Chemically-modified peptide nucleic acids: A versatile approach to complex molecular scaffolding and control of nucleic acid secondary architecture

This dissertation covers the synthesis and study of peptide nucleic acids (PNAs), specifically, derivatives of PNA containing amine-bearing sidechains or cyclopentane portions. PNAs are non-natural nucleic acids that have far reaching potential in therapeutics and nucleic acid detection. Despite immense potential and widespread application, improving on the design and applications of PNA are areas of heavy research. This dissertation describes the successful synthesis of several PNA derivatives that show very promising binding properties while giving us unprecedented control of oligomer characteristics, both as scaffolds for complex molecular display and control of secondary structure.; The first chapter contains the necessary background into nucleic acids and their applications. The development of non-natural nucleic acids, specifically PNA, is described. The chapter also examines the precedent and logic used in the design of the PNA derivatives and experimental approach.; The second chapter pertains to the development of a chiral PNA derivative based on amine-containing "sidechains". The utility of this modification is that further functionality can be appended to each sidechain residue. As these sidechains are amenable to conjugation through amide bond-forming reactions during oligomer synthesis, very few starting PNA monomers need to be synthesized to achieve a wide variety of derivatized PNA residues. Our subsequent studies on the stability of this sidechain PNA demonstrated that the molecular recognition properties (affinity, selectivity) were enhanced for both DNA and RNA. Furthermore, we showed initial evidence that this modification strategy can be useful when designing light-up molecular probes, molecules that fluoresce only when bound to a target nucleic acid.; The third chapter explores a cyclic derivative of PNA in the context of non-Watson-Crick hydrogen bonding motifs. Despite the interest in non-standard PNA secondary structure, very few studies have focused on the effects that cyclic PNA or tethering can produce in non-duplex secondary structure. We discovered significant control over binding affinity and stoichiometry is possible through several entropy-reducing methods.; In the fourth and final chapter, I briefly summarize the dissertation and discuss future avenues of research in this area.