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Master's Dissertation
DOI
https://doi.org/10.11606/D.59.2023.tde-03102023-094003
Document
Author
Full name
Renan Ribeiro Bertoloni
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2023
Supervisor
Committee
Nikolaou, Sofia (President)
Batista, Alzir Azevedo
Silva, Roberto Santana da
Title in Portuguese
Design e desenvolvimento de um novo candidato a metalofármaco de rutênio com ligantes sinérgicos
Keywords in Portuguese
DNA
HSA
Ligantes polipiridínicos
NORMs
Rutênio
Terapia fotodinâmica
Abstract in Portuguese
Esse trabalho consiste na síntese, caracterização e verificação de algumas propriedades biológicas de uma série de três complexos de coordenação de fórmula geral [Ru(tpy)(dppz)L]n+ , onde tpy = 2,2':6',2''-terpiridina, dppz = dipirido-[3,2-a:2',3'-c]-fenazina e L = Cl- (n = 1), H2O (n = 2) ou NO2 (n = 1). Inicialmente, o trabalho se propôs a sintetizar o composto inédito [Ru(tpy)(dppz)NO]3+, porém devido à baixa densidade eletrônica do centro metálico, comprovada através de experimentos e cálculos in silico, esse composto se apresentou instável e o trabalho foi realizado utilizando o substituto [Ru(tpy)(dppz)NO2] + , também inédito. Este último apresenta os mesmos potenciais biológicos do anterior, sendo eles a capacidade de gerar 1O2, intercalação com o DNA e fotoliberação de NO. A série foi sintetizada e caracterizada utilizando as técnicas de espectroscopia de absorção no UV-Vis, espectroscopia de luminescência, espectroscopia de absorção resolvida no tempo, espectroscopia vibracional e espectroscopia de RMN. Todos os compostos estudados foram capazes de gerar 1O2, sendo que o composto [Ru(tpy)(dppz)NO2] + apresentou o maior rendimento quântico de geração. Foi demonstrado que todos os compostos interagem de maneira relativamente intensa com a HSA e o DNA, sendo que ambas as interações foram verificadas pelo método de Stern-Volmer e, no caso da HSA, com docking molecular. A interação com DNA foi determinada como sendo de intercalação através da espectroscopia de dicroísmo circular e medidas de temperatura de desnaturação do DNA. O composto [Ru(tpy)(dppz)NO2] + foi capaz de liberar NO mediante irradiação, e essa liberação gerou um efeito de citoproteção de células saudáveis verificado em um estudo in vitro com células pulmonares tumorais e não-tumorais. Todos os compostos se mostraram levemente citotóxicos de maneira seletiva para as células tumorais. A análise de todos os resultados mostra que esse sistema é promissor para o design de novos metalofármacos, de maneira que leves alterações na estrutura dos ligantes pode gerar mudanças na estrutura eletrônica dos compostos que os tornem capazes de retornar resultados ainda mais promissores para a química inorgânica medicinal.
Title in English
Design and development of a new ruthenium metallodrug candidate with synergistic ligands
Keywords in English
DNA
HSA
NORMs
Photodynamic therapy
Polypyridine ligands
Ruthenium
Abstract in English
This work consists of the synthesis, characterization and verification of some biological properties of a series of three coordination complexes with the general formula [Ru(tpy)(dppz)L]n+, where tpy = 2,2':6',2''-terpyridine, dppz = dipyrido-[3,2-a:2',3'-c]- phenazine and L = Cl- (n = 1), H2O (n = 2) or NO2 (n = 1). Initially, the work proposed to synthesize the new compound [Ru(tpy)(dppz)NO]3+, but due to the low electronic density of the metallic center, proven through experiments and in silico calculations, this compound was unstable and the work was carried out using the substitute [Ru(tpy)(dppz)NO2] + , also new in the literature. This compound presents the same biological potentials as the previous one, namely the ability to generate 1O2, intercalation with DNA and photorelease of NO. The series was synthesized and characterized using UV-Vis absorption spectroscopy, emission spectroscopy, time-resolved absorption spectroscopy, vibrational spectroscopy and NMR spectroscopy. All the studied compounds were able to generate 1O2 and the compound [Ru(tpy)(dppz)NO2] + presented the highest quantum yield of generation. It was demonstrated that all compounds interact relatively strongly with HSA and DNA, and both interactions were verified by the Stern-Volmer method and, in the case of HSA, molecular docking calculations. The interaction with DNA was determined to be intercalation by circular dichroism spectroscopy, DNA melting temperature measurements and molecular docking. The compound [Ru(tpy)(dppz)NO2] + was able to release NO upon irradiation, and this release generated a cytoprotective effect in healthy cells verified in an in vitro study with tumor and non-tumor lung cells. All compounds were selectively mildly cytotoxic to tumor cells. The analysis of all the results shows that this system is promising for the design of new metallopharmaceuticals, in a way that slight alterations in the structure of the ligands may generate changes in the electronic structure of the compounds that make them capable of returning even more promising results for medicinal inorganic chemistry.
 
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Publishing Date
2023-12-18
 
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