Synthesis & evaluation of bipolar biphenyl proteomimetics as nuclear receptor CBIs and applications of palladium chemistry to the development of radiotracers

• Online Access: http://hdl.handle.net/2047/d20001221

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.