Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas
Autor(a) principal: | |
---|---|
Data de Publicação: | 2021 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFSCAR |
Texto Completo: | https://repositorio.ufscar.br/handle/ufscar/16288 |
Resumo: | In this work, the synthesis, characterization, and evaluation of the cytotoxic activity of sixteen Cu(I)/Triphenylphosphine complexes containing the acylthiourea or naphthoquinones ligands are presented. The complexes were divided into two series based on the classes of the ligands used. The first series is composed of the neutral complexes of general formula [Cu(Ln)(PPh3)2] (1-6) and monocationic complexes of general formula [Cu(Ln)(PPh3)2]NO3 (1a 6a), where Ln= acylthiourea and PPh3= triphenylphosphine. The second series is composed of the neutral complexes of general formula [Cu(NQn)(PPh3)2] (1b 4b), where NQn= naphthoquinone and PPh3= triphenylphosphine. All complexes were characterized by different techniques such as elemental analysis, molar conductivity, infrared absorption spectroscopy, 1D and 2D nuclear magnetic resonance (31P{1H}, 1H and 13C{1H}), mass spectrometry, and X-ray diffraction. In the 13C{1H} NMR spectra, the complexes (1-6) stood out by showing the unusual chemical shift pattern, for the C=O and C=S carbon atoms of the acylthiourea ligand after bidentate (S, O) and anionic coordination. The experimental results were supported by DFT studies that suggested that relativistic effects strongly influenced the NMR protection constants of the light atoms due to coordination to the heavy atom Cu. The stability of the complexes in the cell culture medium was investigated and all the complexes were shown to be unstable, directly influencing the biological results obtained. The in vitro cytotoxicity of the complexes was determined in the breast (MCF7 and MDA MB-231) and lung (A549) tumor cell lines and in the corresponding non-tumor breast (MCF-10A) and lung (MRC-5) cell lines, and all complexes were actives exhibiting IC50 values in the same range in different cell lines. The compounds were more active than the free ligands and the precursor salt of the complexes in different cell lines, showing that even unstable complexes are relevant for the cytotoxic action. In general, the acylthiourea series complexes, 1 and 1a, were able to change the morphology of MDA-MB-231 cells, inhibit colony formation, showing cytotoxic and cytostatic effects on this cell line, significantly altering the cytoskeleton of cells, reducing the density, and promoting the condensation of the F-actin filaments. They promoted the increase of cells in the fragmented DNA region (sub-G0) and induced cell death by apoptosis. The complexes of the naphthoquinone series, 1b, and 4b, altered the morphology of MDA-MB-231 cells, inhibited colony formation at concentrations higher than the IC50, and were able to inhibit cell migration. Finally, the compounds synthesized and characterized in this work are relevant reports of copper (I) complexes with cytotoxic properties in different tumor cell lines with potential for future studies in vivo models. |
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Leite, Celisnolia MoraisBatista, Alzir Azevedohttp://lattes.cnpq.br/6469642481998660http://lattes.cnpq.br/96388810501868650c1b17a9-bf39-4691-b185-35217dd329c22022-06-14T19:34:44Z2022-06-14T19:34:44Z2021-07-26LEITE, Celisnolia Morais. Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas. 2021. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2021. Disponível em: https://repositorio.ufscar.br/handle/ufscar/16288.https://repositorio.ufscar.br/handle/ufscar/16288In this work, the synthesis, characterization, and evaluation of the cytotoxic activity of sixteen Cu(I)/Triphenylphosphine complexes containing the acylthiourea or naphthoquinones ligands are presented. The complexes were divided into two series based on the classes of the ligands used. The first series is composed of the neutral complexes of general formula [Cu(Ln)(PPh3)2] (1-6) and monocationic complexes of general formula [Cu(Ln)(PPh3)2]NO3 (1a 6a), where Ln= acylthiourea and PPh3= triphenylphosphine. The second series is composed of the neutral complexes of general formula [Cu(NQn)(PPh3)2] (1b 4b), where NQn= naphthoquinone and PPh3= triphenylphosphine. All complexes were characterized by different techniques such as elemental analysis, molar conductivity, infrared absorption spectroscopy, 1D and 2D nuclear magnetic resonance (31P{1H}, 1H and 13C{1H}), mass spectrometry, and X-ray diffraction. In the 13C{1H} NMR spectra, the complexes (1-6) stood out by showing the unusual chemical shift pattern, for the C=O and C=S carbon atoms of the acylthiourea ligand after bidentate (S, O) and anionic coordination. The experimental results were supported by DFT studies that suggested that relativistic effects strongly influenced the NMR protection constants of the light atoms due to coordination to the heavy atom Cu. The stability of the complexes in the cell culture medium was investigated and all the complexes were shown to be unstable, directly influencing the biological results obtained. The in vitro cytotoxicity of the complexes was determined in the breast (MCF7 and MDA MB-231) and lung (A549) tumor cell lines and in the corresponding non-tumor breast (MCF-10A) and lung (MRC-5) cell lines, and all complexes were actives exhibiting IC50 values in the same range in different cell lines. The compounds were more active than the free ligands and the precursor salt of the complexes in different cell lines, showing that even unstable complexes are relevant for the cytotoxic action. In general, the acylthiourea series complexes, 1 and 1a, were able to change the morphology of MDA-MB-231 cells, inhibit colony formation, showing cytotoxic and cytostatic effects on this cell line, significantly altering the cytoskeleton of cells, reducing the density, and promoting the condensation of the F-actin filaments. They promoted the increase of cells in the fragmented DNA region (sub-G0) and induced cell death by apoptosis. The complexes of the naphthoquinone series, 1b, and 4b, altered the morphology of MDA-MB-231 cells, inhibited colony formation at concentrations higher than the IC50, and were able to inhibit cell migration. Finally, the compounds synthesized and characterized in this work are relevant reports of copper (I) complexes with cytotoxic properties in different tumor cell lines with potential for future studies in vivo models.Neste trabalho são apresentadas a síntese, caracterização e avaliação da atividade citotóxica de dezesseis complexos de Cu(I)/Trifenilfosfina contendo ligantes aciltioureias ou naftoquinonas. Os complexos foram divididos em duas séries baseadas nas classes dos ligantes utilizados. A primeira série é composta pelos complexos neutros de fórmula geral [Cu(Ln)(PPh3)2] (1-6) e complexos monocatiônicos de fórmula geral [Cu(Ln)(PPh3)2]NO3 (1a-6a), em que Ln= ligante aciltioureia e PPh3= trifenilfosfina. A segunda série é composta pelos complexos neutros de fórmula geral [Cu(NQn)(PPh3)2] (1b-4b), em que NQn= ligante naftoquinona e PPh3= trifenilfosfina. Os complexos foram caracterizados por diferentes técnicas como análise elementar, condutividade molar, espectroscopia de absorção na região do infravermelho, ressonância magnética nuclear 1D (31P{1H}, 1H e 13C{1H}) e 2D (COSY 1H-1H, HSQC 1H-13C e HMBC 1H-13C), espectrometria de massas e difração de raios X de monocristal. Na caracterização por RMN de 13C{1H}, os complexos (1-6) se destacaram por apresentar um padrão de deslocamento químico incomum, para os carbonos C=O e C=S dos ligantes aciltioureias após a coordenação bidentada (S, O) e aniônica. Os resultados experimentais foram fundamentados por estudos de DFT que sugeriram que efeitos relativísticos influenciaram fortemente as constantes de proteção de RMN dos átomos leves, devido a coordenação ao átomo pesado (Cu(I)). Os complexos tiveram sua estabilidade em meio de cultura celular investigada, sendo que todos se mostraram instáveis influenciando diretamente nos resultados biológicos obtidos. A citotoxicidade in vitro dos complexos foi determinada nas linhagens celulares tumorais e não tumorais de mama (MCF7, MDA-MB-231 e MCF-10A) e de pulmão (A549 e MRC-5), e todos os complexos foram ativos exibindo valores de IC50 na mesma faixa nas diferentes linhagens celulares. Os compostos foram mais ativos que os ligantes livres e que o sal precursor dos complexos, demonstrando que mesmo instáveis os compostos são importantes para a ação citotóxica. Os complexos 1 e 1a da série 1, contendo os ligantes aciltioureias, foram capazes de alterar a morfologia das células MDA-MB-231 (células de câncer de mama triplo negativo), inibir a formação de colônias, mostrando efeitos citotóxico e citostáticos nessa linhagem celular e alterar significativamente o citoesqueleto das células, reduzindo a densidade e promovendo a condensação dos filamentos de F-actina. Além disso, promoveram o aumento das células com DNA fragmentado (sub-G0) e induziram às células a morte por apoptose. Os complexos 1b e 4b, da série 2, com os ligantes naftoquinonas, alteraram a morfologia das células MDA-MB-231, inibiram a formação de colônias em concentrações maiores que a do IC50 e foram capazes de inibir a migração celular. Enfim os compostos sintetizados e caracterizados neste trabalho são importantes relatos de complexos de cobre (I) com propriedade citotóxica em diferentes linhagens celulares tumorais com potencial para estudos futuros em modelos in vivo.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq: 142348/2016-3porUniversidade 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/openAccessComplexos de cobre (I)AciltioureiaNaftoquinonasCâncerCopper (I) complexesAcylthioureaNaphthoquinonesCancerCIENCIAS EXATAS E DA TERRA::QUIMICAPropriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonasCytotoxic properties of Cu(I)-Triphenylphosphine complexes with acylthiourea or naphthoquinone ligandsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis600600e62fb48f-fa23-4158-8d60-0b17f006946creponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINALTese de Doutorado.pdfTese de Doutorado.pdfTese de Doutoradoapplication/pdf29201739https://repositorio.ufscar.br/bitstream/ufscar/16288/1/Tese%20de%20Doutorado.pdf2f09abb54f7fc8b1fbb36b216c1ed421MD51Carta Comprovante do Orientador.pdfCarta Comprovante do Orientador.pdfCarta comprovante da homologaçãoapplication/pdf409637https://repositorio.ufscar.br/bitstream/ufscar/16288/2/Carta%20Comprovante%20do%20Orientador.pdf2e54ded10730f6e96762542e1ac05508MD52CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufscar.br/bitstream/ufscar/16288/3/license_rdfe39d27027a6cc9cb039ad269a5db8e34MD53TEXTTese de Doutorado.pdf.txtTese de Doutorado.pdf.txtExtracted texttext/plain337862https://repositorio.ufscar.br/bitstream/ufscar/16288/4/Tese%20de%20Doutorado.pdf.txte3f9559a6da84fe2387a4595777ab023MD54Carta Comprovante do Orientador.pdf.txtCarta Comprovante do Orientador.pdf.txtExtracted texttext/plain1118https://repositorio.ufscar.br/bitstream/ufscar/16288/6/Carta%20Comprovante%20do%20Orientador.pdf.txt99c61ed9f405f3f7aa02de93485ab14eMD56THUMBNAILTese de Doutorado.pdf.jpgTese de Doutorado.pdf.jpgIM Thumbnailimage/jpeg9605https://repositorio.ufscar.br/bitstream/ufscar/16288/5/Tese%20de%20Doutorado.pdf.jpg167b7c55e7f297c4f10181a6296ca8c8MD55Carta Comprovante do Orientador.pdf.jpgCarta Comprovante do Orientador.pdf.jpgIM Thumbnailimage/jpeg14881https://repositorio.ufscar.br/bitstream/ufscar/16288/7/Carta%20Comprovante%20do%20Orientador.pdf.jpg26b0f1df326ae36a5242818da969ddaaMD57ufscar/162882023-09-18 18:32:24.421oai:repositorio.ufscar.br:ufscar/16288Repositório InstitucionalPUBhttps://repositorio.ufscar.br/oai/requestopendoar:43222023-09-18T18:32:24Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR)false |
dc.title.por.fl_str_mv |
Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas |
dc.title.alternative.eng.fl_str_mv |
Cytotoxic properties of Cu(I)-Triphenylphosphine complexes with acylthiourea or naphthoquinone ligands |
title |
Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas |
spellingShingle |
Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas Leite, Celisnolia Morais Complexos de cobre (I) Aciltioureia Naftoquinonas Câncer Copper (I) complexes Acylthiourea Naphthoquinones Cancer CIENCIAS EXATAS E DA TERRA::QUIMICA |
title_short |
Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas |
title_full |
Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas |
title_fullStr |
Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas |
title_full_unstemmed |
Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas |
title_sort |
Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas |
author |
Leite, Celisnolia Morais |
author_facet |
Leite, Celisnolia Morais |
author_role |
author |
dc.contributor.authorlattes.por.fl_str_mv |
http://lattes.cnpq.br/9638881050186865 |
dc.contributor.author.fl_str_mv |
Leite, Celisnolia Morais |
dc.contributor.advisor1.fl_str_mv |
Batista, Alzir Azevedo |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/6469642481998660 |
dc.contributor.authorID.fl_str_mv |
0c1b17a9-bf39-4691-b185-35217dd329c2 |
contributor_str_mv |
Batista, Alzir Azevedo |
dc.subject.por.fl_str_mv |
Complexos de cobre (I) Aciltioureia Naftoquinonas Câncer |
topic |
Complexos de cobre (I) Aciltioureia Naftoquinonas Câncer Copper (I) complexes Acylthiourea Naphthoquinones Cancer CIENCIAS EXATAS E DA TERRA::QUIMICA |
dc.subject.eng.fl_str_mv |
Copper (I) complexes Acylthiourea Naphthoquinones Cancer |
dc.subject.cnpq.fl_str_mv |
CIENCIAS EXATAS E DA TERRA::QUIMICA |
description |
In this work, the synthesis, characterization, and evaluation of the cytotoxic activity of sixteen Cu(I)/Triphenylphosphine complexes containing the acylthiourea or naphthoquinones ligands are presented. The complexes were divided into two series based on the classes of the ligands used. The first series is composed of the neutral complexes of general formula [Cu(Ln)(PPh3)2] (1-6) and monocationic complexes of general formula [Cu(Ln)(PPh3)2]NO3 (1a 6a), where Ln= acylthiourea and PPh3= triphenylphosphine. The second series is composed of the neutral complexes of general formula [Cu(NQn)(PPh3)2] (1b 4b), where NQn= naphthoquinone and PPh3= triphenylphosphine. All complexes were characterized by different techniques such as elemental analysis, molar conductivity, infrared absorption spectroscopy, 1D and 2D nuclear magnetic resonance (31P{1H}, 1H and 13C{1H}), mass spectrometry, and X-ray diffraction. In the 13C{1H} NMR spectra, the complexes (1-6) stood out by showing the unusual chemical shift pattern, for the C=O and C=S carbon atoms of the acylthiourea ligand after bidentate (S, O) and anionic coordination. The experimental results were supported by DFT studies that suggested that relativistic effects strongly influenced the NMR protection constants of the light atoms due to coordination to the heavy atom Cu. The stability of the complexes in the cell culture medium was investigated and all the complexes were shown to be unstable, directly influencing the biological results obtained. The in vitro cytotoxicity of the complexes was determined in the breast (MCF7 and MDA MB-231) and lung (A549) tumor cell lines and in the corresponding non-tumor breast (MCF-10A) and lung (MRC-5) cell lines, and all complexes were actives exhibiting IC50 values in the same range in different cell lines. The compounds were more active than the free ligands and the precursor salt of the complexes in different cell lines, showing that even unstable complexes are relevant for the cytotoxic action. In general, the acylthiourea series complexes, 1 and 1a, were able to change the morphology of MDA-MB-231 cells, inhibit colony formation, showing cytotoxic and cytostatic effects on this cell line, significantly altering the cytoskeleton of cells, reducing the density, and promoting the condensation of the F-actin filaments. They promoted the increase of cells in the fragmented DNA region (sub-G0) and induced cell death by apoptosis. The complexes of the naphthoquinone series, 1b, and 4b, altered the morphology of MDA-MB-231 cells, inhibited colony formation at concentrations higher than the IC50, and were able to inhibit cell migration. Finally, the compounds synthesized and characterized in this work are relevant reports of copper (I) complexes with cytotoxic properties in different tumor cell lines with potential for future studies in vivo models. |
publishDate |
2021 |
dc.date.issued.fl_str_mv |
2021-07-26 |
dc.date.accessioned.fl_str_mv |
2022-06-14T19:34:44Z |
dc.date.available.fl_str_mv |
2022-06-14T19:34:44Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/doctoralThesis |
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doctoralThesis |
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dc.identifier.citation.fl_str_mv |
LEITE, Celisnolia Morais. Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas. 2021. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2021. Disponível em: https://repositorio.ufscar.br/handle/ufscar/16288. |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufscar.br/handle/ufscar/16288 |
identifier_str_mv |
LEITE, Celisnolia Morais. Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas. 2021. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2021. Disponível em: https://repositorio.ufscar.br/handle/ufscar/16288. |
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https://repositorio.ufscar.br/handle/ufscar/16288 |
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Universidade Federal de São Carlos Câmpus São Carlos |
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Programa de Pós-Graduação em Química - PPGQ |
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UFSCar |
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Universidade Federal de São Carlos Câmpus São Carlos |
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