RESUMO
The calcium dependent E-selectin/sialyl Lewisx (sLex) interaction plays a key role in inflammation where it mediates the rolling of leukocytes prior to firm adhesion and extravasation from the vasculature. A model of E-selectin/sLex binding, along with previously reported structure-activity relationships of sLex-related oligosaccharide, was used in the rational design of non-oligosaccharide inhibitors of this pivotal interaction. A palladium-mediated biaryl-coupling (Suzuki) reaction was used as the key step to prepare a number of substituted biphenyls which were assayed for their ability to inhibit the binding of E-, P-, and L-selectin-IgG fusion proteins to sLex expressed on the surface of HL60 cells. Some of the compounds developed had greater in vitro potency than the parent sLex tetrasaccharide and are currently being evaluated in in vivo models of inflammation to select a candidate for clinical development.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Selectina E/metabolismo , Manosídeos/síntese química , Manosídeos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Sítios de Ligação , Cálcio/química , Cálcio/metabolismo , Ácidos Carboxílicos/química , Gráficos por Computador , Desenho de Fármacos , Células HL-60 , Humanos , Imunoglobulina G/genética , Imunoglobulina G/metabolismo , Antígenos do Grupo Sanguíneo de Lewis/metabolismo , Manosídeos/química , Camundongos , Modelos Moleculares , Oligossacarídeos/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Selectinas/metabolismo , Antígeno Sialil Lewis X , Relação Estrutura-AtividadeRESUMO
In an earlier study, activated species of Hageman factor (factor XII) induced elaboration of interleukin-1 by human monocytes. These observations did not address whether Hageman factor participated in endotoxin-induced release of interleukin-1. To examine this question, the release of interleukin-1 by endotoxin-stimulated human mononuclear cells was measured in the presence of popcorn inhibitor, a specific inhibitor of Hageman factor. In the experiments herein described, popcorn inhibitor sharply decreased the release of interleukin-1 by human mononuclear cells that were incubated with endotoxin. This observation suggests that Hageman factor may play a role in the elaboration of interleukin-1 by human mononuclear cells. Conforming with this view, the addition of antiserum directed against Hageman factor inhibited the release of interleukin-1 from endotoxin-stimulated mononuclear cells.