Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas

Detalhes bibliográficos
Ano de defesa: 2019
Autor(a) principal: Silva, Ludimila Thayane Paes
Orientador(a): Rocha, Fillipe Vieira lattes
Banca de defesa: Não Informado pela instituição
Tipo de documento: Dissertação
Tipo de acesso: Acesso aberto
Idioma: por
Instituição de defesa: Universidade Federal de São Carlos
Câmpus São Carlos
Programa de Pós-Graduação: Programa de Pós-Graduação em Química - PPGQ
Departamento: Não Informado pela instituição
País: Não Informado pela instituição
Palavras-chave em Português:
DNA
Área do conhecimento CNPq:
Link de acesso: https://repositorio.ufscar.br/handle/ufscar/11968
Resumo: The diversity of cancer diseases and the side effects caused by the drugs commonly used in cancer treatment require different antineoplasic agents able to operate more specific and in a way to minimize the side effects. With that in mind, efforts are made to develop compounds for selective biological target, such as the enzime topoisomeraseIIα, or TOPOIIα, which has been widely studied. In a recent work of our research group, it was found that Pd(II) complexes with thiosemicarbazone ligand (N, S donor) and co-ligands’ phosphinic and halides, in a distorted square planar molecular geometry, showed cytotoxic activity against breast and lung tumor cell lines; they also inhibited TOPOIIα enzime at a 2,8 times smaller concentration than the standard drug, etoposide. This activity was atributed to the interaction of the complexed thiosemicarbazone ligand with enzime’s active sites. Therefore, in the present work, it was attempt to comprehend the importance of the co-ligands and of the thiosemicarbazone identity, as well as the metallic ion influence in the biological activities. Thereunto, in this work, changes in the molecular framework were performed: (i) substitution of co-ligands for another thiosemicarbazone molecule; (ii) changes in the thiosemicarbazone structure; (iii) metal ion identity. It was synthesized six thiosemicarbazones ligands (L) (N, S donor), thirteen new bischelate complexes structures in a square planar geometry : twelve Pd(II), divided in two analogues series of general formulae [Pd(L)2] and [Pd(HL)2]Cl2, differenciated by anionic and neutral ligands coordination, respectively, and a Ni(II) complex, [Ni(L)2]. After obtaining all the compounds (caracterized by spectroscopic and spectrometric thecniques), the investigation of cytotoxic activity of ligands and their Pd(II) complexes against the tumoral cell lines MCF-7 (breast) and DU-145 (prostate) and non-tumoral PNT2 (prostate) showed that the free thiosemicarbazone ligands presented low cytotoxicity (IC50> 50 μmol.L-1), while their Pd(II) complexes containing the lower molecular masses thiosemicarbazone presented IC50 values in the 12,00-0,22 μmol.L-1 interval for tumoral cell lines. It was not observed selectivity among the cell lines tested (tumoral and non-tumoral). Comparing the cytotoxicity exhibited by a Pd(II) complex containing the co-ligands, [PdCl(BT-M)(P(4FPh)3] (IC50 = 0,56 ± 0,1 μmol.L-1), and its bischelate anologues complexes of Pd(II) and Ni(II), [Pd(BT-M)2] (IC50 = 0,43 ± 0,3 μmol.L-1) and [Ni(BT-M)2] (IC50> 12μmol.L-1), against tumoral breast cancer cell line MDA-MD-231, it is suggested that metal ion identity is essencial in the cytotoxicity of complexes. Molecular Docking studies showed that the Pd(II) bischelate complexes do not present affinity with TOPOIIα active sites. Experimentally, it was observed that the most cytotoxic complexes of Pd(II) and the Ni(II) complex do not Interact significantly with DNA and they are not able to inhibit TOPOIIα (at concentrations of 1, 10 e 50 μmol.L-1), pointing out that these are not the biological targets of the complexes. It is suggested that, the absence of co-ligands could be the responsible for the loss of enzimatic inhibitory activity.
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spelling Silva, Ludimila Thayane PaesRocha, Fillipe Vieirahttp://lattes.cnpq.br/5841127259122766http://lattes.cnpq.br/8327323336822123d6778ced-e3c1-42bd-abf1-f042fc3145f02019-10-22T14:02:32Z2019-10-22T14:02:32Z2019-09-20SILVA, Ludimila Thayane Paes. Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas. 2019. Dissertação (Mestrado em Química) – Universidade Federal de São Carlos, São Carlos, 2019. Disponível em: https://repositorio.ufscar.br/handle/ufscar/11968.https://repositorio.ufscar.br/handle/ufscar/11968The diversity of cancer diseases and the side effects caused by the drugs commonly used in cancer treatment require different antineoplasic agents able to operate more specific and in a way to minimize the side effects. With that in mind, efforts are made to develop compounds for selective biological target, such as the enzime topoisomeraseIIα, or TOPOIIα, which has been widely studied. In a recent work of our research group, it was found that Pd(II) complexes with thiosemicarbazone ligand (N, S donor) and co-ligands’ phosphinic and halides, in a distorted square planar molecular geometry, showed cytotoxic activity against breast and lung tumor cell lines; they also inhibited TOPOIIα enzime at a 2,8 times smaller concentration than the standard drug, etoposide. This activity was atributed to the interaction of the complexed thiosemicarbazone ligand with enzime’s active sites. Therefore, in the present work, it was attempt to comprehend the importance of the co-ligands and of the thiosemicarbazone identity, as well as the metallic ion influence in the biological activities. Thereunto, in this work, changes in the molecular framework were performed: (i) substitution of co-ligands for another thiosemicarbazone molecule; (ii) changes in the thiosemicarbazone structure; (iii) metal ion identity. It was synthesized six thiosemicarbazones ligands (L) (N, S donor), thirteen new bischelate complexes structures in a square planar geometry : twelve Pd(II), divided in two analogues series of general formulae [Pd(L)2] and [Pd(HL)2]Cl2, differenciated by anionic and neutral ligands coordination, respectively, and a Ni(II) complex, [Ni(L)2]. After obtaining all the compounds (caracterized by spectroscopic and spectrometric thecniques), the investigation of cytotoxic activity of ligands and their Pd(II) complexes against the tumoral cell lines MCF-7 (breast) and DU-145 (prostate) and non-tumoral PNT2 (prostate) showed that the free thiosemicarbazone ligands presented low cytotoxicity (IC50> 50 μmol.L-1), while their Pd(II) complexes containing the lower molecular masses thiosemicarbazone presented IC50 values in the 12,00-0,22 μmol.L-1 interval for tumoral cell lines. It was not observed selectivity among the cell lines tested (tumoral and non-tumoral). Comparing the cytotoxicity exhibited by a Pd(II) complex containing the co-ligands, [PdCl(BT-M)(P(4FPh)3] (IC50 = 0,56 ± 0,1 μmol.L-1), and its bischelate anologues complexes of Pd(II) and Ni(II), [Pd(BT-M)2] (IC50 = 0,43 ± 0,3 μmol.L-1) and [Ni(BT-M)2] (IC50> 12μmol.L-1), against tumoral breast cancer cell line MDA-MD-231, it is suggested that metal ion identity is essencial in the cytotoxicity of complexes. Molecular Docking studies showed that the Pd(II) bischelate complexes do not present affinity with TOPOIIα active sites. Experimentally, it was observed that the most cytotoxic complexes of Pd(II) and the Ni(II) complex do not Interact significantly with DNA and they are not able to inhibit TOPOIIα (at concentrations of 1, 10 e 50 μmol.L-1), pointing out that these are not the biological targets of the complexes. It is suggested that, the absence of co-ligands could be the responsible for the loss of enzimatic inhibitory activity.A diversidade de tipos de cânceres requer a busca por diferentes agentes antineoplásicos capazes de agir mais especifica e seletivamente minimizando os efeitos colaterais dos medicamentos atualmente utilizados. Neste sentido, uma das estratégias adotadas é o desenvolvimento de compostos que atuem em alvos biológicos específicos; dentre estes alvos, a enzima topoisomerase IIα, ou TOPOIIα tem sido amplamente estudada. Em trabalho recente do nosso grupo de pesquisa, foi encontrado que, complexos de Pd(II) em geometria quadrática plana, contendo tiossemicarbazona (doares S, N) e variações de co-ligantes fosfínicos e halogênios, exibiram boa atividade citotóxica frente à linhagens tumorais de mama e pulmão; além de inibirem a ação da TOPOIIα em concentração 2,8 vezes menor que o medicamento padrão, o etopósido. A inibição da enzima foi atribuída à interações entre a tiossemicarbazona complexada e sítios ativos da enzima. Deste modo, no presente trabalho, buscou-se identificar qual a importância dos co-ligantes, da identidade da tiossemicarbazona e do centro metálico na citotoxicidade frente à células tumorais, bem como na inibição enzimática da TOPOIIα. Para tal, mudanças no arcabouço molecular foram realizadas: (i) modificações na estrutura da tiossemicarbazona; (ii) substituição dos co-ligantes por outra molécula de tiossemicarbazona; (iii) identidade do metal. Com estes objetivos, foram então sintetizados seis ligantes (L) tiossemicarbazonas (S, N doadores), treze novas estruturas de complexos bisquelatos em geometria quadrática plana: doze de Pd(II), divididos em duas séries de seis complexos que se diferenciam pela natureza protonada e desprotonada do ligante (de fórmula geral [Pd(HL)2]Cl2 e [Pd(L)2], respectivamente); e um complexo de Ni(II), [Ni(L)2]. Após obtenção de todos os compostos planejados (os quais foram caracterizados por técnicas espectroscópicas e espectrométricas), a investigação da atividade citotóxica dos ligantes e complexos de Pd(II) frente às linhagens tumoral de mama MCF-7, e linhagens de próstata DU-145 (tumoral) e PNT2 (não-tumoral), mostrou que, as tiossemicarbazonas livres apresentaram baixa citotóxicidade (IC50> 50 μmol.L-1), enquanto, os complexos contendo as tiossemicarbazonas com menor massa molar apresentaram alta citotóxicidade (IC50 em intervalo de 12,00-0,22 μmol.L-1 ). Não foi observada seletividade quanto às linhagens tumorais e não tumoral testadas. Comparou-se também a citotóxidade apresentada por um dos complexos contendo os co-ligantes fosfínico e halogênio, [PdCl(BT-M)(P(4FPh)3] (IC50 = 0,56 ± 0,1 μmol.L-1), e seus análogo bisquelatos [Pd(BT-M)2] ( IC50 = 0,43 ± 0,3 μmol.L-1) e [Ni(BT-M)2] (IC50> 12 μmol.L-1), frente à linhagem tumoral de mama MDA-MD-231. Os valores de IC50 sugerem que a natureza do metal é fundamental na atividade avaliada. Estudos de docagem molecular sugeriram que os complexos de Pd(II) não possuem afinidade com sítios da TOPOIIα, e experimentalmente, foi observado que os complexos de Pd(II) mais citotóxicos e o complexo de Ni(II) não interagem significativamente com o DNA e não são capazes de inibir a enzima TOPOIIα (em contrações de 1, 10 e 50 μmol.L-1), apontando que estes, não são os alvos biológicos dos compelxos. A não inibição da TOPOIIα sugere que a ausência dos co-ligantes pode ter sido responsável pela perca da atividade inibitória enzimáticaCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)001CAPES: código de financiamento 001porUniversidade Federal de São CarlosCâmpus São CarlosPrograma de Pós-Graduação em Química - PPGQUFSCarAttribution-NonCommercial-NoDerivs 3.0 Brazilhttp://creativecommons.org/licenses/by-nc-nd/3.0/br/info:eu-repo/semantics/openAccessCâncerDNATOPOIIαComplexos de Pd(II) e Ni(II) contendo tiossemicarbazonasCIENCIAS EXATAS E DA TERRA::QUIMICASíntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo TiossemicarbazonasSynthesis, characterization and cytotoxicity and biological target studies of square planar complexes containing Thiosemicarbazonesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesis60060054a34865-0da5-4148-8520-028795d9275dreponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINALDissertação Ludimila- Final.pdfDissertação Ludimila- Final.pdfapplication/pdf6377680https://repositorio.ufscar.br/bitstream/ufscar/11968/1/Disserta%c3%a7%c3%a3o%20Ludimila-%20Final.pdf267a86a3324fdf4cffc6c43fecd1134bMD51Declaração Orientador.pdfDeclaração Orientador.pdfCarta comprovante assinada pelo orientadorapplication/pdf1643020https://repositorio.ufscar.br/bitstream/ufscar/11968/3/Declara%c3%a7%c3%a3o%20Orientador.pdf9df4821066beb3c3b4e67121f7b4c507MD53CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufscar.br/bitstream/ufscar/11968/2/license_rdfe39d27027a6cc9cb039ad269a5db8e34MD52TEXTDissertação Ludimila- Final.pdf.txtDissertação Ludimila- Final.pdf.txtExtracted texttext/plain188934https://repositorio.ufscar.br/bitstream/ufscar/11968/4/Disserta%c3%a7%c3%a3o%20Ludimila-%20Final.pdf.txtd3ac2cd0fcd4fe0bea9caa106d91b1f3MD54Declaração Orientador.pdf.txtDeclaração Orientador.pdf.txtExtracted texttext/plain1https://repositorio.ufscar.br/bitstream/ufscar/11968/6/Declara%c3%a7%c3%a3o%20Orientador.pdf.txt68b329da9893e34099c7d8ad5cb9c940MD56THUMBNAILDissertação Ludimila- Final.pdf.jpgDissertação Ludimila- Final.pdf.jpgIM Thumbnailimage/jpeg9312https://repositorio.ufscar.br/bitstream/ufscar/11968/5/Disserta%c3%a7%c3%a3o%20Ludimila-%20Final.pdf.jpg4c054c5a271a9994e472eb07b2d1f521MD55Declaração Orientador.pdf.jpgDeclaração Orientador.pdf.jpgIM Thumbnailimage/jpeg13128https://repositorio.ufscar.br/bitstream/ufscar/11968/7/Declara%c3%a7%c3%a3o%20Orientador.pdf.jpgf2f96757bf4b739d381be7ed3ecd600eMD57ufscar/119682023-09-18 18:31:45.439oai:repositorio.ufscar.br:ufscar/11968Repositório InstitucionalPUBhttps://repositorio.ufscar.br/oai/requestopendoar:43222023-09-18T18:31:45Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR)false
dc.title.por.fl_str_mv Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas
dc.title.alternative.eng.fl_str_mv Synthesis, characterization and cytotoxicity and biological target studies of square planar complexes containing Thiosemicarbazones
title Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas
spellingShingle Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas
Silva, Ludimila Thayane Paes
Câncer
DNA
TOPOIIα
Complexos de Pd(II) e Ni(II) contendo tiossemicarbazonas
CIENCIAS EXATAS E DA TERRA::QUIMICA
title_short Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas
title_full Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas
title_fullStr Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas
title_full_unstemmed Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas
title_sort Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas
author Silva, Ludimila Thayane Paes
author_facet Silva, Ludimila Thayane Paes
author_role author
dc.contributor.authorlattes.por.fl_str_mv http://lattes.cnpq.br/8327323336822123
dc.contributor.author.fl_str_mv Silva, Ludimila Thayane Paes
dc.contributor.advisor1.fl_str_mv Rocha, Fillipe Vieira
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/5841127259122766
dc.contributor.authorID.fl_str_mv d6778ced-e3c1-42bd-abf1-f042fc3145f0
contributor_str_mv Rocha, Fillipe Vieira
dc.subject.por.fl_str_mv Câncer
DNA
TOPOIIα
Complexos de Pd(II) e Ni(II) contendo tiossemicarbazonas
topic Câncer
DNA
TOPOIIα
Complexos de Pd(II) e Ni(II) contendo tiossemicarbazonas
CIENCIAS EXATAS E DA TERRA::QUIMICA
dc.subject.cnpq.fl_str_mv CIENCIAS EXATAS E DA TERRA::QUIMICA
description The diversity of cancer diseases and the side effects caused by the drugs commonly used in cancer treatment require different antineoplasic agents able to operate more specific and in a way to minimize the side effects. With that in mind, efforts are made to develop compounds for selective biological target, such as the enzime topoisomeraseIIα, or TOPOIIα, which has been widely studied. In a recent work of our research group, it was found that Pd(II) complexes with thiosemicarbazone ligand (N, S donor) and co-ligands’ phosphinic and halides, in a distorted square planar molecular geometry, showed cytotoxic activity against breast and lung tumor cell lines; they also inhibited TOPOIIα enzime at a 2,8 times smaller concentration than the standard drug, etoposide. This activity was atributed to the interaction of the complexed thiosemicarbazone ligand with enzime’s active sites. Therefore, in the present work, it was attempt to comprehend the importance of the co-ligands and of the thiosemicarbazone identity, as well as the metallic ion influence in the biological activities. Thereunto, in this work, changes in the molecular framework were performed: (i) substitution of co-ligands for another thiosemicarbazone molecule; (ii) changes in the thiosemicarbazone structure; (iii) metal ion identity. It was synthesized six thiosemicarbazones ligands (L) (N, S donor), thirteen new bischelate complexes structures in a square planar geometry : twelve Pd(II), divided in two analogues series of general formulae [Pd(L)2] and [Pd(HL)2]Cl2, differenciated by anionic and neutral ligands coordination, respectively, and a Ni(II) complex, [Ni(L)2]. After obtaining all the compounds (caracterized by spectroscopic and spectrometric thecniques), the investigation of cytotoxic activity of ligands and their Pd(II) complexes against the tumoral cell lines MCF-7 (breast) and DU-145 (prostate) and non-tumoral PNT2 (prostate) showed that the free thiosemicarbazone ligands presented low cytotoxicity (IC50> 50 μmol.L-1), while their Pd(II) complexes containing the lower molecular masses thiosemicarbazone presented IC50 values in the 12,00-0,22 μmol.L-1 interval for tumoral cell lines. It was not observed selectivity among the cell lines tested (tumoral and non-tumoral). Comparing the cytotoxicity exhibited by a Pd(II) complex containing the co-ligands, [PdCl(BT-M)(P(4FPh)3] (IC50 = 0,56 ± 0,1 μmol.L-1), and its bischelate anologues complexes of Pd(II) and Ni(II), [Pd(BT-M)2] (IC50 = 0,43 ± 0,3 μmol.L-1) and [Ni(BT-M)2] (IC50> 12μmol.L-1), against tumoral breast cancer cell line MDA-MD-231, it is suggested that metal ion identity is essencial in the cytotoxicity of complexes. Molecular Docking studies showed that the Pd(II) bischelate complexes do not present affinity with TOPOIIα active sites. Experimentally, it was observed that the most cytotoxic complexes of Pd(II) and the Ni(II) complex do not Interact significantly with DNA and they are not able to inhibit TOPOIIα (at concentrations of 1, 10 e 50 μmol.L-1), pointing out that these are not the biological targets of the complexes. It is suggested that, the absence of co-ligands could be the responsible for the loss of enzimatic inhibitory activity.
publishDate 2019
dc.date.accessioned.fl_str_mv 2019-10-22T14:02:32Z
dc.date.available.fl_str_mv 2019-10-22T14:02:32Z
dc.date.issued.fl_str_mv 2019-09-20
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dc.identifier.citation.fl_str_mv SILVA, Ludimila Thayane Paes. Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas. 2019. Dissertação (Mestrado em Química) – Universidade Federal de São Carlos, São Carlos, 2019. Disponível em: https://repositorio.ufscar.br/handle/ufscar/11968.
dc.identifier.uri.fl_str_mv https://repositorio.ufscar.br/handle/ufscar/11968
identifier_str_mv SILVA, Ludimila Thayane Paes. Síntese, caracterização e estudos de citotoxicidade e alvo biológico de complexos quadráticos planos contendo Tiossemicarbazonas. 2019. Dissertação (Mestrado em Química) – Universidade Federal de São Carlos, São Carlos, 2019. Disponível em: https://repositorio.ufscar.br/handle/ufscar/11968.
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rights_invalid_str_mv Attribution-NonCommercial-NoDerivs 3.0 Brazil
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dc.publisher.none.fl_str_mv Universidade Federal de São Carlos
Câmpus São Carlos
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