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

Chemical probes for steroid receptors have proven useful in providing molecular details about important hormone-receptor interactions. 16α,17α- ((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. 16α,17α-((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 (17aβ-hydroxy-16α,17 α-oxacyclopentan-1$\sp\prime$-one-D-homoandrost-4-en-3-one (78) and 15α-formyl-16α-hydroxy-16 β-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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2014

Author dc:creator

• Kym, Philip Ryan

Contributors dc:contributor

• Katzenellenbogen, John A.

• Chemistry, Organic
• Chemistry, Pharmaceutical

Identifier

(UMI)AAI9512443

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/70435