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Master's Dissertation
DOI
https://doi.org/10.11606/D.46.2019.tde-09032020-100915
Document
Author
Full name
Sandra Cristel Quispe Martínez
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
de Oliveira Silva, Denise (President)
Colquhoun, Alison
Costa, Iguatinã de Melo
Title in Portuguese
Estudo de um metalofármaco de dirutênio(II,III) contendo o enantiômero (S)-ibuprofeno e sua interação com alvos biológicos
Keywords in Portuguese
Albumina
Anticâncer
Diutênio
DNA
Ibuprofeno
Metalofármaco
Abstract in Portuguese
Compostos inorgânicos de rutênio têm demonstrado serem bons candidatos para a terapia contra o câncer. O nosso grupo de pesquisa tem desenvolvido metalofármacos de dirutênio(II,III) de valência mista contendo como ligantes fármacos anti-inflamatórios não esteroides, os quais tem se mostrado promissores para tratamento de gliomas humanos. Visando a um melhor entendimento do modo de ação desses compostos, nesse trabalho foram realizados estudos de comparação do complexo de dirutênio(II,III)- ibuprofeno contendo o ligante Ibp racêmico, [Ru2(Ibp-Rac)4Cl], com o seu análogo inédito contendo o isômero Ipb-S, [Ru2(Ibp-S)4Cl]. As interações desses dois compostos com biomoléculas alvo importantes (albumina de soro humano, HSA, e CT-DNA) foram investigadas. Foram também realizados estudos de comparação dos efeitos desses compostos sobre a viabilidade celular e a migração celular em células de glioma humano da linhagem U87MG in vitro. O complexo [Ru2(Ibp-Rac)4Cl], foi re-preparado por metodologia conhecida do grupo e o complexo inédito [Ru2(Ibp-S)4Cl] foi sintetizado nesse trabalho pela primeira vez. Ambos foram totalmente caracterizados por meio de diversas técnicas. Os estudos com albumina de soro humano e CT-DNA foram efetuados utilizando-se espectroscopia de absorção eletrônica no UV-Visível, espectroscopia de fluorescência, dicroísmo circular e investigação de desnaturalização. Os resultados mostraram que os dois complexos interagem com a HSA com a afinidades similares, sem indicações de enantioseletividade. Os dados de parâmetros termodinâmicos e de mudanças da estrutura secundária da albumina sugerem interação predominantemente hidrofóbica. As interações dos compostos com o CT-DNA também parecem envolver forças hidrofóbicas. Ambos os compostos apresentaram efeitos similares nos estudos de viabilidade celular frente às células U87MG. No entanto, os resultados dos estudos de migração celular mostraram diferenças significativas, o que poderia ser associado a mecanismos enantioseletivos envolvidos na interação com os compostos com as proteínas encarregadas da mobilidade celular.
Title in English
Study of diruthenium(II,III) metallodrug containing the (S)- ibuprofen enantiomer and its interaction with biological targets
Keywords in English
Albumin
Anticancer
Diuthenium
DNA
Ibuprofen
Metallodrug
Abstract in English
Inorganic ruthenium compounds have been shown as good candidates for cancer therapy. Our research group has developed mixed valence diruthenium(II,III) metallodrugs containing non-steroidal anti-inflammatory drug ligands, which are promising metallopharmaceuticals for the treatment of human gliomas. Aiming a better understanding of the mode of action of these compounds, in this work a comparative study between the diruthenium(II,III)-ibuprofen containing the Ibp racemic ligand, [Ru2(IbpRac)4Cl], and its inedited analogue containing the Ibp-S isomer, [Ru2(Ibp-S)4Cl] has been performed. The interactions of these two compounds with important target biomolecules (human serum albumin, HSA, and CT-DNA) have been investigated. A comparative study of the effects of these compounds on the cellular viability and cell migration of U87MG human glioma cell line in vitro was also conducted. The [Ru2(Ibp-Rac)4Cl] complex was reprepared by a methodology previously developed in our group, and the inedited complex [Ru2(Ibp-S)4Cl] has been synthesized here for the first time. Both complexes have been fully characterized by several techniques. The studies with human serum albumin and CTDNA were performed by UV-Visible electronic absorption spectroscopy, fluorescence spectroscopy, circular dichroism and denaturalization investigation. The results showed that both compounds interact with the HSA with similar affinity, without indications of enantioselectivity. The thermodynamic parameters and changes on the secondary structure of the albumin suggest predominant hydrophobic interactions. The interactions of the compounds with CT-DNA seems also to involve hydrophobic forces. Both compounds showed similar effects on the studies of cell viability against the U87MG cells. However, the findings from the cell migration studies revealed significant differences, what might be associated to enantioselective mechanisms involved in the interactions of the compounds with proteins responsible for the cell mobility.
 
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Publishing Date
2020-08-07
 
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