Síntese e caracterização de complexos de cobre, gálio e nióbio,estudos de suas citotoxicidades e interações com alvos celulares
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | http://hdl.handle.net/1843/SFSA-B9HPK6 |
Resumo: | One of the most important uses of metal compounds is in the treatment of cancer. In this work, twelve metal complexes with anticancer potential were synthesized and characterized: ten with copper(II), one with gallium(III), and a peroxocomplex of niobium(V). The copper complexes exhibit the following formula: [Cu(HL1)2] (1), [Cu2(phen)2(L1)(ClO4)2] (2), [Cu2(bpy)2(L1)(ClO4)2(H2O)2] (3), [Cu2(dmp)2(L1)(ClO4)2(H2O)2] (4), [Cu(L2)2(H2O)2] (5), [Cu(phen)(L2)](ClO4) (6), [Cu(bpy)(L2)(H2O)](ClO4) (7), [Cu(dmp)(L2)](ClO4) (8), [Cu(aap)(phen)(ClO4)2] (9) e [Cu(aap)(bpy)(ClO4)2] (10); in which H2L1 = 1,4-dihydroxyanthracene-9,10-dione; HL2 = 1-hydroxyanthracene-9,10-dione; aap = 4-aminoantipyrine; phen = 1,10-phenanthroline; bpy = 2,2-bipyridine e dmp = 2,9-dimethyl-1,10-phenanthroline. The complexes were characterized by elemental and conductivity analyses, FTIR, electronic, EPR and ESI-MS spectrometries. Slow evaporation of a solution of complex 2, in DMSOand isopropyl alcohol, yielded complex 2.1, Cu2(phen)2(L1)(dmso)2](PF6)2. The structures of complexes 2.1 and 6 were determined by single-crystal X ray diffraction. Complexes 2, 3, and 4 are dinuclear, with a bridgind L12- ligand, whereas complexes 6,7, 8, 9 and 10 are mononuclear. All copper complexes are significantly cytotoxic in myelogenous leukemia cells, K562 line, with the IC50 values of 1.0; 1.13; 10.0; 0.078; 0.945; 1.84; 12.7; 0.099; 1.8 and 26 µmol L-1 for 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, respectively. The copper complexes interact with DNA with binding constants around 104. Interactions with DNA were also studied by spectrofluorimetry with the help of a fluorescent probe, the ethidium bromide (Eb). Complexes 2, 3, 4, 6, 7 and 8 are capableof displacing Eb from DNA base pairs. The ability of complexes 2, 3, 4, 6, 9 and 10 to oxidatively cleave plasmid DNA was investigated by agarose gel electrophoresis, in the absence and presence of reactive oxygen species (ROS) scavengers. Different ROS are generated in the DNA cleavage process and the nuclease activity follows the order 2 > 4~ 6 ~ 9 > 10 > 3. In addition, it was demonstrated that the complexes are capable of inhibiting topoisomerase-I activity. The complex [Ga2(phen)2(L1)(NO3)2(H2O)2](NO3)2. 4H2O (11) was characterized by elemental and conductivity analyses, FTIR, UV-Vis and fluorescence spectroscopies (excitation = 520 nm), ESI-MS and 1H and 13C NMR. In the FTIR spectrum of 11 the main absorptions are shifted in comparison to the free ligand spectra, evidencing the formation of a complex. In the UV-Vis spectrum, a bathocromic shift evidences the presence of the complexes in solution. The complex is fluorescent, and the fluorescence intensity is affected by the nature of the solvent. Complex 11 inhibitsthe growth of K562 cells with the IC50 = 1.0 µmol L-1 and interacts with DNA. An alternative form of cancer treatment, the photodynamic therapy (PDT), has gainedincreasing interest. The cytotoxic and photocytotoxic activities of the peroxoniobium complex, NbO2(OH)O2 - (12), was studied. The cytotoxic activity of 12 increases by 5 times upon 5 min of UV-A irradiation, with an IC50 value of 6,2 µmol L-1. The effect of12 on the activity of methylene blue, a photosensitizing agent used in PDT, was also studied. The addition of the peroxoniobate doubles the photocytotoxic effect of methylene blue. Therefore, the peroxoniobium compound prepared is a promising candidate for PDT, alone or in combination with other sensitizing agents, such as methylene blue dye. |
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Síntese e caracterização de complexos de cobre, gálio e nióbio,estudos de suas citotoxicidades e interações com alvos celularesFotocitotoxicidadeInteração com DNAComplexos MetálicosCitotoxicidadeTopoisomeraseAntraquinonasClivagem oxidativaComplexos metálicosDNAAntraquinonasQuímica inorgânicaOne of the most important uses of metal compounds is in the treatment of cancer. In this work, twelve metal complexes with anticancer potential were synthesized and characterized: ten with copper(II), one with gallium(III), and a peroxocomplex of niobium(V). The copper complexes exhibit the following formula: [Cu(HL1)2] (1), [Cu2(phen)2(L1)(ClO4)2] (2), [Cu2(bpy)2(L1)(ClO4)2(H2O)2] (3), [Cu2(dmp)2(L1)(ClO4)2(H2O)2] (4), [Cu(L2)2(H2O)2] (5), [Cu(phen)(L2)](ClO4) (6), [Cu(bpy)(L2)(H2O)](ClO4) (7), [Cu(dmp)(L2)](ClO4) (8), [Cu(aap)(phen)(ClO4)2] (9) e [Cu(aap)(bpy)(ClO4)2] (10); in which H2L1 = 1,4-dihydroxyanthracene-9,10-dione; HL2 = 1-hydroxyanthracene-9,10-dione; aap = 4-aminoantipyrine; phen = 1,10-phenanthroline; bpy = 2,2-bipyridine e dmp = 2,9-dimethyl-1,10-phenanthroline. The complexes were characterized by elemental and conductivity analyses, FTIR, electronic, EPR and ESI-MS spectrometries. Slow evaporation of a solution of complex 2, in DMSOand isopropyl alcohol, yielded complex 2.1, Cu2(phen)2(L1)(dmso)2](PF6)2. The structures of complexes 2.1 and 6 were determined by single-crystal X ray diffraction. Complexes 2, 3, and 4 are dinuclear, with a bridgind L12- ligand, whereas complexes 6,7, 8, 9 and 10 are mononuclear. All copper complexes are significantly cytotoxic in myelogenous leukemia cells, K562 line, with the IC50 values of 1.0; 1.13; 10.0; 0.078; 0.945; 1.84; 12.7; 0.099; 1.8 and 26 µmol L-1 for 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, respectively. The copper complexes interact with DNA with binding constants around 104. Interactions with DNA were also studied by spectrofluorimetry with the help of a fluorescent probe, the ethidium bromide (Eb). Complexes 2, 3, 4, 6, 7 and 8 are capableof displacing Eb from DNA base pairs. The ability of complexes 2, 3, 4, 6, 9 and 10 to oxidatively cleave plasmid DNA was investigated by agarose gel electrophoresis, in the absence and presence of reactive oxygen species (ROS) scavengers. Different ROS are generated in the DNA cleavage process and the nuclease activity follows the order 2 > 4~ 6 ~ 9 > 10 > 3. In addition, it was demonstrated that the complexes are capable of inhibiting topoisomerase-I activity. The complex [Ga2(phen)2(L1)(NO3)2(H2O)2](NO3)2. 4H2O (11) was characterized by elemental and conductivity analyses, FTIR, UV-Vis and fluorescence spectroscopies (excitation = 520 nm), ESI-MS and 1H and 13C NMR. In the FTIR spectrum of 11 the main absorptions are shifted in comparison to the free ligand spectra, evidencing the formation of a complex. In the UV-Vis spectrum, a bathocromic shift evidences the presence of the complexes in solution. The complex is fluorescent, and the fluorescence intensity is affected by the nature of the solvent. Complex 11 inhibitsthe growth of K562 cells with the IC50 = 1.0 µmol L-1 and interacts with DNA. An alternative form of cancer treatment, the photodynamic therapy (PDT), has gainedincreasing interest. The cytotoxic and photocytotoxic activities of the peroxoniobium complex, NbO2(OH)O2 - (12), was studied. The cytotoxic activity of 12 increases by 5 times upon 5 min of UV-A irradiation, with an IC50 value of 6,2 µmol L-1. The effect of12 on the activity of methylene blue, a photosensitizing agent used in PDT, was also studied. The addition of the peroxoniobate doubles the photocytotoxic effect of methylene blue. Therefore, the peroxoniobium compound prepared is a promising candidate for PDT, alone or in combination with other sensitizing agents, such as methylene blue dye.Uma das aplicações de grande destaque de complexos metálicos é na terapia do câncer. Neste trabalho foram sintetizados e caracterizados doze complexos metálicos com potencial antitumoral: dez de cobre(II), um de gálio(III) e um peroxocomplexo de nióbio(V). Os complexos de cobre(II) apresentam as seguintes fórmulas: [Cu(HL1)2] (1), [Cu2(phen)2(L1)(ClO4)2] (2), [Cu2(bpy)2(L1)(ClO4)2(H2O)2] (3), [Cu2(dmp)2(L1)(ClO4)2(H2O)2] (4), [Cu(L2)2(H2O)2] (5), [Cu(phen)(L2)](ClO4) (6), [Cu(bpy)(L2)(H2O)](ClO4) (7), [Cu(dmp)(L2)](ClO4) (8), [Cu(aap)(phen)(ClO4)2] (9) e [Cu(aap)(bpy)(ClO4)2] (10); onde H2L1 = 1,4-diidroxiantraceno-9,10-diona; HL2 = 1- hidroxiantraceno-9,10-diona; aap = 4-aminoantipirina; phen = 1,10-fenantrolina; bpy = 2,2'bipiridina e dmp = 2,9-dimetil-1,10-fenantrolina. Os complexos foram caracterizados por análise elementar, medidas condutimétricas, espectroscopia vibracional na região do IV e eletrônica na região do UV-Vis, RPE e ESI-MS. A evaporação lenta de uma solução do complexo 2, em DMSO e álcool isopropílico, levou à formação do complexo 2.1, Cu2(phen)2(L1)(DMSO)2](PF6)2. Os complexos 2.1 e 6 tiveram suas estruturas determinadas por difração de raios X de monocristais. Os complexos 2, 3 e 4 são dinucleares, com o ligante L12- em ponte. Já os complexos 1, 5, 6, 7, 8, 9 e 10 são mononucleares. Todos os complexos de cobre sintetizados são significativamente citotóxicos em células de leucemia mielóide crônica, linhagem K562, com valores de CI50de 1,0; 1,13; 10,0; 0,078; 0,945; 1,84; 12,7; 0,099; 1,8 e 26 µmol L-1 para os complexos 1, 2, 3, 4, 5, 6, 7, 8, 9 e 10, respectivamente. Estes complexos interagem com o DNA e apresentam constantes de afinidade da ordem de 104. Interações com o DNA também foram estudadas por espectroscopia de fluorescência, usando brometo de etídio (Eb) como sonda fluorescente. Os complexos 2, 3, 4, 6, 7 e 8 são capazes de substituir o Eb entre os pares de base do DNA. A habilidade dos complexos 2, 3, 4, 6, 9 e 10 em promover a clivagem oxidativa de DNA de plasmídeo foi estudada por eletroforese, em gel de agarose, na presença e na ausência de sequestradores de espécies reativas de oxigênio (ERO's). Diferentes ERO's são geradas no processo de clivagem do DNA pelos complexos e foi verificado que a atividade nucleásica segue a ordem 2 > 4 ~ 6 ~ 9 > 10 > 3. Além disto, foi demonstrado que estes complexos são capazes de inibir a atividade da topoisomerase. O complexo [Ga2(phen)2(L1)(NO3)2(H2O)2](NO3)2·4H2O (11) foi sintetizado e caracterizado por análise elementar, medidas condutimétricas, espectroscopias vibracional na região do IV, eletrônica na região do UV-Vis e de fluorescência (?excitação = 520 nm), ESI-MS e RMN. Na região do IV, o espectro mostrou deslocamento das principais bandas de ambos os ligantes, evidenciando a coordenação do íon metálico. Já o deslocamento batocrômico observado na região do UV-vis evidenciou a presença do complexo em solução. O complexo 11, que é fluorescente, com a intensidade da fluorescência afetada pela natureza do solvente, é ativo na linhagem K562 com CI50 = 1,0 µmol L-1 e é capaz de interagir com o DNA. Como proposta alternativa ao tratamento do câncer, a terapia fotodinâmica (TFD) vem ganhando crescente interesse. A atividade citotóxica de um peroxocomplexo de nióbio(V), aqui identificado por 12, NbO2(OH)O2.-, foi estudada na ausência e na presença de luz UV-A. A atividade citotóxica de 12 aumenta 5 vezes quando o complexo é irradiado, com valor de CI50 igual a 6,2 µmol L-1. O efeito de 12 na atividade do azul de metileno (AM), um agente fotossensibilizador utilizado na TFD, também foi estudado. A adição de 12 duplica o efeito fotocitotóxico do AM. Portanto, 12 é um candidato promissor para TFD, sozinho ou combinado com outros agentes sensibilizadores, tal como o corante AM. Universidade Federal de Minas GeraisUFMGElene Cristina Pereira MaiaDenise de Oliveira SilvaWendell GuerraCynthia Lopes Martins PereiraLeticia Regina de Souza TeixeiraIvina Paula de Souza2019-08-11T12:23:49Z2019-08-11T12:23:49Z2018-10-19info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/1843/SFSA-B9HPK6info:eu-repo/semantics/openAccessporreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMG2019-11-14T12:03:48Zoai:repositorio.ufmg.br:1843/SFSA-B9HPK6Repositório InstitucionalPUBhttps://repositorio.ufmg.br/oairepositorio@ufmg.bropendoar:2019-11-14T12:03:48Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.none.fl_str_mv |
Síntese e caracterização de complexos de cobre, gálio e nióbio,estudos de suas citotoxicidades e interações com alvos celulares |
title |
Síntese e caracterização de complexos de cobre, gálio e nióbio,estudos de suas citotoxicidades e interações com alvos celulares |
spellingShingle |
Síntese e caracterização de complexos de cobre, gálio e nióbio,estudos de suas citotoxicidades e interações com alvos celulares Ivina Paula de Souza Fotocitotoxicidade Interação com DNA Complexos Metálicos Citotoxicidade Topoisomerase Antraquinonas Clivagem oxidativa Complexos metálicos DNA Antraquinonas Química inorgânica |
title_short |
Síntese e caracterização de complexos de cobre, gálio e nióbio,estudos de suas citotoxicidades e interações com alvos celulares |
title_full |
Síntese e caracterização de complexos de cobre, gálio e nióbio,estudos de suas citotoxicidades e interações com alvos celulares |
title_fullStr |
Síntese e caracterização de complexos de cobre, gálio e nióbio,estudos de suas citotoxicidades e interações com alvos celulares |
title_full_unstemmed |
Síntese e caracterização de complexos de cobre, gálio e nióbio,estudos de suas citotoxicidades e interações com alvos celulares |
title_sort |
Síntese e caracterização de complexos de cobre, gálio e nióbio,estudos de suas citotoxicidades e interações com alvos celulares |
author |
Ivina Paula de Souza |
author_facet |
Ivina Paula de Souza |
author_role |
author |
dc.contributor.none.fl_str_mv |
Elene Cristina Pereira Maia Denise de Oliveira Silva Wendell Guerra Cynthia Lopes Martins Pereira Leticia Regina de Souza Teixeira |
dc.contributor.author.fl_str_mv |
Ivina Paula de Souza |
dc.subject.por.fl_str_mv |
Fotocitotoxicidade Interação com DNA Complexos Metálicos Citotoxicidade Topoisomerase Antraquinonas Clivagem oxidativa Complexos metálicos DNA Antraquinonas Química inorgânica |
topic |
Fotocitotoxicidade Interação com DNA Complexos Metálicos Citotoxicidade Topoisomerase Antraquinonas Clivagem oxidativa Complexos metálicos DNA Antraquinonas Química inorgânica |
description |
One of the most important uses of metal compounds is in the treatment of cancer. In this work, twelve metal complexes with anticancer potential were synthesized and characterized: ten with copper(II), one with gallium(III), and a peroxocomplex of niobium(V). The copper complexes exhibit the following formula: [Cu(HL1)2] (1), [Cu2(phen)2(L1)(ClO4)2] (2), [Cu2(bpy)2(L1)(ClO4)2(H2O)2] (3), [Cu2(dmp)2(L1)(ClO4)2(H2O)2] (4), [Cu(L2)2(H2O)2] (5), [Cu(phen)(L2)](ClO4) (6), [Cu(bpy)(L2)(H2O)](ClO4) (7), [Cu(dmp)(L2)](ClO4) (8), [Cu(aap)(phen)(ClO4)2] (9) e [Cu(aap)(bpy)(ClO4)2] (10); in which H2L1 = 1,4-dihydroxyanthracene-9,10-dione; HL2 = 1-hydroxyanthracene-9,10-dione; aap = 4-aminoantipyrine; phen = 1,10-phenanthroline; bpy = 2,2-bipyridine e dmp = 2,9-dimethyl-1,10-phenanthroline. The complexes were characterized by elemental and conductivity analyses, FTIR, electronic, EPR and ESI-MS spectrometries. Slow evaporation of a solution of complex 2, in DMSOand isopropyl alcohol, yielded complex 2.1, Cu2(phen)2(L1)(dmso)2](PF6)2. The structures of complexes 2.1 and 6 were determined by single-crystal X ray diffraction. Complexes 2, 3, and 4 are dinuclear, with a bridgind L12- ligand, whereas complexes 6,7, 8, 9 and 10 are mononuclear. All copper complexes are significantly cytotoxic in myelogenous leukemia cells, K562 line, with the IC50 values of 1.0; 1.13; 10.0; 0.078; 0.945; 1.84; 12.7; 0.099; 1.8 and 26 µmol L-1 for 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, respectively. The copper complexes interact with DNA with binding constants around 104. Interactions with DNA were also studied by spectrofluorimetry with the help of a fluorescent probe, the ethidium bromide (Eb). Complexes 2, 3, 4, 6, 7 and 8 are capableof displacing Eb from DNA base pairs. The ability of complexes 2, 3, 4, 6, 9 and 10 to oxidatively cleave plasmid DNA was investigated by agarose gel electrophoresis, in the absence and presence of reactive oxygen species (ROS) scavengers. Different ROS are generated in the DNA cleavage process and the nuclease activity follows the order 2 > 4~ 6 ~ 9 > 10 > 3. In addition, it was demonstrated that the complexes are capable of inhibiting topoisomerase-I activity. The complex [Ga2(phen)2(L1)(NO3)2(H2O)2](NO3)2. 4H2O (11) was characterized by elemental and conductivity analyses, FTIR, UV-Vis and fluorescence spectroscopies (excitation = 520 nm), ESI-MS and 1H and 13C NMR. In the FTIR spectrum of 11 the main absorptions are shifted in comparison to the free ligand spectra, evidencing the formation of a complex. In the UV-Vis spectrum, a bathocromic shift evidences the presence of the complexes in solution. The complex is fluorescent, and the fluorescence intensity is affected by the nature of the solvent. Complex 11 inhibitsthe growth of K562 cells with the IC50 = 1.0 µmol L-1 and interacts with DNA. An alternative form of cancer treatment, the photodynamic therapy (PDT), has gainedincreasing interest. The cytotoxic and photocytotoxic activities of the peroxoniobium complex, NbO2(OH)O2 - (12), was studied. The cytotoxic activity of 12 increases by 5 times upon 5 min of UV-A irradiation, with an IC50 value of 6,2 µmol L-1. The effect of12 on the activity of methylene blue, a photosensitizing agent used in PDT, was also studied. The addition of the peroxoniobate doubles the photocytotoxic effect of methylene blue. Therefore, the peroxoniobium compound prepared is a promising candidate for PDT, alone or in combination with other sensitizing agents, such as methylene blue dye. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-10-19 2019-08-11T12:23:49Z 2019-08-11T12:23:49Z |
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.uri.fl_str_mv |
http://hdl.handle.net/1843/SFSA-B9HPK6 |
url |
http://hdl.handle.net/1843/SFSA-B9HPK6 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais UFMG |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais UFMG |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
instname_str |
Universidade Federal de Minas Gerais (UFMG) |
instacron_str |
UFMG |
institution |
UFMG |
reponame_str |
Repositório Institucional da UFMG |
collection |
Repositório Institucional da UFMG |
repository.name.fl_str_mv |
Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG) |
repository.mail.fl_str_mv |
repositorio@ufmg.br |
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1823248354912501760 |