RESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Bencimidazoles/farmacología , Complejos de Coordinación/farmacología , Osmio/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Apoptosis/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/química , Línea Celular Tumoral , Chlorocebus aethiops , Cisplatino/farmacología , Colchicina/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Ligandos , NAD/metabolismo , Necrosis/inducido químicamente , Especies Reactivas de Oxígeno/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
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.
Asunto(s)
Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/toxicidad , Bencimidazoles/química , Neuronas/efectos de los fármacos , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/toxicidad , Multimerización de Proteína/efectos de los fármacos , Animales , Técnicas de Química Sintética , Diseño de Fármacos , Femenino , Iridio/química , Ligandos , Ratones , Modelos Moleculares , Conformación Molecular , Neuronas/citología , Compuestos Organometálicos/química , Platino (Metal)/química , Embarazo , Estructura Secundaria de Proteína , Rutenio/químicaRESUMEN
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.