Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana

Detalhes bibliográficos
Autor(a) principal: Almeida, Patrícia Saraiva Vilas Boas de
Data de Publicação: 2019
Tipo de documento: Tese
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da UFRRJ
Texto Completo: https://rima.ufrrj.br/jspui/handle/20.500.14407/10245
Resumo: Câncer e infecções bacterianas são doenças que causam um grande número de mortes e, apesar dos tratamentos existentes, ainda se fazem necessários novos fármacos que causem menos danos aos pacientes e que sejam mais ativos às células resistentes. Derivados de cumarina e diversas classes de complexos de Ru(II) vêm sendo estudados quanto ao seu potencial como agentes antimicrobianos e antitumorais. Sendo assim, quatro novos ligantes híbridos de cumarina-N-acilidrazonas do tipo (E)-(N’-4-R-benzilideno-7-(dietilamino)-2-oxo-2H-cromona-3-carboidrazida (HL2: R=H; HL3: R=Cl, HL4: R=Br, HL5: R= OCH3), foram obtidos através da condensação de uma hidrazida (7-(dietilamino)-2-oxo-2H-cromona-3-carboidrazida, HL1) e diferentes aldeídos p-substituídos. Reações entre HL2-5 e cis-[RuCl2(DMSO)4] resultaram em complexos trans-cis-[RuCl2(DMSO)2(HL2-5)], C2-5 (classe Ru(II)-Cl-DMSO). Concomitantemente, a hidrólise do ligante ocorreu, resultando na formação do complexo trans-cis-[RuCl2(DMSO)2(HL1)] C1, contendo a hidrazida coordenada. As estruturas cristalinas dos ligantes HL2 e HL3 e dos complexos C2-5 foram determinadas por DRX, que revelaram a isomerização de E para Z das cumarinas-N-acilidrazonas resultante da coordenação. Os complexos C2-5 exibiram o átomo de Ru(II) em uma geometria octaédrica distorcida com o ligante coordenado na forma ceto através da carbonila da hidrazona e do nitrogênio imínico. Na tentativa de sintetizar uma segunda classe de complexos carregados e contendo bipiridina como ligante auxiliar ([Ru(bipy)2(HLn)]PF6 - classe Ru(II)-bipy), realizou-se a reação entre HL2 e cis-[Ru(bipy)2Cl2]. Porém, a possível hidrólise do ligante impossibilitou a obtenção do complexo desejado. Uma metodologia similar utilizando híbridos de cumarina-β-cetoéster HL6-8 originou os complexos da classe Ru(II)-bipy, [Ru(bipy)2(HL6-8)]PF6 C6-8. A análise de DRX de C7 mostrou o Ru(II) em um ambiente octaédrico distorcido com o ligante coordenado pela porção β-cetoéster desprotonada e duas bipiridinas na esfera de coordenação. A avaliação antiproliferativa dos compostos contra linhagens de células tumorais (4T1: carcinoma mamário murino e B16-F10: melanoma murino metastático) e não tumoral (BHK-21: rim de hamster) mostrou que, de uma maneira geral, os ligantes híbridos cumarina-N-acilidrazona e cumarina-hidrazida HL1-5 foram mais ativos que seus complexos C1-5, cujos valores de IC50 (metade da concentração inibitória máxima) foram encontrados na faixa de 10,6 a 50,4 µM para os ligantes e entre 17,7 e 97,8 µM para os complexos. Por outro lado, os ligantes cumarina-β-cetoéster HL6-8 foram inativos (IC50 > 100 µM), mas os complexos C6-8 apresentaram alta citotoxicidade, com valores de IC50 entre 2,0 e 12,8 µM. Para o teste antibacteriano, HL1 foi o único ligante ativo frente a uma cepa de bactéria gram-negativa, porém seu MIC não foi determinado nas concentrações estudadas. Todos os complexos demostraram atividade somente frente a cepas de bactérias gram positivas. Para os complexos Ru(II)-Cl-DMSO, somente C3 e C4 (R = Cl e Br) apresentaram MIC nas concentrações utilizadas (40,5 e 86 µM). Por outro lado, os complexos Ru(II)-bipy C6-8 apresentaram MIC entre 2,20-9,22 µM. A maior atividade apresentada pelos derivados Ru(II)-bipy em ambos os testes biológicos, comparada aos complexos Ru(II)-DMSO, foi atribuída à presença de carga no complexo e aos ligantes bipiridina. Estudos de interação com DNA dos complexos [Ru(bipy)2(HL6-8)]PF6 (C6-8) estão em andamento.
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spelling Almeida, Patrícia Saraiva Vilas Boas deNeves, Amanda PortoCPF: 055.195.997-50Kummerle, Arthur EugenCPF: 053.978.487-78Lima, Áurea Echevarria Aznar NevesSilva, Gustavo Bezerra daVargas, Maria DominguesScarpellini, MarcielaCPF: 087.759.696-45http://lattes.cnpq.br/71432537393733482023-12-21T18:59:30Z2023-12-21T18:59:30Z2019-07-31ALMEIDA, Patrícia Saraiva Vilas Boas de. Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana. 2019. 234 f. Tese (Doutorado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica - RJ, 2019.https://rima.ufrrj.br/jspui/handle/20.500.14407/10245Câncer e infecções bacterianas são doenças que causam um grande número de mortes e, apesar dos tratamentos existentes, ainda se fazem necessários novos fármacos que causem menos danos aos pacientes e que sejam mais ativos às células resistentes. Derivados de cumarina e diversas classes de complexos de Ru(II) vêm sendo estudados quanto ao seu potencial como agentes antimicrobianos e antitumorais. Sendo assim, quatro novos ligantes híbridos de cumarina-N-acilidrazonas do tipo (E)-(N’-4-R-benzilideno-7-(dietilamino)-2-oxo-2H-cromona-3-carboidrazida (HL2: R=H; HL3: R=Cl, HL4: R=Br, HL5: R= OCH3), foram obtidos através da condensação de uma hidrazida (7-(dietilamino)-2-oxo-2H-cromona-3-carboidrazida, HL1) e diferentes aldeídos p-substituídos. Reações entre HL2-5 e cis-[RuCl2(DMSO)4] resultaram em complexos trans-cis-[RuCl2(DMSO)2(HL2-5)], C2-5 (classe Ru(II)-Cl-DMSO). Concomitantemente, a hidrólise do ligante ocorreu, resultando na formação do complexo trans-cis-[RuCl2(DMSO)2(HL1)] C1, contendo a hidrazida coordenada. As estruturas cristalinas dos ligantes HL2 e HL3 e dos complexos C2-5 foram determinadas por DRX, que revelaram a isomerização de E para Z das cumarinas-N-acilidrazonas resultante da coordenação. Os complexos C2-5 exibiram o átomo de Ru(II) em uma geometria octaédrica distorcida com o ligante coordenado na forma ceto através da carbonila da hidrazona e do nitrogênio imínico. Na tentativa de sintetizar uma segunda classe de complexos carregados e contendo bipiridina como ligante auxiliar ([Ru(bipy)2(HLn)]PF6 - classe Ru(II)-bipy), realizou-se a reação entre HL2 e cis-[Ru(bipy)2Cl2]. Porém, a possível hidrólise do ligante impossibilitou a obtenção do complexo desejado. Uma metodologia similar utilizando híbridos de cumarina-β-cetoéster HL6-8 originou os complexos da classe Ru(II)-bipy, [Ru(bipy)2(HL6-8)]PF6 C6-8. A análise de DRX de C7 mostrou o Ru(II) em um ambiente octaédrico distorcido com o ligante coordenado pela porção β-cetoéster desprotonada e duas bipiridinas na esfera de coordenação. A avaliação antiproliferativa dos compostos contra linhagens de células tumorais (4T1: carcinoma mamário murino e B16-F10: melanoma murino metastático) e não tumoral (BHK-21: rim de hamster) mostrou que, de uma maneira geral, os ligantes híbridos cumarina-N-acilidrazona e cumarina-hidrazida HL1-5 foram mais ativos que seus complexos C1-5, cujos valores de IC50 (metade da concentração inibitória máxima) foram encontrados na faixa de 10,6 a 50,4 µM para os ligantes e entre 17,7 e 97,8 µM para os complexos. Por outro lado, os ligantes cumarina-β-cetoéster HL6-8 foram inativos (IC50 > 100 µM), mas os complexos C6-8 apresentaram alta citotoxicidade, com valores de IC50 entre 2,0 e 12,8 µM. Para o teste antibacteriano, HL1 foi o único ligante ativo frente a uma cepa de bactéria gram-negativa, porém seu MIC não foi determinado nas concentrações estudadas. Todos os complexos demostraram atividade somente frente a cepas de bactérias gram positivas. Para os complexos Ru(II)-Cl-DMSO, somente C3 e C4 (R = Cl e Br) apresentaram MIC nas concentrações utilizadas (40,5 e 86 µM). Por outro lado, os complexos Ru(II)-bipy C6-8 apresentaram MIC entre 2,20-9,22 µM. A maior atividade apresentada pelos derivados Ru(II)-bipy em ambos os testes biológicos, comparada aos complexos Ru(II)-DMSO, foi atribuída à presença de carga no complexo e aos ligantes bipiridina. Estudos de interação com DNA dos complexos [Ru(bipy)2(HL6-8)]PF6 (C6-8) estão em andamento.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPERJ - Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de JaneiroCancer and bacterial infections are diseases that cause a large number of deaths, and despite the existing treatments, drugs being less harmful to the patients and more active against resistant cells are still needed. Coumarin derivatives and several classes of Ru(II) complexes have been studied for their potential as antimicrobial and antitumor agents. For this reason, four novel coumarin-N-acylhydrazone hybrid ligands of the type (E)-7-(diethylamino)-N'-(4-R-benzylidene)-2-oxo-2H-chromene-3-carbohydrazide (HL2: R=H; HL3: R=Cl, HL4: R=Br, HL5: R= OCH3), were obtained from condensation reactions, using one hydrazide (7-(diethylamine)-2-oxo-2H-chromone-3-carbohydrazide, HL1) and different p-substituted aldehydes. Reactions between HL2-5 and cis-[RuCl2(DMSO)4] afforded the complexes trans-cis-[RuCl2(DMSO)2(HL2-5)], C2-5 (Ru(II)-Cl-DMSO class). Concomitantly, hydrolysis of the ligand occurred, resulting in the formation of the complex trans-cis-[RuCl2(DMSO)2(HL1)] C1, containing the hydrazide as ligand. Crystal structures of HL2, HL3 and the complexes C2-5 were determined by single crystal XRD, that revealed an E to Z isomerization of the coumarin-N-acylhydrazones upon coordination. Complexes C2-5 exhibited the Ru(II) atom in a distorted octahedral geometry, where the coumarin ligand is coordinated in the keto form through the hydrazone carbonyl and the iminic nitrogen. In an attempt to synthesize a second class of complexes, containing bipyridine as auxiliary ligand and charged, ([Ru(bipy)2(HLn)]PF6 -Ru(II)-bipy class), the reaction between HL2 and cis-[Ru(bipy)2Cl2] was carried out. However, possible hydrolysis of the ligand precluded the isolation of the desired complex. A similar methodology using cumarin-β-ketoester hybrids HL6-8 yielded the complexes of the Ru(II)-bipy class, [Ru(bipy)2(HL6-8)]PF6 C6-8. The XRD analysis of C7 shows the Ru(II) ion in a distorted octahedral environment with the ligand coordinated through the deprotonated β-ketoester portion and two bypiridines in the coordination sphere. Antiproliferative evaluation of the compounds against tumor cell lines (4T1: murine mammary carcinoma and B16-F10: murine melanoma metastatic) and a non-tumor cell line (BHK-21: hamster kidney) showed that overall, the coumarin-N-acylhydrazone and coumarin-hydrazyde hybrids HL1-5 were more active than the complexes C1-5, where the IC50 (half of the maximum inhibitory concentration) values for the ligands were found in the range of 10.6 to 50.4 µM and between 17.7, and 97.8 µM for the complexes. On the other hand, the coumarin-β-ketoester ligands HL6-8 were inactive (IC50 > 100 µM), yet the complexes C6-8 presented high cytotoxicity, with IC50 values ranging from 2.0 and 12.8 µM. For the antimicrobial assays, HL1 was the only ligand active against one gram-negative bacteria strain, however its MIC was not determined within the studied concentrations. Among the complexes, all demonstrated activity only against gram-positive bacteria strains. Within the Ru(II)-Cl-DMSO series, only C3 and C4 (R = Cl and Br) exhibited MIC at the concentrations used (40.5 and 86 μM). On the other hand, the complexes of the Ru(II)-bipy class C6-8 presented MIC between 2.20 and 9.22 μM. Comparing the classes of complexes, Ru(II)-bipy and Ru(II)-DMSO, the higher activities presented by the former in both biological studies was attributed to the presence of charge and of bipyridine ligands. The investigation of DNA interaction of the complexes [Ru(bipy)2(HLn)]PF6 (C6-8) are in progress.application/pdfporUniversidade Federal Rural do Rio de JaneiroPrograma de Pós-Graduação em QuímicaUFRRJBrasilInstituto de Químicacomplexos de rutêniohíbridos de cumarinaatividade antitumoralatividade antibacterianaruthenium complexescoumarinantitumor activityantibacterial activityQuímicaComplexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacterianaRu(II) complexes containing coumarin hybrid ligands: synthesis and evaluation of cytotoxic and antibacterial activitiesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis1 - WHO - World Health Organization. What is câncer? Disponível em: https://www.who.int/cancer/en/. Acessado em: Novembro de 2018. 2 - HASSANPOUR, S. H.; DEHGHANI, M. Review of cancer from perspective of molecular. 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dc.title.por.fl_str_mv Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana
dc.title.alternative.eng.fl_str_mv Ru(II) complexes containing coumarin hybrid ligands: synthesis and evaluation of cytotoxic and antibacterial activities
title Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana
spellingShingle Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana
Almeida, Patrícia Saraiva Vilas Boas de
complexos de rutênio
híbridos de cumarina
atividade antitumoral
atividade antibacteriana
ruthenium complexes
coumarin
antitumor activity
antibacterial activity
Química
title_short Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana
title_full Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana
title_fullStr Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana
title_full_unstemmed Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana
title_sort Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana
author Almeida, Patrícia Saraiva Vilas Boas de
author_facet Almeida, Patrícia Saraiva Vilas Boas de
author_role author
dc.contributor.author.fl_str_mv Almeida, Patrícia Saraiva Vilas Boas de
dc.contributor.advisor1.fl_str_mv Neves, Amanda Porto
dc.contributor.advisor1ID.fl_str_mv CPF: 055.195.997-50
dc.contributor.advisor-co1.fl_str_mv Kummerle, Arthur Eugen
dc.contributor.advisor-co1ID.fl_str_mv CPF: 053.978.487-78
dc.contributor.referee1.fl_str_mv Lima, Áurea Echevarria Aznar Neves
dc.contributor.referee2.fl_str_mv Silva, Gustavo Bezerra da
dc.contributor.referee3.fl_str_mv Vargas, Maria Domingues
dc.contributor.referee4.fl_str_mv Scarpellini, Marciela
dc.contributor.authorID.fl_str_mv CPF: 087.759.696-45
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/7143253739373348
contributor_str_mv Neves, Amanda Porto
Kummerle, Arthur Eugen
Lima, Áurea Echevarria Aznar Neves
Silva, Gustavo Bezerra da
Vargas, Maria Domingues
Scarpellini, Marciela
dc.subject.por.fl_str_mv complexos de rutênio
híbridos de cumarina
atividade antitumoral
atividade antibacteriana
topic complexos de rutênio
híbridos de cumarina
atividade antitumoral
atividade antibacteriana
ruthenium complexes
coumarin
antitumor activity
antibacterial activity
Química
dc.subject.eng.fl_str_mv ruthenium complexes
coumarin
antitumor activity
antibacterial activity
dc.subject.cnpq.fl_str_mv Química
description Câncer e infecções bacterianas são doenças que causam um grande número de mortes e, apesar dos tratamentos existentes, ainda se fazem necessários novos fármacos que causem menos danos aos pacientes e que sejam mais ativos às células resistentes. Derivados de cumarina e diversas classes de complexos de Ru(II) vêm sendo estudados quanto ao seu potencial como agentes antimicrobianos e antitumorais. Sendo assim, quatro novos ligantes híbridos de cumarina-N-acilidrazonas do tipo (E)-(N’-4-R-benzilideno-7-(dietilamino)-2-oxo-2H-cromona-3-carboidrazida (HL2: R=H; HL3: R=Cl, HL4: R=Br, HL5: R= OCH3), foram obtidos através da condensação de uma hidrazida (7-(dietilamino)-2-oxo-2H-cromona-3-carboidrazida, HL1) e diferentes aldeídos p-substituídos. Reações entre HL2-5 e cis-[RuCl2(DMSO)4] resultaram em complexos trans-cis-[RuCl2(DMSO)2(HL2-5)], C2-5 (classe Ru(II)-Cl-DMSO). Concomitantemente, a hidrólise do ligante ocorreu, resultando na formação do complexo trans-cis-[RuCl2(DMSO)2(HL1)] C1, contendo a hidrazida coordenada. As estruturas cristalinas dos ligantes HL2 e HL3 e dos complexos C2-5 foram determinadas por DRX, que revelaram a isomerização de E para Z das cumarinas-N-acilidrazonas resultante da coordenação. Os complexos C2-5 exibiram o átomo de Ru(II) em uma geometria octaédrica distorcida com o ligante coordenado na forma ceto através da carbonila da hidrazona e do nitrogênio imínico. Na tentativa de sintetizar uma segunda classe de complexos carregados e contendo bipiridina como ligante auxiliar ([Ru(bipy)2(HLn)]PF6 - classe Ru(II)-bipy), realizou-se a reação entre HL2 e cis-[Ru(bipy)2Cl2]. Porém, a possível hidrólise do ligante impossibilitou a obtenção do complexo desejado. Uma metodologia similar utilizando híbridos de cumarina-β-cetoéster HL6-8 originou os complexos da classe Ru(II)-bipy, [Ru(bipy)2(HL6-8)]PF6 C6-8. A análise de DRX de C7 mostrou o Ru(II) em um ambiente octaédrico distorcido com o ligante coordenado pela porção β-cetoéster desprotonada e duas bipiridinas na esfera de coordenação. A avaliação antiproliferativa dos compostos contra linhagens de células tumorais (4T1: carcinoma mamário murino e B16-F10: melanoma murino metastático) e não tumoral (BHK-21: rim de hamster) mostrou que, de uma maneira geral, os ligantes híbridos cumarina-N-acilidrazona e cumarina-hidrazida HL1-5 foram mais ativos que seus complexos C1-5, cujos valores de IC50 (metade da concentração inibitória máxima) foram encontrados na faixa de 10,6 a 50,4 µM para os ligantes e entre 17,7 e 97,8 µM para os complexos. Por outro lado, os ligantes cumarina-β-cetoéster HL6-8 foram inativos (IC50 > 100 µM), mas os complexos C6-8 apresentaram alta citotoxicidade, com valores de IC50 entre 2,0 e 12,8 µM. Para o teste antibacteriano, HL1 foi o único ligante ativo frente a uma cepa de bactéria gram-negativa, porém seu MIC não foi determinado nas concentrações estudadas. Todos os complexos demostraram atividade somente frente a cepas de bactérias gram positivas. Para os complexos Ru(II)-Cl-DMSO, somente C3 e C4 (R = Cl e Br) apresentaram MIC nas concentrações utilizadas (40,5 e 86 µM). Por outro lado, os complexos Ru(II)-bipy C6-8 apresentaram MIC entre 2,20-9,22 µM. A maior atividade apresentada pelos derivados Ru(II)-bipy em ambos os testes biológicos, comparada aos complexos Ru(II)-DMSO, foi atribuída à presença de carga no complexo e aos ligantes bipiridina. Estudos de interação com DNA dos complexos [Ru(bipy)2(HL6-8)]PF6 (C6-8) estão em andamento.
publishDate 2019
dc.date.issued.fl_str_mv 2019-07-31
dc.date.accessioned.fl_str_mv 2023-12-21T18:59:30Z
dc.date.available.fl_str_mv 2023-12-21T18:59:30Z
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.citation.fl_str_mv ALMEIDA, Patrícia Saraiva Vilas Boas de. Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana. 2019. 234 f. Tese (Doutorado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica - RJ, 2019.
dc.identifier.uri.fl_str_mv https://rima.ufrrj.br/jspui/handle/20.500.14407/10245
identifier_str_mv ALMEIDA, Patrícia Saraiva Vilas Boas de. Complexos de Ru(II) contendo ligantes híbridos de cumarina: síntese e avaliação das atividades citotóxica e antibacteriana. 2019. 234 f. Tese (Doutorado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica - RJ, 2019.
url https://rima.ufrrj.br/jspui/handle/20.500.14407/10245
dc.language.iso.fl_str_mv por
language por
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