Complexos difenil-pirazólicos de platina: estrutura, interação com biomoléculas e citotoxicidade

Detalhes bibliográficos
Autor(a) principal: Ana Luiza de Andrade Querino
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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spelling 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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