Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas

Detalhes bibliográficos
Autor(a) principal: Leite, Celisnolia Morais
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.
id SCAR_893f1db30fa4d53e510a9524798bc02c
oai_identifier_str oai:repositorio.ufscar.br:ufscar/16288
network_acronym_str SCAR
network_name_str Repositório Institucional da UFSCAR
repository_id_str 4322
spelling 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
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 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.
url https://repositorio.ufscar.br/handle/ufscar/16288
dc.language.iso.fl_str_mv por
language por
dc.relation.confidence.fl_str_mv 600
600
dc.relation.authority.fl_str_mv e62fb48f-fa23-4158-8d60-0b17f006946c
dc.rights.driver.fl_str_mv Attribution-NonCommercial-NoDerivs 3.0 Brazil
http://creativecommons.org/licenses/by-nc-nd/3.0/br/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivs 3.0 Brazil
http://creativecommons.org/licenses/by-nc-nd/3.0/br/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Universidade Federal de São Carlos
Câmpus São Carlos
dc.publisher.program.fl_str_mv Programa de Pós-Graduação em Química - PPGQ
dc.publisher.initials.fl_str_mv UFSCar
publisher.none.fl_str_mv Universidade Federal de São Carlos
Câmpus São Carlos
dc.source.none.fl_str_mv reponame:Repositório Institucional da UFSCAR
instname:Universidade Federal de São Carlos (UFSCAR)
instacron:UFSCAR
instname_str Universidade Federal de São Carlos (UFSCAR)
instacron_str UFSCAR
institution UFSCAR
reponame_str Repositório Institucional da UFSCAR
collection Repositório Institucional da UFSCAR
bitstream.url.fl_str_mv https://repositorio.ufscar.br/bitstream/ufscar/16288/1/Tese%20de%20Doutorado.pdf
https://repositorio.ufscar.br/bitstream/ufscar/16288/2/Carta%20Comprovante%20do%20Orientador.pdf
https://repositorio.ufscar.br/bitstream/ufscar/16288/3/license_rdf
https://repositorio.ufscar.br/bitstream/ufscar/16288/4/Tese%20de%20Doutorado.pdf.txt
https://repositorio.ufscar.br/bitstream/ufscar/16288/6/Carta%20Comprovante%20do%20Orientador.pdf.txt
https://repositorio.ufscar.br/bitstream/ufscar/16288/5/Tese%20de%20Doutorado.pdf.jpg
https://repositorio.ufscar.br/bitstream/ufscar/16288/7/Carta%20Comprovante%20do%20Orientador.pdf.jpg
bitstream.checksum.fl_str_mv 2f09abb54f7fc8b1fbb36b216c1ed421
2e54ded10730f6e96762542e1ac05508
e39d27027a6cc9cb039ad269a5db8e34
e3f9559a6da84fe2387a4595777ab023
99c61ed9f405f3f7aa02de93485ab14e
167b7c55e7f297c4f10181a6296ca8c8
26b0f1df326ae36a5242818da969ddaa
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR)
repository.mail.fl_str_mv
_version_ 1813715649195671552