RESUMEN
Neuroinflammation contributes to the pathogenesis of neurological disorders including stroke, head trauma, multiple sclerosis, amyotrophic lateral sclerosis as well as age-associated neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Therefore, anti-inflammatory drugs could be used to slow the progression of these diseases. We studied the anti-neuroinflammatory activity of four novel square planar cobalt(II) compounds bearing tetradentate ß-ketoaminato ligands with variation in the number of CF(3) ligand substituents, as well as their corresponding unmetallated organic ligands. Cobalt (Co) complexes were consistently more active than their corresponding ligands. One of the complexes, L(3)Co at concentrations (1-10 µM) that were not toxic to cells, significantly reduced cytotoxic secretions by human monocytic THP-1 cells, astrocytoma U-373 MG cells, and primary human microglia. This anti-neurotoxic action of L(3)Co was reduced by SP600125 and PD98059, selective inhibitors of c-Jun NH2-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) kinase (MEK)1/2 respectively. L(3)Co had no effect on secretion of monocyte chemotactic protein-1 (MCP-1) by THP-1 cells, but it inhibited the NADPH oxidase-dependent respiratory burst activity of differentiated human HL-60 cells. L(3)Co upregulated heme oxygenase-1 (HOX-1) expression by THP-1 cells, which may be one of the molecular mechanisms responsible for its anti-inflammatory properties. Two of the Co compounds tested showed activity only at high concentrations (50 µM), but L(2)Co was highly toxic to all cell types used. Select Co complexes, such as L(3)Co, may exhibit pharmacological properties beneficial in human diseases involving neuroinflammatory processes. Further studies of the in vivo efficacy, safety and pharmacokinetics of L(3)Co are warranted.
Asunto(s)
Aminas/química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Cobalto/química , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Antiinflamatorios/uso terapéutico , Astrocitos/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Células HL-60 , Hemo-Oxigenasa 1/genética , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Ligandos , Microglía/efectos de los fármacos , Monocitos/efectos de los fármacos , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , Compuestos Organometálicos/uso terapéutico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
A series of square planar cobalt(II) compounds bearing tetradentate ß-ketoaminato ligands with variation in the number of -CF(3) ligand substituents has been prepared and structurally and spectroscopically characterized. The fluorinated ß-ketoamine ligands were prepared utilizing a multistep reaction sequence employing a silylenol protecting group. An additional tetrahedral cobalt compound bearing two bidentate ß-ketoaminato ligands was also prepared and characterized. Cytotoxic activity of the cobalt-containing complexes was evaluated using six human cell lines; including two different prostate cancer cell lines (PC-3 and VCaP), acute monocytic leukemia (THP-1), astrocytoma (U-373 MG), hepatocellular carcinoma (HepG2), and neuroblastoma (SH-SY5Y) cells. The cobalt compounds are more active than their corresponding ligands. The activity is cell type specific; the cobalt compounds exhibit strong activity against human prostate cancer and monocytic leukemia cells but weak or no activity against neuroblastoma, astrocytoma, and liver carcinoma cells. Activity generally increases with a greater number of -CF(3) substituents, and square planar complexes exhibit greater activity than the tetrahedral derivative. The mechanisms of activity against human PC-3 prostate cancer cells involve caspase-3 and two different mitogen-activated protein kinases. The addition of a thiol antioxidant reduced cytotoxicity, suggesting the possible involvement of reactive oxygen species. These cobalt complexes may represent a novel class of cytotoxic drugs selective towards certain types of tumors.