Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias

Detalhes bibliográficos
Autor(a) principal: Cunha, Beatriz Nogueira da
Data de Publicação: 2018
Tipo de documento: Tese
Idioma: por
Título da fonte: Repositório Institucional da UFSCAR
Texto Completo: https://repositorio.ufscar.br/handle/ufscar/11491
Resumo: This thesis shows a study based on the synthesis, characterization and biological evaluation of 19 new organometallic Ru(II) complexes with acylthioureas. The complexes have general formula Ru(6-p-cymene)Cl(PPh3)Tu]PF6 e [Ru(6-p-cymene)(PPh3)Tu]PF6 where PPh3= triphenylphosphine and Tu= N-(methylfuroyl)-N’-2-furoylthiourea (1 e 1a); N-(methyltiophenyl)-N-2-tiophenylthiourea (2); N-(methylfuroyl)-N’-2-furoyltiourea; N-(methylfuroyl)-N’-2-tiophenylthiourea (3); N-(methyl-1,3-benzodioxolyl)-N’-2-furoylthiourea (4 e 4a); N-(methyl-1,3-benzodioxolyl)-N’-2-tiophenylthiourea (5); N,N-(dimethyl)-N’-benzoylthiourea (1m e 1b); N,N-(diethyl)-N’-benzoyltiourea (2m e 2b); N,N-(dimethyl)-N’-2-furoyltiourea (3m e 3b); N,N-(diethyl)-N’-2-furoyltiourea (4m e 4b); N,N-(dimethyl)-N’-2-tiophenylthiourea (5m e 5b); N,N-(diethyl)-N’-2-tiophenylthiourea (6m e 6b). Complexes characterization was carried out by elemental analysis, molar conductivity, absorption spectroscopy in infrared region, 31P {1H}, 1H e 13C {1H} nuclear magnetic resonance and single crystal X-ray diffraction. Three different coordination modes of the acylthiourea ligands, monodentate via S atom (1-5 e 1m-6m), bidentate via S and O atoms (1b-6b) or via S and N atoms (1a e 4a), were obtained from different synthetic routes. One of the synthetic routes base on hydrolysis reaction of monodentate complexes, which promotes the conversion of coordination mode of acylthioureas to bidentate. The cytotoxicity of the complexes was evaluated in breast (MDA-MB-231), lung (A549) and prostate (DU-145) human tumor cell lines and breast (MCF-10A) and lung (MRC-5) human nontumorigenic cell lines. IC50 values of the complexes 1-5, 1a e 4a, in A549 cells, which correspond the range from 0.25 to 0.61 M, after 48 h incubation, indicate a considerable cytotoxicity with values significantly lower than the reference drug, cisplatin (11.84 M). For the complexes 1m-6m e 1b-6b, the IC50 values in the prostate cell line (2.89-7.49 M), despite indicating cell proliferative inhibition, showed lower cytotoxicity than cisplatin (2.00 M). For breast (2.89-7.49 M), and lung (IC50= 0.51-1.83 M) cell lines, the complexes 1m-6m e 1b-6b were notably more active than cisplatin, as also showed expressive selectivity (IS= 4.66-19.34) toward breast tumor cell line. Base on both activity and selectivity, the complexes 1a, 5b e 6b, as well as their respective analogous complexes in monodentate coordination 1, 5m e 6m, were chosen to continuity of biological investigations in the breast (5m, 6m, 5b e 6b) and lung (1 e 1a) tumor cell lines. These complexes induced morphology changes in their respective cell lines, were able to inhibit the colony formation, and cell migration. In addition, the complexes promoted cell cycle arrest at Sub-G1 phase and induced apoptosis cell death. Interaction studies carried out by viscosity measurements, electrophoretic mobility and competitive assays suggest the interaction between the complexes and DNA is via minor groove. The complexes also showed high HSA protein affinity (Kb= 104-106). The competitive assay using dansylglycine indicates complexes interaction with HSA site II (subdomain IIIA).
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spelling Cunha, Beatriz Nogueira daMoreira, Wânia da Conceiçãohttp://lattes.cnpq.br/3016270106775634Batista, Alzir Azevedohttp://lattes.cnpq.br/6469642481998660http://lattes.cnpq.br/0178000276198418ace7a794-0f3a-458c-afc4-3845b30ded182019-07-15T12:55:00Z2019-07-15T12:55:00Z2018-08-16CUNHA, Beatriz Nogueira da. Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias. 2018. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2018. Disponível em: https://repositorio.ufscar.br/handle/ufscar/11491.https://repositorio.ufscar.br/handle/ufscar/11491This thesis shows a study based on the synthesis, characterization and biological evaluation of 19 new organometallic Ru(II) complexes with acylthioureas. The complexes have general formula Ru(6-p-cymene)Cl(PPh3)Tu]PF6 e [Ru(6-p-cymene)(PPh3)Tu]PF6 where PPh3= triphenylphosphine and Tu= N-(methylfuroyl)-N’-2-furoylthiourea (1 e 1a); N-(methyltiophenyl)-N-2-tiophenylthiourea (2); N-(methylfuroyl)-N’-2-furoyltiourea; N-(methylfuroyl)-N’-2-tiophenylthiourea (3); N-(methyl-1,3-benzodioxolyl)-N’-2-furoylthiourea (4 e 4a); N-(methyl-1,3-benzodioxolyl)-N’-2-tiophenylthiourea (5); N,N-(dimethyl)-N’-benzoylthiourea (1m e 1b); N,N-(diethyl)-N’-benzoyltiourea (2m e 2b); N,N-(dimethyl)-N’-2-furoyltiourea (3m e 3b); N,N-(diethyl)-N’-2-furoyltiourea (4m e 4b); N,N-(dimethyl)-N’-2-tiophenylthiourea (5m e 5b); N,N-(diethyl)-N’-2-tiophenylthiourea (6m e 6b). Complexes characterization was carried out by elemental analysis, molar conductivity, absorption spectroscopy in infrared region, 31P {1H}, 1H e 13C {1H} nuclear magnetic resonance and single crystal X-ray diffraction. Three different coordination modes of the acylthiourea ligands, monodentate via S atom (1-5 e 1m-6m), bidentate via S and O atoms (1b-6b) or via S and N atoms (1a e 4a), were obtained from different synthetic routes. One of the synthetic routes base on hydrolysis reaction of monodentate complexes, which promotes the conversion of coordination mode of acylthioureas to bidentate. The cytotoxicity of the complexes was evaluated in breast (MDA-MB-231), lung (A549) and prostate (DU-145) human tumor cell lines and breast (MCF-10A) and lung (MRC-5) human nontumorigenic cell lines. IC50 values of the complexes 1-5, 1a e 4a, in A549 cells, which correspond the range from 0.25 to 0.61 M, after 48 h incubation, indicate a considerable cytotoxicity with values significantly lower than the reference drug, cisplatin (11.84 M). For the complexes 1m-6m e 1b-6b, the IC50 values in the prostate cell line (2.89-7.49 M), despite indicating cell proliferative inhibition, showed lower cytotoxicity than cisplatin (2.00 M). For breast (2.89-7.49 M), and lung (IC50= 0.51-1.83 M) cell lines, the complexes 1m-6m e 1b-6b were notably more active than cisplatin, as also showed expressive selectivity (IS= 4.66-19.34) toward breast tumor cell line. Base on both activity and selectivity, the complexes 1a, 5b e 6b, as well as their respective analogous complexes in monodentate coordination 1, 5m e 6m, were chosen to continuity of biological investigations in the breast (5m, 6m, 5b e 6b) and lung (1 e 1a) tumor cell lines. These complexes induced morphology changes in their respective cell lines, were able to inhibit the colony formation, and cell migration. In addition, the complexes promoted cell cycle arrest at Sub-G1 phase and induced apoptosis cell death. Interaction studies carried out by viscosity measurements, electrophoretic mobility and competitive assays suggest the interaction between the complexes and DNA is via minor groove. The complexes also showed high HSA protein affinity (Kb= 104-106). The competitive assay using dansylglycine indicates complexes interaction with HSA site II (subdomain IIIA).Esta tese apresenta um estudo baseado na síntese, caracterização e avaliação biológica de 19 novos complexos organometálicos de Ru(II) com aciltioureias. Os complexos apresentam fórmula geral [Ru(6-p-cimeno)Cl(PPh3)Tu]PF6 e [Ru(6-p-cimeno)(PPh3)Tu]PF6 onde PPh3= trifenilfosfina e Tu= N-(metilfuroil)-N’-2-furoiltioureia (1 e 1a); T= N-(metiltiofenil)-N-2-tiofeniltioureia (2); N-(metilfuroil)-N’-2-furoiltioureia; N-(metilfuroil)-N’-2-tiofeniltioureia (3); N-(metil-1,3-benzodioxolil)-N’-2-furoiltioureia (4 e 4a); N-(metil-1,3-benzodioxolil)-N’-2-tiofeniltioureia (5); N,N-(dimetil)-N’-benzoiltioureia (1m e 1b); N,N-(dietil)-N’-benzoiltioureia (2m e 2b); N,N-(dimetil)-N’-2-furoiltioureia (3m e 3b); N,N-(dietil)-N’-2-furoiltioureia (4m e 4b); N,N-(dimetil)-N’-2-tiofeniltioureia (5m e 5b); N,N-(dietil)-N’-2-tiofeniltioureia (6m e 6b). A caracterização dos complexos foi realizada mediante análise elementar, condutividade molar, espectroscopia de absorção na região do infravermelho, ressonância magnética nuclear de 31P {1H}, 1H e 13C {1H} e difração de raios X (monocristal). Três distintos modos de coordenação dos ligantes aciltioureia, monodentado via átomo de S (1-5 e 1m-6m), e bidentandos via átomos de S e O (1b-6b) ou via átomos de S e N (1a e 4a), foram obtidos a partir de diferentes rotas sintéticas. Uma das rotas sintéticas baseia-se na reação de hidrólise dos complexos monodentados, que propicia a conversão do modo de coordenação dos ligantes aciltioureias para o bidentado. A citotoxicidade dos complexos foi avaliada nas linhagens tumorais de mama (MDA-MB-231), pulmão (A549) e próstata (DU-145) e linhagens não tumorais de mama (MCF-10A) e pulmão (MRC-5). Os valores de IC50 dos complexos 1-5, 1a e 4a, na linhagem A549 que corresponde a faixa de 0,25 a 0, 61 µM, após 48 h de incubação, indicam uma pronunciada citotoxicidade dos complexos com valores significativamente menores do que o observado para o fármaco de referência, cisplatina (11,84 µM). Para os complexos 1m-6m e 1b-6b, os valores de IC50 para a linhagem de próstata (2,89-7,49 µM), apesar de indicarem a inibição da proliferação celular, apresentaram menor citotoxicidade do que o cisplatina (2,00 µM). Para as linhagens tumorais de mama (IC50= 0,28-0,74 µM) e pulmão (IC50= 0,51-1,83 µM), os complexos 1m-6m e 1b-6b foram notavelmente mais ativos do que a cisplatina, também apresentaram expressiva seletividade frente à linhagem tumoral de mama (IS= 4,66-19,34). Baseando-se na atividade e seletividade, os complexos 1a, 5b e 6b, bem como seus respectivos complexos análogos na coordenação monodentada 1, 5m e 6m, foram selecionados para a continuidade das investigações biológicas na linhagens tumorais de pulmão (1 e 1a) e mama (5m, 6m, 5b e 6b). Esses complexos induziram alterações morfológicas nas respectivas linhagens, como também foram capazes de inibir a formação de colônias e migração celular. Além disso, os complexos promoveram acúmulo na fase Sub-G1 do ciclo celular e induziram morte por apoptose. Os Estudos de interação com o DNA realizados por meio de medidas de viscosidade, mobilidade eletroforética e ensaio de competitividade, sugerem a interação dos complexos com o DNA via sulco menor. Os complexos também apresentaram alta afinidade à proteína HSA (Kb= 104 a 106). O ensaio competitivo com o dansilglicina sugere interação com o sitío II (subdomínio IIIA) desta proteína.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq: 143334/2014-0porUniversidade Federal de São CarlosCâmpus São CarlosPrograma de Pós-Graduação em Química - PPGQUFSCarComplexos organometálicos de Ru(II)Ligantes aciltioureiaAvaliação citotóxicaInteração com DNA/HSACIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA::CAMPOS DE COORDENACAOCIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA::COMPOSTOS ORGANO-METALICOSAvaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureiasEvaluation of anticancer properties of organometallic Ru(II) complexes with acylthioureasinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis24 meses após a data da defesa600600b990c508-1a04-4981-aa02-ca9a0ab0bd94info:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINALTESE BIA - correções pós defesa 2 com folha aprovação.pdfTESE BIA - correções pós defesa 2 com folha aprovação.pdfTese - versão final com folha aprovaçãoapplication/pdf24100739https://repositorio.ufscar.br/bitstream/ufscar/11491/2/TESE%20BIA%20-%20corre%c3%a7%c3%b5es%20p%c3%b3s%20defesa%202%20com%20folha%20aprova%c3%a7%c3%a3o.pdff3118bb70d51079810b1717c30fe2d37MD52LICENSElicense.txtlicense.txttext/plain; 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dc.title.por.fl_str_mv Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias
dc.title.alternative.eng.fl_str_mv Evaluation of anticancer properties of organometallic Ru(II) complexes with acylthioureas
title Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias
spellingShingle Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias
Cunha, Beatriz Nogueira da
Complexos organometálicos de Ru(II)
Ligantes aciltioureia
Avaliação citotóxica
Interação com DNA/HSA
CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA::CAMPOS DE COORDENACAO
CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA::COMPOSTOS ORGANO-METALICOS
title_short Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias
title_full Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias
title_fullStr Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias
title_full_unstemmed Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias
title_sort Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias
author Cunha, Beatriz Nogueira da
author_facet Cunha, Beatriz Nogueira da
author_role author
dc.contributor.authorlattes.por.fl_str_mv http://lattes.cnpq.br/0178000276198418
dc.contributor.author.fl_str_mv Cunha, Beatriz Nogueira da
dc.contributor.advisor1.fl_str_mv Moreira, Wânia da Conceição
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/3016270106775634
dc.contributor.advisor-co1.fl_str_mv Batista, Alzir Azevedo
dc.contributor.advisor-co1Lattes.fl_str_mv http://lattes.cnpq.br/6469642481998660
dc.contributor.authorID.fl_str_mv ace7a794-0f3a-458c-afc4-3845b30ded18
contributor_str_mv Moreira, Wânia da Conceição
Batista, Alzir Azevedo
dc.subject.por.fl_str_mv Complexos organometálicos de Ru(II)
Ligantes aciltioureia
Avaliação citotóxica
Interação com DNA/HSA
topic Complexos organometálicos de Ru(II)
Ligantes aciltioureia
Avaliação citotóxica
Interação com DNA/HSA
CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA::CAMPOS DE COORDENACAO
CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA::COMPOSTOS ORGANO-METALICOS
dc.subject.cnpq.fl_str_mv CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA::CAMPOS DE COORDENACAO
CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA::COMPOSTOS ORGANO-METALICOS
description This thesis shows a study based on the synthesis, characterization and biological evaluation of 19 new organometallic Ru(II) complexes with acylthioureas. The complexes have general formula Ru(6-p-cymene)Cl(PPh3)Tu]PF6 e [Ru(6-p-cymene)(PPh3)Tu]PF6 where PPh3= triphenylphosphine and Tu= N-(methylfuroyl)-N’-2-furoylthiourea (1 e 1a); N-(methyltiophenyl)-N-2-tiophenylthiourea (2); N-(methylfuroyl)-N’-2-furoyltiourea; N-(methylfuroyl)-N’-2-tiophenylthiourea (3); N-(methyl-1,3-benzodioxolyl)-N’-2-furoylthiourea (4 e 4a); N-(methyl-1,3-benzodioxolyl)-N’-2-tiophenylthiourea (5); N,N-(dimethyl)-N’-benzoylthiourea (1m e 1b); N,N-(diethyl)-N’-benzoyltiourea (2m e 2b); N,N-(dimethyl)-N’-2-furoyltiourea (3m e 3b); N,N-(diethyl)-N’-2-furoyltiourea (4m e 4b); N,N-(dimethyl)-N’-2-tiophenylthiourea (5m e 5b); N,N-(diethyl)-N’-2-tiophenylthiourea (6m e 6b). Complexes characterization was carried out by elemental analysis, molar conductivity, absorption spectroscopy in infrared region, 31P {1H}, 1H e 13C {1H} nuclear magnetic resonance and single crystal X-ray diffraction. Three different coordination modes of the acylthiourea ligands, monodentate via S atom (1-5 e 1m-6m), bidentate via S and O atoms (1b-6b) or via S and N atoms (1a e 4a), were obtained from different synthetic routes. One of the synthetic routes base on hydrolysis reaction of monodentate complexes, which promotes the conversion of coordination mode of acylthioureas to bidentate. The cytotoxicity of the complexes was evaluated in breast (MDA-MB-231), lung (A549) and prostate (DU-145) human tumor cell lines and breast (MCF-10A) and lung (MRC-5) human nontumorigenic cell lines. IC50 values of the complexes 1-5, 1a e 4a, in A549 cells, which correspond the range from 0.25 to 0.61 M, after 48 h incubation, indicate a considerable cytotoxicity with values significantly lower than the reference drug, cisplatin (11.84 M). For the complexes 1m-6m e 1b-6b, the IC50 values in the prostate cell line (2.89-7.49 M), despite indicating cell proliferative inhibition, showed lower cytotoxicity than cisplatin (2.00 M). For breast (2.89-7.49 M), and lung (IC50= 0.51-1.83 M) cell lines, the complexes 1m-6m e 1b-6b were notably more active than cisplatin, as also showed expressive selectivity (IS= 4.66-19.34) toward breast tumor cell line. Base on both activity and selectivity, the complexes 1a, 5b e 6b, as well as their respective analogous complexes in monodentate coordination 1, 5m e 6m, were chosen to continuity of biological investigations in the breast (5m, 6m, 5b e 6b) and lung (1 e 1a) tumor cell lines. These complexes induced morphology changes in their respective cell lines, were able to inhibit the colony formation, and cell migration. In addition, the complexes promoted cell cycle arrest at Sub-G1 phase and induced apoptosis cell death. Interaction studies carried out by viscosity measurements, electrophoretic mobility and competitive assays suggest the interaction between the complexes and DNA is via minor groove. The complexes also showed high HSA protein affinity (Kb= 104-106). The competitive assay using dansylglycine indicates complexes interaction with HSA site II (subdomain IIIA).
publishDate 2018
dc.date.issued.fl_str_mv 2018-08-16
dc.date.accessioned.fl_str_mv 2019-07-15T12:55:00Z
dc.date.available.fl_str_mv 2019-07-15T12:55:00Z
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dc.identifier.citation.fl_str_mv CUNHA, Beatriz Nogueira da. Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias. 2018. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2018. Disponível em: https://repositorio.ufscar.br/handle/ufscar/11491.
dc.identifier.uri.fl_str_mv https://repositorio.ufscar.br/handle/ufscar/11491
identifier_str_mv CUNHA, Beatriz Nogueira da. Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias. 2018. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2018. Disponível em: https://repositorio.ufscar.br/handle/ufscar/11491.
url https://repositorio.ufscar.br/handle/ufscar/11491
dc.language.iso.fl_str_mv por
language por
dc.relation.confidence.fl_str_mv 600
600
dc.relation.authority.fl_str_mv b990c508-1a04-4981-aa02-ca9a0ab0bd94
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
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
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