Complexos de cobalto(III) contendo naftoquinonas como protótipos de pró-drogas biorredutíveis

• Autor(a) principal: Bustamante, Francisco Lucio de Schneider
• Data de Publicação: 2012
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da Universidade Federal Fluminense (RIUFF)
• Texto Completo: https://app.uff.br/riuff/handle/1/20702
• topic: Ensaio de seleção de medicamento antitumoral; Neoplasia; Antineoplásico; Assay selection of antitumor drug; Neoplasia; Antineoplastic; CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA

Cancer is a leading cause of human deaths according to the World Health Organization (WHO). An obstacle in the treatment of solid tumors is the resistance to treatment, caused by several factors including disorganized tumor growth that creates regions of reduced blood flow. These regions are in a condition of hypoxia due to low oxygen concentration. Hypoxic cells are a major concern regarding chemo- and radiotherapy. Nonetheless, they also have a great potential for the development of new selective prodrugs. As hypoxic cells are characteristic of solid tumors they can be a target for new treatments. Low oxygen concentrations guarantee a reducing environment in these regions, compared with normal cells, so that the reduction of a prodrug can generate cytotoxic species. In this context, this work presents the synthesis and characterization of two Co(III) complexes as prototypes for bioreductible prodrugs. Other six complexes of Co(II), Zn(II) and Ga(III) were also synthesized and characterized for comparison purposes. Compounds with the empirical formula [M(OH2)2(NQ)2] for M = Co or Zn and HNQ = 2-hydroxy-1,4-naphthoquinone, also known as lawsone, were synthesized with the aim of understand the behavior of HNQ as a ligand. The occurrence of geometrical isomerism was observed among zinc complexes. The two cobalt(III) complexes were [Co(bhnq)(L1)]BF4.H2O and [Co(bhnq)(L2)]BF4.H2O for L1 = N,N -bis(pyridin-2-ylmethyl)ethane-1,2-diamine, L2 = N1,N2-dimethyl-N1,N2-bis(pyridin-2-ylmethyl)ethane-1,2-diamine and bhnq2- being the deprotonated form of H2bhnq = 2,2'-bis(3-hydroxy-1,4-naphthoquinone), dimer of lawsone. The dimerization was not expected since HQN was supposed to work as a drug model to be released after reduction of the Co(III) center. Crystallographic data shown that ligand bhnq2- was coordinated in an unusual way not yet reported in literature. Attempts were made in order to synthesize [Co(bhnq)(L3)] for L3 = 3-((bis-(pyridin-2-ylmethyl)amino)methyl)-2-hydroxy-5-methyllbenzaldehyde, but they all have failed. Ga(III) analogous of the cobalt(III) complexes were synthesized suggesting that the dimerization mechanism did not involve redox reactions with the metal center. Crystallographic data (when available), spectroscopic and electrochemical data are shown for all ligands and complexes. Preliminary biological studies are presented for HNQ, H2bhnq and Co(II) and Co(III) complexes. Reactivity studies for Co(III) complexes in the presence of the reducing agent ascorbic acid were made in YPD 2% medium, water, and MES buffer, and monitored by electronic spectroscopy. It was observed that the release rate of the bhnq2- ligand is related to the CoIII/CoII reduction potential in each complex. A dependence of the release rate with the oxygen concentration was also observed, with a slower rate in oxygen saturated solution. These results suggest that the cobalt(III) complexes reported in this work are prototypes of bioreductible prodrugs.