Introducing diversity into 12-helical beta-peptides: Toward biologically active foldamers

The design and characterization of unnatural foldamers, oligomers that adopt specific secondary structures in solution, has emerged as an exciting new sub-field of physical organic chemistry. Several potential applications provide impetus for the discovery and characterization of novel oligomers that mimic the sequence-specific folding and organization of natural biopolymers, such as proteins, in solution. Stable secondary structures composed of non-natural monomers would allow the rational design of a new class of pharmaceuticals, capable of interacting with large binding surface areas to disrupt deleterious biomolecular interactions. In a complementary application, efforts directed towards the design of biomimetic polymers will test our understanding of the forces responsible for secondary and tertiary structures found in natural biopolymers. Finally, foldamers should provide novel substrates for study by the materials science community.; The most thoroughly investigated foldamers to date are oligomers of beta-amino acids, or beta-peptides. Short beta-peptides have been shown to adopt all regular secondary structure types displayed by alpha-peptides (i.e. turns, sheets, and helices). In addition, beta-peptides have been shown to display biological activity. That beta-peptides can adopt discrete secondary structures with as few as six residues in aqueous solution and the unnatural backbone is resistant to proteases suggests that beta-peptides might be useful as medicinal agents.; Medicinal applications of beta-peptides require site-specific introduction of diverse functionality along the beta-peptide backbone. This Thesis reports the results of initial investigations into strategies to introduce such diverse functionality into the 12-helix, one helical conformation displayed by beta-peptides. After a brief review of beta-peptides, Chapter Two describes an optimized synthesis of the ACPC residue, which facilitates further studies of 12-helical beta-peptides. Chapter Three demonstrates one method of introducing diversity into 12-helical beta-peptides. This strategy involves incorporation of acyclic beta3-homoamino acid residues into oligomers that adopt 12-helical conformations. Chapter Three also includes the results of antimicrobial studies of a beta-peptide that incorporates hydrophobic functionality via acyclic beta3-homoleucine residues while maintaining a 12-helical conformation in aqueous solution. Finally, Chapter Four applies the strategy developed in Chapter Three to investigate the aggregation properties of amphiphilic 12-helical beta-peptides in which hydrophobicity is introduced via acyclic beta3-homoleucine residues.