Synthesis and evaluation of bipolar biphenyl proteomimetics as nuclear receptor CBIs and applications of palladium chemistry to the development of radiotracers
Robert N. Hanson
Graham B. Jones, Alexandros Makriyannis, Rein U. Kirss
Date of Award
Doctor of Philosophy
Department or Academic Unit
College of Science. Department of Chemistry and Chemical Biology.
organic chemistry, chemistry, alpha helix mimetics, biphenyl, nuclear receptor, palladium catalysis, proteomimetics, radiotracer
Protein-protein interactions, Nuclear receptors (Biochemistry)
Protein-protein interactions (PPIs) are essential activation and communication mechanisms for countless biological processes. The ability to inhibit PPIs therefore exposes therapeutic pathways for ailments that may have otherwise been deemed untreatable. Recognition that a subset of PPIs are frequently mediated by the binding of short conserved alpha helices has resulted in the investigation of a number of approaches to mimicking alpha helices, including the use of substituted biphenyl and related poly-aryl scaffolds. Inhibition of nuclear receptor (NR) promoted gene transcription is of interest due to the role of NRs in promoting various human pathologies, including breast and prostate cancer. Because NR activity is in part mediated by the binding of coactivator proteins (CoA) through a short, conserved alpha helix, this NR-CoA interaction is an ideal system for evaluating alpha helix mimetics. Encouraged by recent success in the design of small molecules capable of disrupting NR-CoA interactions, and intrigued by the potential of substituted poly-aromatics as flexible mimics of alpha helices, our group has designed a bipolar biphenyl scaffold functionalized to mimic the key interactions that mediate NR-CoA binding. Chapter 1 introduces this and other relevant background information for this project.
Chapter 2 describes a small series of 3,3'-disubstituted derivatives of the bipolar biphenyl scaffold which were synthesized and subsequently evaluated as ERá and AR CBIs. This study was performed as an initial proof-of-concept to establish the capability of this scaffold, when substituted, to directly inhibit NR-CoA binding interactions.
In the interest of expanding the compound series, in terms of both the identity and the arrangement of substituents on the biphenyl scaffold, efficient synthetic methods were developed. Chapter 3 outlines this methodology with particular focus on the optimization of Suzuki chemistry which was used to couple the biphenyls. Additionally, the synthesis resulted in a 2nd generation compound series, including mono- (2; 2'), and di- (2,3'; 3,2'; 2,2') methylated and benzylated biphenyl derivatives which would be subject to further evaluation as NR-CBIs.
Chapter 4 describes the evaluation of the 2nd generation biphenyls. Biological assays were again used to assess the effectiveness of these compounds as NR CBIs. Additionally, spectral methods were also used to assess the properties of the biphenyls themselves. The characterization of the 2,2'-dibenzylated biphenyls by 1H NMR revealed spectral anomalies which eventually led to the distinction of intramolecular probes by which biaryl atropisomerization could be physically observed. Once distinguished, methods were developed to exploit these resonances to evaluate the favored configurations and rotational energy barriers of the biphenyls.
Future directions for the development of biphenyl scaffolds as alpha helix mimetics are presented in Chapter 5. This discussion introduces both fundamental and applied objectives for invoking regio- and/or enantio- specificity to the biphenyls.
A distinct area of work is introduced in Chapter 6. Palladium catalysis was applied to a conceptually unrelated problem, to facilitate the conversion of halogenated indoles to their radiohalogenated analogues. 5- and 6- halogenated indoles were separately stannylated and boronated via palladium catalysis. The resultant metalated derivatives were then subjected to site-specific radiolabeling via electrophilic aromatic halogenation. Particular facets of this work are discussed including the optimization of the palladium-catalyzed metalations and the apparent challenges of functionalizing 5- and 6- indoles.
Anna B. Williams
Williams, Anna B., "Synthesis & evaluation of bipolar biphenyl proteomimetics as nuclear receptor CBIs and applications of palladium chemistry to the development of radiotracers" (2011). Chemistry Dissertations. Paper 33. http://hdl.handle.net/2047/d20001221
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