 activity was not disturbed in those conditions. Lastly, complexes were properly obtained and bioinorganic analysis suggest that C3 has better interaction with DNA (the main biological target), managing to circumvent biomolecules such as BSA and GSH that can cause its deactivation. |
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Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidadePlatinum diphenyl-pyrazole complexes: structure, interaction studies with biomolecules and cytotoxicityComplexos metálicosLigantes nitrogenadosAntitumoraisDNAAlbuminaGlutationaQuímica inorgânicaComplexos metálicos .Ligantes (Bioquímica)Agentes antineoplásicosDNAAlbuminaGlutationaPlatinum(II)-based drugs are well known and widely used in cancer chemotherapy since the serendipitous discovery of the antitumor properties of cisplatin. However, toxic side effects and intrinsic or acquired cell resistance by some patients under cisplatin treatment can compromise its efficacy and have been stimulating the search for analog compounds with a more promising effects profile. This work presents the synthesis and structural characterization of platinum complexes of general formula [PtII(Pz)2Cl2], where Pz are diphenyl-pyrazole derived ligands, aiming to obtain potential antitumor agents. Pyrazole heterocycle derivatives are biologically relevant for their wide range of bioactivities reported in the literature. The diphenyl-pyrazole ligands used in this work have structure modifications on aryl groups, one is a para-fluorophenyl and the other phenyl is para-substituted by R groups (-CH3, -F or -Cl), L1, L2 e L3 respectively, in order to investigate their structure-activity relationships. The complexes were characterized by elemental, conductivity and thermogravimetric analysis, FTIR, electronic, NMR and mass spectrometry, as well as single-crystal X-ray diffraction. The interaction of synthesized compounds with DNA and BSA through spectrophotometric assay was also evaluated, resulting in similar or superior binding ability compared to the free ligands. In addition, agarose gel electrophoresis with plasmid DNA revealed that complexes are capable of interaction with DNA and modify its electrophoretic mobility. Antiproliferative activities were assessed against tumor (B16F10 and 4T1) and non-tumor (BHK21) cell lines, and the cytotoxicity of the compounds was strongly increased after metal complexation displaying promising activity, especially complexes C1 and C3, despite its low selectivity. It was also assessed the ability of BSA and GSH biomolecules to decrease the cytotoxicity of the complexes against B16F10. It can be highlighted here that the C3 activity was not disturbed in those conditions. Lastly, complexes were properly obtained and bioinorganic analysis suggest that C3 has better interaction with DNA (the main biological target), managing to circumvent biomolecules such as BSA and GSH that can cause its deactivation.Fármacos baseados em platina(II) são bem conhecidos e amplamente utilizados na quimioterapia do câncer desde a descoberta das propriedades antitumorais da cisplatina. No entanto, efeitos colaterais tóxicos e resistência celular intrínseca ou adquirida por alguns pacientes decorrentes da administração destes compostos comprometem a sua eficácia e estimulam a busca por análogos com um perfil de efeitos mais favorável. Este trabalho apresenta a síntese e caracterização estrutural de três complexos inéditos de platina(II), de fórmula geral [PtII(Pz)2Cl2], em que Pz são ligantes derivados do difenil-pirazol, visando a obtenção de potenciais agentes antitumorais. Derivados do heterociclo pirazol são biologicamente relevantes apresentando uma ampla gama de bioatividades relatadas na literatura. Os ligantes difenil-pirazol utilizados neste trabalho possuem modificações estruturais nos grupos fenil, sendo um para-fluorofenil e o outro para-substituído pelos grupos R -CH3, -F ou -Cl (L1, L2 e L3, respectivamente), a fim de se investigar a relação estrutura-atividade. As caracterizações foram realizadas por meio de análise elementar, condutimetria, análise termogravimétrica, espectroscopia de absorção na região do infravermelho e do UV-vis, espectroscopia de RMN de 1H, 13C e 195Pt, espectrometria de massas e difração de raios X por monocristal. Também foi avaliada a interação dos complexos sintetizados com o DNA e a BSA (albumina do soro bovino) por meio de ensaios espectrofotométricos, em que estes apresentam constantes de interação similares ou superiores às apresentadas pelos ligantes livres. Além disso, o experimento de eletroforese em gel de agarose utilizando DNA plasmidial demonstrou a capacidade dos complexos interagirem com o DNA e alterarem sua mobilidade eletroforética. A atividade antiproliferativa dos compostos foi avaliada frente às linhagens celulares tumorais B16F10 e 4T1, e não tumoral BHK21, por meio da qual foi demonstrada a potencialização da ação citotóxica dos complexos sobre os ligantes. Os complexos apresentaram atividade promissora, principalmente os complexos C1 e C3, apesar da baixa seletividade. Foi avaliada, também, a capacidade de biomoléculas como BSA e GSH (glutationa) interagirem com os complexos em meio biológico e afetarem a atividade citotóxica dos mesmos frente à linhagem B16F10, sendo que o complexo C3 não sofreu perturbação. Por fim, os complexos foram devidamente obtidos e as análises bioinorgânicas sugerem que o complexo C3 tem melhor interação com o DNA (principal alvo celular) conseguindo driblar biomoléculas como BSA e GSH que possam causar sua desativação.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorUniversidade Federal de Minas GeraisBrasilICX - DEPARTAMENTO DE QUÍMICAPrograma de Pós-Graduação em QuímicaUFMGHeveline Silvahttp://lattes.cnpq.br/2841612483879436Priscila Pereira Silva CaldeiraDayse Carvalho da Silva MartinsAna Luiza de Andrade Querino2022-04-26T22:30:28Z2022-04-26T22:30:28Z2020-02-21info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/1843/411620000-0003-4581-2814porinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMG2022-04-26T22:30:29Zoai:repositorio.ufmg.br:1843/41162Repositório InstitucionalPUBhttps://repositorio.ufmg.br/oairepositorio@ufmg.bropendoar:2022-04-26T22:30:29Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.none.fl_str_mv |
Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidade Platinum diphenyl-pyrazole complexes: structure, interaction studies with biomolecules and cytotoxicity |
title |
Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidade |
spellingShingle |
Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidade Ana Luiza de Andrade Querino Complexos metálicos Ligantes nitrogenados Antitumorais DNA Albumina Glutationa Química inorgânica Complexos metálicos . Ligantes (Bioquímica) Agentes antineoplásicos DNA Albumina Glutationa |
title_short |
Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidade |
title_full |
Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidade |
title_fullStr |
Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidade |
title_full_unstemmed |
Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidade |
title_sort |
Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidade |
author |
Ana Luiza de Andrade Querino |
author_facet |
Ana Luiza de Andrade Querino |
author_role |
author |
dc.contributor.none.fl_str_mv |
Heveline Silva http://lattes.cnpq.br/2841612483879436 Priscila Pereira Silva Caldeira Dayse Carvalho da Silva Martins |
dc.contributor.author.fl_str_mv |
Ana Luiza de Andrade Querino |
dc.subject.por.fl_str_mv |
Complexos metálicos Ligantes nitrogenados Antitumorais DNA Albumina Glutationa Química inorgânica Complexos metálicos . Ligantes (Bioquímica) Agentes antineoplásicos DNA Albumina Glutationa |
topic |
Complexos metálicos Ligantes nitrogenados Antitumorais DNA Albumina Glutationa Química inorgânica Complexos metálicos . Ligantes (Bioquímica) Agentes antineoplásicos DNA Albumina Glutationa |
description |
Platinum(II)-based drugs are well known and widely used in cancer chemotherapy since the serendipitous discovery of the antitumor properties of cisplatin. However, toxic side effects and intrinsic or acquired cell resistance by some patients under cisplatin treatment can compromise its efficacy and have been stimulating the search for analog compounds with a more promising effects profile. This work presents the synthesis and structural characterization of platinum complexes of general formula [PtII(Pz)2Cl2], where Pz are diphenyl-pyrazole derived ligands, aiming to obtain potential antitumor agents. Pyrazole heterocycle derivatives are biologically relevant for their wide range of bioactivities reported in the literature. The diphenyl-pyrazole ligands used in this work have structure modifications on aryl groups, one is a para-fluorophenyl and the other phenyl is para-substituted by R groups (-CH3, -F or -Cl), L1, L2 e L3 respectively, in order to investigate their structure-activity relationships. The complexes were characterized by elemental, conductivity and thermogravimetric analysis, FTIR, electronic, NMR and mass spectrometry, as well as single-crystal X-ray diffraction. The interaction of synthesized compounds with DNA and BSA through spectrophotometric assay was also evaluated, resulting in similar or superior binding ability compared to the free ligands. In addition, agarose gel electrophoresis with plasmid DNA revealed that complexes are capable of interaction with DNA and modify its electrophoretic mobility. Antiproliferative activities were assessed against tumor (B16F10 and 4T1) and non-tumor (BHK21) cell lines, and the cytotoxicity of the compounds was strongly increased after metal complexation displaying promising activity, especially complexes C1 and C3, despite its low selectivity. It was also assessed the ability of BSA and GSH biomolecules to decrease the cytotoxicity of the complexes against B16F10. It can be highlighted here that the C3 activity was not disturbed in those conditions. Lastly, complexes were properly obtained and bioinorganic analysis suggest that C3 has better interaction with DNA (the main biological target), managing to circumvent biomolecules such as BSA and GSH that can cause its deactivation. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-02-21 2022-04-26T22:30:28Z 2022-04-26T22:30:28Z |
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.uri.fl_str_mv |
http://hdl.handle.net/1843/41162 0000-0003-4581-2814 |
url |
http://hdl.handle.net/1843/41162 |
identifier_str_mv |
0000-0003-4581-2814 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais Brasil ICX - DEPARTAMENTO DE QUÍMICA Programa de Pós-Graduação em Química UFMG |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais Brasil ICX - DEPARTAMENTO DE QUÍMICA Programa de Pós-Graduação em Química UFMG |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
instname_str |
Universidade Federal de Minas Gerais (UFMG) |
instacron_str |
UFMG |
institution |
UFMG |
reponame_str |
Repositório Institucional da UFMG |
collection |
Repositório Institucional da UFMG |
repository.name.fl_str_mv |
Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG) |
repository.mail.fl_str_mv |
repositorio@ufmg.br |
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1823248163972055040 |