DNA as molecular target of analogous palladium and platinum anti-Trypanosoma cruzi compounds: a comparative study |
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Authors: | Vieites Marisol Smircich Pablo Pagano Mariana Otero Lucía Fischer Francielle Luane Terenzi Hernán Prieto María José Moreno Virtudes Garat Beatriz Gambino Dinorah |
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Institution: | a Cátedra de Química Inorgánica, Facultad de Química, UDELAR, Gral. Flores 2124, 11800 Montevideo, Uruguayb Laboratorio de Interacciones Moleculares, Facultad de Ciencias, UDELAR, Iguá 4225, 11400 Montevideo, Uruguayc Centro de Biologia Molecular Estrutural, Departamento de Bioquímica CCB, Universidade Federal de Santa Catarina, 88040-900 Florianópolis SC, Brazild Departament de Microbiología, Universitat de Barcelona, Barcelona, Spaine Departamento de Química Inorgánica, Universitat Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain |
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Abstract: | In the search for drugs with anti-trypanosome activity, we had previously synthesized two series of platinum and palladium analogous compounds of the formula MIICl2(HL)], where HL were bioactive 5-nitrofuryl or 5-nitroacroleine thiosemicarbazone derivatives. In this work, we thoroughly characterized MIICl2(HL)] complexes interaction with DNA by using different techniques: gel electrophoresis, DNA viscosity measurements, circular dichroism (CD) and atomic force microscopy (AFM). Electrophoresis results showed that all complexes induced a withdrawal of DNA superhelicity demonstrated by a decrease in electrophoretic mobility of supercoiled DNA form. This effect on migration was dependent on dose but also on the nature of both the metal and the ligand. In general, the effect produced by palladium complexes was significantly more intense than that observed for the corresponding platinum analogs. Differences between palladium and platinum complexes were also observed in CD experiments. While palladium complexes induce evident calf thymus (CT)-DNA profile changes compatible with B-DNA to Z-DNA conformational transition, no clear effect was observed for platinum ones. Additionally, AFM studies showed that changes in the shape of plasmid DNA, like supercoiling, kinks and thickness increase resulted more intense for the former. In addition, either Pd or Pt complexes increased the viscosity of CT DNA solutions in a concentration dependent manner. Although the nature of DNA interaction of both series of analogous palladium and platinum complexes seemed to be similar, an explanation for the observed differential intensity of the effect could be related to the known kinetic stability differences between palladium and platinum compounds. |
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Keywords: | Palladium Platinum 5-nitrofuryl containing thiosemicarbazones Chagas disease American Trypanosomiasis DNA interaction |
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