Thesis (doctoral)--Katholieke Universiteit te Nijmegen.

Submitted by Ana Hilda Fonseca (anahilda@ufba.br) on 2016-03-07T15:04:14Z No. of bitstreams: 1 Dissertação Juliana Guerreiro 27.10.15 VERSAO FINAL.pdf: 2348495 bytes, checksum: 5316533c110ebdfedfebff05bf8ca3c7 (MD5) / Approved for entry into archive by Ana Hilda Fonseca (anahilda@ufba.br) on 2016-05-10T15:37:59Z (GMT) No. of bitstreams: 1 Dissertação Juliana Guerreiro 27.10.15 VERSAO FINAL.pdf: 2348495 bytes, checksum: 5316533c110ebdfedfebff05bf8ca3c7 (MD5) / Made available in DSpace on 2016-05-10T15:37:59Z (GMT). No. of bitstreams: 1 Dissertação Juliana Guerreiro 27.10.15 VERSAO FINAL.pdf: 2348495 bytes, checksum: 5316533c110ebdfedfebff05bf8ca3c7 (MD5) / CNPq / Considerando a importância biológica do NO para a boa manutenção do organismo, verifica-se grande interesse no estudo de agentes terapêuticos que auxiliem no controle do teor de óxido nítrico no organismo, seja liberando ou capturando NO. Nesse sentido, nitrosilo complexos de rutênio têm despertado interesse. Da mesma forma a molécula de diflunisal apresenta-se como um potente anti-inflamatório não esteroide, tanto na forma livre como coordenado a centros metálicos. Neste trabalho buscou-se sintetizar, caracterizar e realizar alguns estudos de reatividade química dos compostos contendo na sua composição tanto o óxido nítrico como o diflunisal, visando combinar as suas propriedades biológicas. Os complexos sintetizados foram: cis-[Ru(NO)(DF)(cyclen)]2+, cis- [Ru(NO)(NO2)(cyclen)]2+, cis-[Ru(DF)2(cyclen)] e cis-[Ru(DF)(cyclen)]. Análises dos espectros vibracionais mostraram o aparecimento de bandas características dos ligantes DF e cyclen, bem como de sinais próximo de 1880 cm-1, característico de NO (NO+). Os espectros eletrônicos apresentaram bandas associadas a transições IL e TCML. As técnicas de análise elementar e RMN, realizada para alguns compostos, foram suficientes para ratificar a formulação proposta. Estudos de VPD permitiram avaliar os processos redox atribuídos aos ligantes NO e diflunisal e ao centro metálico (Ru), bem como investigar qualitativamente, a liberação de NO dos nitrosilo compostos, quando submetidos a estímulos eletroquímicos. Através de estudos cinéticos e termodinâmico foi possível determinar as constantes associadas a aquação dos cloretos no complexo cis-[RuCl2(cyclen)]+, Os quais são muito relevantes para o entendimento relativo a reação de coordenação dos ligantes diflunisal e nitrosilo ao centro metálico, nos complexos precursores. Portanto, os resultados obtidos sustentam a formulação dos complexos sintetizados, ao passo que constata a liberação de NO pelos nitrosilo complexos, justificando a importância do trabalho e incentivando estudos futuros que contemplem análises de reatividade eletroquímica e fotoquímica e atividade biológica dos compostos. / Given the biological importance of NO to the proper maintenance of the organism, there is great interest in the study of therapeutic agents that assist in control of the content of nitric oxide in the body, or capturing or releasing NO. In this sense, nitrosyl ruthenium complexes have attracted interest. Similarly the molecule of diflunisal get introduced as a potent non-steroidal anti-inflammatory drugs, as free or coordinate to metal centres. In this paper we sought to synthesize, characterize and perform some chemical reactivity studies of compounds containing in their composition both nitric oxide as the diflunisal aiming to combine their biological properties. The complexes were synthesized: cis-[Ru(NO)(DF)(cyclen)]2+, cis- [Ru(NO)(NO2)(cyclen)]2+, cis-[Ru(DF)2(cyclen)] and cis-[Ru(DF)(cyclen)]. Analysis of the vibrational spectra showed the appearance of characteristic bands of DF and cyclen ligands as well as signals near 1880 cm-1, characteristic of NO (NO+). The electronic spectra showed bands associated LI and LMCT transitions. The techniques of elemental analysis and NMR, held for some compounds were enough to ratify the proposed wording. DPV study allowed us to evaluate redox processes associated with NO and diflunisal ligands and metallic Centre (Ru), as well as investigate qualitatively the release of NO from nitrosyl compounds, when subjected to electrochemical stimuli. Through kinetic and thermodynamic studies it was possible to determine the constants associated with change of chloride for water in the cis-[RuCl2(cyclen)]+ complex, which are highly relevant for the understanding on the coordination reaction of diflunisal and nitrosyl ligands to the metal center, in the complex precursors. Therefore, the results support the formulation of the synthesized complex, while noting the release of NO by nitrosyl complex, justifying the importance of work and encouraging future studies that include electrochemical reactivity analyzes and photochemical and biological activity of the compounds.

From the reaction of ZnCl2 with the non-steroidal anti-inflammatory drug diflunisal (Hdifl), complex [Zn(difl-O)(2)(MeOH)(4)], 1 was formed, while in the presence of a N,N'-donor heterocyclic ligand 2,2'-bipyridylamine (bipyam), 2,2'-bipyridine (bipy), 1,10-phenanthroline (phen) and 2,2'-dipyridylketone oxime (Hpko), the complexes [Zn(difl-O,O')(2)(bipyam)], 2, [Zn(difl-O,O')(2)(bipy)], 3, [Zn(difl-O,O')(2)(phen)], 4 and [Zn(difl-O)2(Hpko)(2)], 5 were isolated, respectively. The complexes were characterized by physicochemical and spectroscopic techniques and the crystal structures of complexes 2, 3 and 5 were determined by X-ray crystallography. The ability of the complexes to scavenge 1,1-diphenyl-picrylhydrazyl, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and hydroxyl radicals and to inhibit soybean lipoxygenase was studied and the complexes were more active than free Hdifl. The interaction of the complexes with serum albumins was monitored by fluorescence emission spectroscopy and the corresponding binding constants were calculated. UV-vis spectroscopy, viscosity measurements and fluorescence emission spectroscopy for the competitive studies of the complexes with ethidium bromide were employed to investigate the interaction of the complexes with calf-thymus DNA and revealed intercalation as the most possible DNA-binding mode. Computational techniques were used to identify possible binding sites of albumins and DNA, and determine the druggability of human and bovine serum albumins with the five novel complexes. The majority of the complexes are stronger binders than the free Hdifl. This is the first study incorporating experimental and computational results to explore the binding activity of metal-NSAID complexes with DNA and serum albumins, suggesting their application as potential metallodrugs.