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Síntese de complexos de Cu(I) e Fe(II) com potencial aplicação anti‐tumoral
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O cancro é a segunda maior causa de morte no mundo. Até o momento, a Cisplatina e seus análogos são os únicos metalofármacos aprovados para uso clínico e, embora sejam muito eficazes para uma variedade de cancros, apresentam efeitos colaterais bastante nefastos. Estas limitações estimularam uma extensa pesquisa de complexos inorgânicos e organometálicos antitumorais com melhores propriedades farmacológicas. Os complexos de Cu(I) e de Fe(II) têm atraído muito interesse como potenciais fármacos quimioterapeuticos alternativos, uma vez que têm mostrado resultados promissores como agentes atitumorais. No trabalho apresentado, foram sintetizados e caracterizados vinte e cinco novos complexos, divididos em três famílias principais de fórmulas gerais [Cu(dppf)(LL)][BF4] (1-9), [Cu(LL)(glucofuranose-3,5,6-fosfito)x][BF4] (10-17), onde x=1 ou 2, e [Cu(dppe)(L)2][BF4] (18 e 19) e [Cu(PP)(μ-L)2Cu(PP)][(BF4)2] (20-23). Todos os complexos foram caracterizados por espectroscopia de RMN, de UV-Vis. e de FT-IR, sendo a estrutura fluxional do complexo [Cu(dppf)(dpp)][BF4] estudada por RMN a baixa temperatura (-40ºC). Quando aplicável, a pureza dos complexos foi avaliada por análise elementar. A família de complexos [Cu(dppf)(LL)][BF4] foi também estudada por voltametria cíclica. Obtiveram-se cinco estruturas de difração raios-X correspondentes aos complexos [Cu(dppf)(pBI)][BF4] (6), [Cu(dppf)(dpytz)][BF4] (7), [Cu(dppf)(aphen)][BF4] (8), ([Cu(PPh3)(4,4ʹbipy)2)][(BF4)])n (24) e [Fe(η5-C5H5)(dppe)(NCCH3)][CF3SO3] (25). A estabilidade das famílias de complexos de fórmula geral [Cu(dppf)(LL)][BF4] (1-9) e [Cu(LL)(glucofuranose-3,5,6-fosfito)x][BF4] (10-17) foi estudada em DMSO e em 2 ou 5% DMSO/DMEM (v/v) por espectroscopia de RMN e de UV-Vis. durante um período de 24h, mostrando de um modo geral que são estáveis. A citotoxicidade da família de compostos [Cu(dppf)(LL)][BF4] foi avaliada in vitro nas células do adenocarcinoma humano da mama MDAMB231 e MCF7, sugerindo que estes são promissores. Para avaliar a seletividade dos mesmos, foram também testados em células saudáveis. Aguardam-se os resultados relativos à família de compostos [Cu(LL)(glucofuranose-3,5,6-fosfito)x][BF4] (10-17).
Cancer is the second major cause of death in the world. Up to date, Cisplatin and its analogues are the only metallodrugs approved for clinical use. Although they are highly effective for a variety of cancers, they present quite adverse side effects. These limitations stimulated an extensive search for other antitumor inorganic complexes with improved pharmacological properties. Cu(I) and Fe(II) complexes have attracted much interest as possible alternative chemotherapeutic drugs thus theyʹve shown promising results as antitumor agents. In this work, twenty-five new complexes were synthesized and characterized, which were divided into three main families of general formulas [Cu(dppf)(LL)][BF4] (1-9), [Cu(LL)(glucofuranose-3,5,6-fosfito)x][BF4] (10-17), where x=1 or 2, and [Cu(dppe)(L)2][BF4] (18 and 19) and [Cu(PP)(μ-L)2Cu(PP)][(BF4)2] (20-23). All complexes were characterized by NMR, UV-Vis. and FTIR spectroscopy, and the fluxional structure of the compound [Cu(dppf)(dpp)][BF4] was studied under low temperature NMR (-40ºC). When applicable, the purity of the complexes was evaluated by elemental analysis. The family of complexes [Cu(dppf)(LL)][BF4] was also studied by cyclic voltammetry. Five X-ray diffraction structures correspondent to the compouds [Cu(dppf)(pBI)][BF4] (6), [Cu(dppf)(dpytz)][BF4] (7), [Cu(dppf)(aphen)][BF4] (8), ([Cu(PPh3)(4,4ʹbipy)2)][(BF4)])n (24) and [Fe(η5-C5H5)(dppe)(NCCH3)][CF3SO3] (25) were obtained. The stability of the compounds of general formula [Cu(dppf)(LL)][BF4] (1-9) and [Cu(LL)(glucofuranose-3,5,6-fosfito)x][BF4] (10-17) was studied in DMSO and in 2 or 5% DMSO/DMEM (v/v) by UV-Vis. and NMR spectroscopy, during a period of 24 hours, exhibiting overall a stable behaviour. The cytotoxicity of the family of compounds [Cu(dppf)(LL)] [BF4] was evaluated in vitro in breast adenocarcinoma MDAMB231 and MCF7 cell lines, suggesting promising results. To evaluate their selectivity, they were also tested in healthy cells (fibroblasts). The correspondent results for the family of compounds [Cu(LL)(glucofuranose-3,5,6-fosfito)x][BF4] (10-17) are still expected.
Cancer is the second major cause of death in the world. Up to date, Cisplatin and its analogues are the only metallodrugs approved for clinical use. Although they are highly effective for a variety of cancers, they present quite adverse side effects. These limitations stimulated an extensive search for other antitumor inorganic complexes with improved pharmacological properties. Cu(I) and Fe(II) complexes have attracted much interest as possible alternative chemotherapeutic drugs thus theyʹve shown promising results as antitumor agents. In this work, twenty-five new complexes were synthesized and characterized, which were divided into three main families of general formulas [Cu(dppf)(LL)][BF4] (1-9), [Cu(LL)(glucofuranose-3,5,6-fosfito)x][BF4] (10-17), where x=1 or 2, and [Cu(dppe)(L)2][BF4] (18 and 19) and [Cu(PP)(μ-L)2Cu(PP)][(BF4)2] (20-23). All complexes were characterized by NMR, UV-Vis. and FTIR spectroscopy, and the fluxional structure of the compound [Cu(dppf)(dpp)][BF4] was studied under low temperature NMR (-40ºC). When applicable, the purity of the complexes was evaluated by elemental analysis. The family of complexes [Cu(dppf)(LL)][BF4] was also studied by cyclic voltammetry. Five X-ray diffraction structures correspondent to the compouds [Cu(dppf)(pBI)][BF4] (6), [Cu(dppf)(dpytz)][BF4] (7), [Cu(dppf)(aphen)][BF4] (8), ([Cu(PPh3)(4,4ʹbipy)2)][(BF4)])n (24) and [Fe(η5-C5H5)(dppe)(NCCH3)][CF3SO3] (25) were obtained. The stability of the compounds of general formula [Cu(dppf)(LL)][BF4] (1-9) and [Cu(LL)(glucofuranose-3,5,6-fosfito)x][BF4] (10-17) was studied in DMSO and in 2 or 5% DMSO/DMEM (v/v) by UV-Vis. and NMR spectroscopy, during a period of 24 hours, exhibiting overall a stable behaviour. The cytotoxicity of the family of compounds [Cu(dppf)(LL)] [BF4] was evaluated in vitro in breast adenocarcinoma MDAMB231 and MCF7 cell lines, suggesting promising results. To evaluate their selectivity, they were also tested in healthy cells (fibroblasts). The correspondent results for the family of compounds [Cu(LL)(glucofuranose-3,5,6-fosfito)x][BF4] (10-17) are still expected.
Descrição
Tese de mestrado, Química (Química), Universidade de Lisboa, Faculdade de Ciências, 2018
Palavras-chave
Cobre Ferro Dppf Complexos heteronucleares Citotoxicidade Teses de mestrado - 2018