Synthesis, properties, and applications of: Modified peptide nucleic acids,p53 rescue using small molecules, and biomimetic acyl anion additions

The focus of this body of work is concentrated in three synthetic and bioorganic areas. These include: modified peptide nucleic acids, p53 rescue using small molecules, and biomimetic acyl anion additions. The theme of this thesis is in the development of new synthetic methodology. The first chapter will compromise the development and synthesis of modified peptide nucleic acids (PNAs). Cyclic PNAs have been synthesized as single enantiomers and incorporated into oligomers using solid phase techniques. The modifications presented within this chapter also incorporate acyclic constraints that we have termed polyamine nucleic acids (PANAs). The contributions of this work have added a much needed general PNA constraint for significant binding affinity improvements leading to enhancements in current DNA detection applications. The second chapter focuses on creating a focused library of small molecules that mimic the p53 rescue properties of a small molecule named PRIMA-1. Synthesis and SAR studies, on the molecules we developed, indicate increased potency compared to PRIMA-1. The highly collaborative nature of this project, across three institutions, has been invaluable toward learning about the synthetic and biological properties of the active molecules and their implications in apoptotic processes. The third chapter focuses on the development of new biomimetic methodology utilizing the chemistry that thiamin diphosphate (ThDP) dependent enzymes employ. The first non-enzymatic use of α-keto carboxylates in buffered aqueous conditions has been accomplished for generating reactive acyl anion equivalents over a broad pH range. N-Heterocyclic carbenes (NHCs) are employed catalytically in this new process and an investigation of the mechanism is discussed. The products of this methodology are useful substrates toward pharmaceutical and material based applications and three collaborations illustrate their importance toward preparing furans and pyrroles. The synthetic chemistry and methodology presented within this body of work will highlight both the fundamental research and application based elements that have been the goals throughout my thesis.