RESUMO
Prodigiosins (Ps) represent a family of naturally occurring red pigments characterized by a common pyrrolylpyrromethene skeleton. Some members of this family have been shown to possess interesting immunosuppressive properties exerted with a novel mechanism of action, different from that of currently used drugs. In fact, Ps inhibit phosphorylation and activation of JAK-3, a cytoplasmic tyrosine kinase associated with a cell surface receptor component called common gamma-chain, which is exclusive of all IL-2 cytokine family receptors. Blocking common gamma-chain transduction activity results in a potent and specific immunosuppressive activity. With respect to the interesting and unexploited immunomodulating properties of this family of compounds we initiated a medicinal chemistry program aimed at finding novel prodigiosin derivatives with improved immunosuppressive activity and lower toxicity. Utilizing an unprecedented and flexible way of assembling the prodigiosin frame, a number of new derivatives have been prepared and tested leading to the choice of 4-benzyloxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2, 2'-bi-1H-pyrrole (PNU-156804, 16) as a lead immunosuppressant.
Assuntos
Imunossupressores/síntese química , Prodigiosina/análogos & derivados , Pirróis/síntese química , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Hipersensibilidade Tardia/tratamento farmacológico , Imunossupressores/química , Imunossupressores/farmacologia , Imunossupressores/toxicidade , Técnicas In Vitro , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Prodigiosina/síntese química , Prodigiosina/química , Prodigiosina/farmacologia , Prodigiosina/toxicidade , Pirróis/química , Pirróis/farmacologia , Pirróis/toxicidade , Baço/citologia , Baço/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of condensed N-aryl-2-cyano-3-oxo-3-pyrazolyl-propanamides were synthesized and evaluated for immunomodulating activity following intraperitoneal administration. These new molecules were found to enhance macrophage cytotoxicity and stimulate host mediated antibacterial defences in mice. The compound 3-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol- 3-yl]-3-oxo-N-phenyl-propanamide, chosen for wider pharmacological investigation, proved effective in preventing adjuvant-induced arthritis development in rats.
