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J Inorg Biochem ; 153: 68-87, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26485179

RESUMO

The synthesis, physico-chemical characterization and cytotoxicity of four new ligands and their respective copper(II) complexes toward two human leukemia cell lines (THP-1 and U937) are reported (i.e. [(HL1)Cu(µ-Cl)2Cu(HL1)]Cl2·H2O (1), [(H2L2)Cu(µ-Cl)2Cu(H2L2)]Cl2·5H2O (2), [(HL3)Cu(µ-Cl)2Cu(HL3)]Cl2·4H2O (3), [(H2L4)Cu(µ-Cl)2Cu(H2L4)]Cl2·6H2O (4)). Ligands HL1 and HL3 contain two pyridines, amine and alcohol moieties with a naphthyl pendant unit yielding a N3O coordination metal environment. Ligands H2L2 and H2L4 have pyridine, phenol, amine and alcohol groups with a naphthyl pendant unit providing a N2O2 coordination metal environment. These compounds are likely to be dinuclear in the solid state but form mononuclear species in solution. The complexes have an antiproliferative effect against both leukemia cell lines; complex (2) exhibits higher activity than cisplatin against U937 (8.20 vs 16.25µmoldm(-3)) and a comparable one against THP-1. These human neoplastic cells are also more susceptible than peripheral blood mononuclear cells (PBMCs) toward the tested compounds. Using C57BL/6 mice an LD50 of 55mgkg(-1) was determined for complex (2), suggesting that this compound is almost four times less toxic than cisplatin (LD50=14.5mgkg(-1)). The mechanism of cell death promoted by ligand H2L2 and by complexes (2) and (4) was investigated by a range of techniques demonstrating that the apoptosis signal triggered at least by complex (2) starts from an extrinsic pathway involving the activation of caspases 4 and 8. This signal is amplified by mitochondria with the concomitant release of cytochrome c and the activation of caspase 9.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Cobre/química , Naftalenos/farmacologia , Receptores de Morte Celular/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Citocromos c/análise , Fragmentação do DNA/efeitos dos fármacos , Feminino , Humanos , Ligantes , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Naftalenos/síntese química , Naftalenos/química , Naftalenos/toxicidade , Células U937
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