Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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COS Cells
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Chlorocebus aethiops
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Desoxycorticosterone / analogs & derivatives*
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Desoxycorticosterone / chemical synthesis
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Desoxycorticosterone / pharmacology
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Dexamethasone / pharmacology
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Glucocorticoids / antagonists & inhibitors*
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HeLa Cells
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Humans
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Immune Tolerance / drug effects*
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In Vitro Techniques
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Male
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Mice
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Molecular Conformation
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Molecular Structure
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NF-kappa B / antagonists & inhibitors
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Progesterone / analogs & derivatives*
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Progesterone / chemical synthesis*
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Progesterone / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Progesterone / antagonists & inhibitors
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Receptors, Progesterone / genetics
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Stereoisomerism
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Structure-Activity Relationship
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Sulfides / chemical synthesis*
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Sulfides / pharmacology
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Thymus Gland / cytology
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Thymus Gland / drug effects
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Tumor Necrosis Factor-alpha / physiology
Substances
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21-hydroxy-6,19-epithiopregn-4-ene-3,20-dione
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Glucocorticoids
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NF-kappa B
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Receptors, Progesterone
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Sulfides
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Tumor Necrosis Factor-alpha
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Desoxycorticosterone
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Progesterone
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Dexamethasone