RESUMO
A series of nitrobenzene compounds has been discovered as potent inhibitors of VCAM-1 expression and, therefore, potential drug candidates for autoimmune and allergic inflammatory diseases. Structure-activity relationship (SAR) studies showed that a nitro group and two other electron-withdrawing groups are essential for these compounds to be potent inhibitors of VCAM-1 expression.
Assuntos
Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Nitrobenzenos/síntese química , Nitrobenzenos/farmacologia , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacos , Doenças Autoimunes/tratamento farmacológico , Células Cultivadas/citologia , Transporte de Elétrons , Endotélio/citologia , Humanos , Hipersensibilidade/tratamento farmacológico , Inflamação/tratamento farmacológico , Concentração Inibidora 50 , Integrina alfa4beta1 , Integrinas/metabolismo , Receptores de Retorno de Linfócitos/metabolismo , Relação Estrutura-Atividade , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
Dithiocarbamates are a well-defined family of antioxidants that may have therapeutic uses such as in treatment of inflammation and atherosclerosis. A critical event in the pathogenesis of atherosclerosis is the infiltration of inflammatory cells into the vessel wall. Vascular cell adhesion molecule-1 (VCAM-1) plays a pivotal role in this process by mediating leukocyte binding to endothelial cells. VCAM-1 expression is stimulated by oxidized polyunsaturated fatty acids such as 13-hydroperoxy-octadecadienoic acid (13-HPODE), and this lipid hydroperoxide has been proposed to be a second messenger for induction of VCAM-1 gene expression. Pyrrolidine dithiocarbamate (PDTC) markedly represses cytokine-induced VCAM-1 gene expression in cultured human endothelial cells; however, its effects on the oxidative second messenger pathway are unknown. Using a lipoxygenase (LO) inhibition assay in tandem with a colorimetric assay for lipid peroxides, we determined that PDTC does not inhibit the enzymatic oxidation of linoleic acid to 13-HPODE by LO, but directly interacts with and chemically reduces 13-HPODE. We hypothesize that dithiocarbamates may intercept the oxidative second-messenger-induced expression of VCAM-1 and other redox-regulated genes important in inflammation and atherosclerosis.
Assuntos
Peróxidos Lipídicos/metabolismo , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Molécula 1 de Adesão de Célula Vascular/genética , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Ácidos Graxos/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Ácidos Linoleicos/metabolismo , Oxirredução , Sistemas do Segundo Mensageiro/efeitos dos fármacosRESUMO
The immunosuppressants FK506 and rapamycin bind to the same immunophilin, FK506 binding protein (FKBP), and inhibit distinct signal transduction pathways in T lymphocytes. A nonnatural immunophilin ligand, 506BD, which contains only the common structural elements of FK506 and rapamycin, was synthesized and found to be a high-affinity ligand of FKBP and a potent inhibitor of FKBP rotamase activity. Whereas 506BD does not interfere with T cell activation, it does block the immunosuppressive effects of both FK506 and rapamycin. Thus, the common immunophilin binding element of these immunosuppressants, which is responsible for rotamase inhibition, is fused to different effector elements, resulting in the inhibition of different signaling pathways. Inhibition of rotamase activity is an insufficient requirement for mediating these effects.
