RESUMO
A series of six osmium(ii) complexes of the type [(η6-p-cymene)Os(C^N)X] (X = chlorido or acetato) containing benzimidazole C^N ligands with an ester group as a handle for further functionalization have been synthesized. They exhibit IC50 values in the low micromolar range in a panel of cisplatin (CDDP)-resistant cancer cells (approximately 10× more cytotoxic than CDDP in MCF-7), decrease the levels of intracellular ROS and reduce the NAD+ coenzyme, and inhibit tubulin polymerization. This discovery could open the door to a new large family of osmium(ii)-based bioconjugates with diverse modes of action.
Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Benzimidazóis/farmacologia , Complexos de Coordenação/farmacologia , Osmio/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Benzimidazóis/síntese química , Benzimidazóis/química , Linhagem Celular Tumoral , Chlorocebus aethiops , Cisplatino/farmacologia , Colchicina/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Ligantes , NAD/metabolismo , Necrose/induzido quimicamente , Espécies Reativas de Oxigênio/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
The design of small molecules that can target the aggregation of Aß as potential therapeutic agents for Alzheimer's disease is an area of study that has attracted a lot of attention recently. The novel ligand methyl 1-butyl-2-pyridyl-benzimidazole carboxylate was prepared for the synthesis of a series of new iridium(III), ruthenium(II), and platinum(II) 2-pyridyl-benzimidazole complexes. The crystal structure of the half-sandwich iridium(III) complex was established by X-ray diffraction. An arrangement of two cationic complexes in the unit cell is observed, and it seems to be organized by weak π···π interactions that are taking place between two symmetry-related benzimidazole ring systems. All new compounds inhibited aggregation of Aß1-42 in vitro as shown by both thioflavin T fluorescence assay and transmission electron microscopy. Among them the Ir compound rescued the toxicity of Aß1-42 in primary cortical neurons effectively.
Assuntos
Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/toxicidade , Benzimidazóis/química , Neurônios/efeitos dos fármacos , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/toxicidade , Multimerização Proteica/efeitos dos fármacos , Animais , Técnicas de Química Sintética , Desenho de Fármacos , Feminino , Irídio/química , Ligantes , Camundongos , Modelos Moleculares , Conformação Molecular , Neurônios/citologia , Compostos Organometálicos/química , Platina/química , Gravidez , Estrutura Secundária de Proteína , Rutênio/químicaRESUMO
Smart design and efficient synthesis of benzimidazole Ru, Ir and Rh cyclometalated complexes are reported with promising cytotoxic activity against HT29, T47D, A2780 and A2780cisR cancer cell lines. Their apoptosis, accumulation, cell cycle arrest, protein binding and DNA binding effects are also discussed.
