RESUMO

Sulfur-bridged pregnanes 6,19-epithioprogesterone, 21-hydroxy-6,19-epithioprogesterone, and the corresponding sulfoxides and sulfones were synthesized and tested as blockers of the immunosuppresive activity of dexamethasone in rat thymocytes. A new one-pot procedure is described for the preparation of 6,19-epithioprogesterone and related compounds by iodocyclization of a 19-sulfanylpregn-5-ene. Antiimmunosuppresive activity was evaluated by the ability of the different steroids to block dexamethasone-mediated apoptosis in thymocytes and dexamethasone-mediated inhibition of the NFkappa-B transcription factor activity. DNA fragmentation and annexin V-FITC positive cells were taken as parameters of apoptosis whereas NFkappa-B activity was tested by the expression of the reporter vector kappaB-luciferase by TNF-alpha in Hela cells. 21-Hydroxy-6,19-epithioprogesterone S,S-dioxide had improved activity in both parameters, while 21-hydroxy-6,19-epithioprogesterone had improved activity only in blocking dexamethasone-induced programmed cell death.

Assuntos

Desoxicorticosterona/análogos & derivados , Glucocorticoides/antagonistas & inibidores , Tolerância Imunológica/efeitos dos fármacos , Progesterona/análogos & derivados , Progesterona/síntese química , Sulfetos/síntese química , Animais , Apoptose/efeitos dos fármacos , Células COS , Chlorocebus aethiops , Desoxicorticosterona/síntese química , Desoxicorticosterona/farmacologia , Dexametasona/farmacologia , Células HeLa , Humanos , Técnicas In Vitro , Masculino , Camundongos , Conformação Molecular , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , Progesterona/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/genética , Estereoisomerismo , Relação Estrutura-Atividade , Sulfetos/farmacologia , Timo/citologia , Timo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/fisiologia