Dissertation/Thesis Abstract

Determining Conformational Preferences of Shape-Persistent Aromatic Oligoamides and Folding of Aromatic Oligoureas with Ion-Pair Associations
by Connor, Alan Lee, Ph.D., State University of New York at Buffalo, 2019, 391; 13426856
Abstract (Summary)

The synthesis and characterization of folding aromatic oligoamides with reduced constraint, ion-pair associations and solvent-mediated folding of aromatic oligoureas, and oligoamides with unique conformational variations involving simple structural inversion are presented in this thesis.

Chapter 1 is a review of the foldamer field defining structural features of peptides that are desired for replication by artificial building blocks. Foldamers are characterized as either peptidomimetic or abiotic based on intrinsic properties of the building blocks utilized. Each section of peptidomimetic and abiotic foldamers demonstrates the systematic design and characterization utilized for each system, including highlights of progressive developments within the field. This leads into the early development of helical aromatic oligoamides, developed by Gong and coworkers, incorporating rotation restricting three-center hydrogen bonds imbedded in the backbone. Overall, providing the relationship between our helical aromatic oligoamides and their place in the foldamer field.

Chapter 2 presents modifications in the design of robust aromatic oligoamides to incorporate reduced hydrogen bonding constraint within the backbone. This increased flexibility was to improve protein-like folding behavior for these previously robust oligoamides. Flexibility was designed by removing aromatic side chains adjacent to the benzene residues allowing only 5-membered ring (two-center) hydrogen bonding to remain. Two variations of oligoamides were synthesized involving alternating constraint consisting of interchanging three- and two-center hydrogen bonding along the aromatic backbone, and reduced constraint with only 2-center hydrogen bonding. Folding potentials are presented utilizing a combination of circular dichroism, 1D/ 2D NMR experiments, thermal denaturation and titration experiments in varying solvent conditions.

Chapter 3 begins with an overview of past aromatic oligourea design and cationic recognition of uncyclized and cyclized aromatic tetraureas. Anionic recognition of halides with ureas observed in literature was confirmed by concentration-dependent 1H-NMR experiments for aromatic urea dimers, similar in structure to elongated oligourea sequences. Anions were also observed to associate with oligourea trimers with similar affinities compared to their iv tetraethylammonium salt counterions, not previously observed for the dimers. Cation binding within the cavity of these trimers was confirmed by 2D NMR experiments. Correlations between 2D NMR spectra and results from concentration-dependent 1H-NMR experiments led to the conclusion of positive cooperative association between anion and cation pairs with oligourea trimer hosts. The conformational preference of longer aromatic oligoureas, incorporating fivemembered hydrogen bonding constraining the urea-linkage, was determined to favor a trans-trans conformation based on urea-linkage bond rotations that were computationally derived in collaboration with Professor Eva Zurek and Daniel Miller. Longer oligoureas were confirmed to also to bind tetraethyl- and tetrabutylammonium cations by 2D NMR experiments. Folding and chain-length dependence of these longer oligoureas were characterized by circular dichroism and 1H-NMR, confirming solvent-dependent folding and aggregation. Finally an aromatic oligourea 9mer was confirmed to favor a helical structure stabilized by dimethylformamide.

Chapter 4 presents two aromatic oligoamides with a simple inversion between their αβ and βα-amino acid spacers which caused the individual conformational identity to differ dramatically, preventing these complementary strands to associate. A qualitative examination compared differences in structural properties by 1H-NMR concentration-dependent, titrationdependent and temperature-dependent experiments. It was concluded that the oligoamide involving the αβ spacer preferred to fold upon itself, generating a stable β-turn which was confirmed by 2D NMR. The oligoamide incorporating a βα spacer self-dimerized with significant conformational interconversion, requiring the oligoamide to be examined at cryogenic temperatures to derive a specific conformation. In collaboration with Professor Eva Zurek and Daniel Miller, conformations derived from NOEs observed by 2D NMR experiments were examined computationally. A favored model paired with atomic distances calculated from optimized NOEs concluded the refinement of a specific conformation regarding this oligoamide.

Indexing (document details)
Advisor: Gong, Bing
Commitee: Benedict, Jason, Rezayev, Javid, Velarde, Luis
School: State University of New York at Buffalo
Department: Chemistry
School Location: United States -- New York
Source: DAI-B 80/07(E), Dissertation Abstracts International
Subjects: Chemistry
Keywords: Duplex, Foldamer, Helical, Oligoamide, Oligourea
Publication Number: 13426856
ISBN: 9780438945074
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