Title: Exploring an Interface Between Synthetic Chemistry and Chemical Biology
Description: PART I Controllable Synthesis of Complex Members of the Resveratrol Oligomer Family Chapter 1. Synthesis and Biological Evaluation of Resveratrol Family Oligomeric Natural Products This introductory chapter traces the history of resveratrol, highlighting the substantial interest in elucidating its potential pharmacological benefits and the ensuing impact on the synthetic community. A plethora of research groups have sought to investigate strategies towards accessing higher order oligomers within the resveratrol family, and these approaches provide context for our own endeavors. Chapter 2. Uniquely Functionalized Resveratrol Dimers: Total Syntheses of Hopeanol and Hopeahainol A In this chapter, we expand upon the utility of a divergent strategy, which has enabled the synthesis of multiple oligomeric, resveratrol-based natural products from a common intermediate. We demonstrate applicability to two exceptional dimeric natural products of the resveratrol family, further developing the truly robust nature of this particular synthetic approach.

Chapter 3. Harnessing Redox Reactivity: The Total Synthesis of (±)-Vaticanol A In the final installment of this section, we incorporate distinct methodology into the established chemical toolkit for accessing resveratrol oligomers. Targeting a formidable trimeric resveratrol-based natural product, this work takes advantage of several key insights generated from previous endeavors, particularly selective functionalization techniques. PART II Unexploited Paradigms for Chemical Probe Design, Focusing on Cancer Biology Chapter 1. Introduction to the Drug Discovery Landscape The introduction to Part II presents current approaches to the development of small molecule therapeutics and chemical probes, while concurrently obviating their limitations and the necessity to embrace underappreciated paradigms. Such endeavors could be capable of providing access to many elusive molecular targets. Chapter 2. Small Molecule Inhibitors of GPX4: Attempts at Targeted Covalent Inhibition This chapter discusses a recently validated protein target and our efforts to establish a platform for the development of highly selective, irreversible inhibitors.

A unique mechanism of enzymatic activity informs a novel approach towards evaluating the capacity to target specific amino acid residues. Chapter 3. In Silico Design of Protein-Protein Interaction Inhibitors Targeted at the RAS Family of GTPases The final chapter embraces in silico inhibitor design as a strategy towards effectively modulating one of the most challenging protein targets of contemporary drug discovery efforts. As a caveat to traditional in silico approaches, this work sought to validate a multivalent ligand approach towards abrogating key protein-protein interactions.