6,19-Sulfur-bridged progesterone analogues with antiimmunosuppressive activity.
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.
Veleiro
Adriana S
AS
Departamento de Química Orgánica, UMYMFOR (CONICET-FCEN) and Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina.
Pecci
Adali
A
Monteserín
María C
MC
Baggio
Ricardo
R
Garland
María T
MT
Lantos
Carlos P
CP
Burton
Gerardo
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D006367:HeLa Cells; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011374:Progesterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
C504984:21-hydroxy-6,19-epithiopregn-4-ene-3,20-dione; D005938:Glucocorticoids; D016328:NF-kappa B; D011980:Receptors, Progesterone; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; D003900:Desoxycorticosterone; D011374:Progesterone; D003907:Dexamethasone