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

Kym, Philip Ryan

Permalink

https://hdl.handle.net/2142/70435 Copy

Description

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

Issue Date

1994

Doctoral Committee Chair(s)

Katzenellenbogen, John A.

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(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.

Graduation Semester

1994

Type of Resource

text

Permalink

http://hdl.handle.net/2142/70435

Owning Collections