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Title:I. Molecular Probes for the Progesterone Receptor. II. Design and Synthesis of a Rigidly Constrained Peptidomimetic as a Potential Beta-Turn Mimic. III. Isolation and Characterization of Novel Ion Channel Modulators From Commercial Phenol Red Preparations
Author(s):Kym, Philip Ryan
Doctoral Committee Chair(s):Katzenellenbogen, John A.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Chemistry, Organic
Chemistry, Pharmaceutical
Abstract:Chemical probes for steroid receptors have proven useful in providing molecular details about important hormone-receptor interactions. $16\alpha,17\alpha$- ((R)-1$\sp\prime$-(4-Azidophenyl)-ethylidenedioxy) pregn-4-ene-3,20-dione (12) was prepared in high specific activity tritium-labeled form (20 Ci/mmol), and shown to bind to the PR with an affinity (K$\sb{\rm d}$ = 0.801 nM) that is 47% of the affinity of ($\sp3$H) -R 5020 (K$\sb{\rm d}$ = 0.379 nM). ($\sp3$H) -progestin aryl azide 12 exhibits high photoattachment efficiency (60% at 1 h) compared to the commonly used PR PAL reagent ($\sp3$H) -R 5020 (2.2% at 1 h), and is the most efficient progesterone receptor PAL reagent prepared to date. $16\alpha,17\alpha$-((R)-1$\sp\prime$-(4-Fluorophenyl)ethylidenedioxy) pregn-4-ene-3,20-dione (34) was prepared in fluorine-18 labeled form, and evaluated for its in vivo biodistribution in rats. The fluorine-18 labeled progestin showed selective uterine uptake, which was blocked by coinjection of a saturating dose of the unlabeled progestin ORG 2058. Metabolic stability of the radiolabel was indicated by the low radioactivity levels seen in bone. The structures of two novel steroids (17$a\beta$-hydroxy-16$\alpha,17 \alpha$-oxacyclopentan-1$\sp\prime$-one-D-homoandrost-4-en-3-one (78) and 15$\alpha$-formyl-16$\alpha$-hydroxy-16$ \beta$-methylandrost-4-ene-3,17-dione (79)), formed by treatment of 16-dehydroprogesterone with cetyltrimethyl-ammonium permanganate, have been determined by corroboration of $\sp1$H and $\sp $C NMR methods, IR, and mass spectrometry. The X-ray crystal structure of D-homosteroid 78, and putative mechanisms for formation of 78 and 79 are presented.
A novel, rigidly constrained 2-azacyclodec-6-enone ring system was designed as a potential $\beta$-turn mimic. A precursor to the potential $\beta$-turn mimic, (3R,10S),(3S,10R)-($\pm$)-(6E)-3,10-diethyl-2-azacyclodec-6-enone dicarboxylate (103), was prepared by classical ring closure via an intramolecular amine condensation on an ethyl ester. Only the enantiomeric pair that positions both the C$\sb3$ and C$\sb $ substituents in equatorial positions was formed during the cyclization reaction. This methodology has been used in the asymmetric synthesis of a diester precursor to the putative $\beta$-turn mimic.
Two novel bisphenol derivatives have been isolated from the lipophilic impurities present in a commercial preparation of phenol red, and their structures have been determined by corroboration of $\sp1$H and $\sp $C NMR methods and mass spectrometry. The bisphenol fluorene derivative, 9,9-bis(4$\sp\prime$-hydroxyphenyl)-3-hydroxyfluorene (170), has been found to exhibit a dramatic effect on the intracellular concentrations of K$\sp+$ and Na$\sp+$ ions in human fibroblasts at low concentrations (EC$\sb{50}$ between 30 and 60 ng/mL). The bisphenol xanthene derivative, 9,9-bis(4$\sp\prime$-hydroxyphenyl)xanthene (169), elicits a similar biological response, but is less potent. Xanthene 169 exhibits a dramatic effect on cell adhesion, causing release of cells from the plastic substrate at concentrations as low as 2 $\mu$g/mL.
Issue Date:1994
Description:234 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1994.
Other Identifier(s):(UMI)AAI9512443
Date Available in IDEALS:2014-12-15
Date Deposited:1994

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