Development of Collagen Macrocycle Host Peptides and Solid-Phase Photochemistry / Michael Birch Elbaum.

Format:

Book

Thesis/Dissertation

Author/Creator:

Elbaum, Michael Birch, author.

Contributor:

University of Pennsylvania. Chemistry, degree granting institution.

Language:

English

Subjects (All):

Chemistry.

Organic chemistry.

Chemistry--Penn dissertations.

Penn dissertations--Chemistry.

Local Subjects:

Chemistry.

Organic chemistry.

Chemistry--Penn dissertations.

Penn dissertations--Chemistry.

Physical Description:

1 online resource (557 pages)

Contained In:

Dissertations Abstracts International 84-08B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.

Ann Arbor : ProQuest Dissertations & Theses, 2022

Language Note:

English

Summary:

Peptides are a critical class of therapeutics, as they occupy a chemical space between small molecules and large biologics and can modulate a vast array of biological processes. However, peptides lack the large domains and repeating structures required to maintain the structural stability of proteins, making them prone to conformational disorder. The most common strategies to reinforce the natural conformational bias of peptide sequences are covalent macrocyclization and non-natural amino acid substitution. Of the chemical transformations available for peptide cyclization and non-natural amino acid synthesis, those that form C(sp3)-C(sp3) bonds are highly sought after for enhanced permeability, as well as proteolytic and chemical stability. There are two objectives to this research. The first objective is to minimize the size and control the homogeneity of the collagen triple-helix tertiary structure through peptide cyclization and aza-Glycine substitution. This research includes developing a synthetic route to hetero-hairpin collagen macrocycles, optimization of their structure, developing a host/guest system, and miniaturization of that host guest/system. The interactions of these host/guest systems were confirmed by NMR, circular dichroism (CD) and size exclusion chromatography electron spray ionization (SEC-ESI) mass spectrometry. These results demonstrate the combined ability of peptide cyclization and non-natural amino acid substitution to stabilize collagen tertiary structure which could lead to a new class of therapeutics or chemical probes. The second objective is the adaptation of photochemical decarboxylative conjugate addition to solid-phase peptide methodology for the synthesis of C(sp3)-C(sp3) bonds. We used on-resin acrylamides with solution-phase N-(acyloxy)phthalimides (NHPI) radical precursors and quantitative NMR to identify several photosensitizers that lead to > 90 % reaction yields. Using electron donor-acceptor (EDA) complexes between Hantzsch ester and NHPI to generate a solution-phase radical led to full conversion within 30 min under ambient conditions and demonstrated compatibility with a broad scope of NHPI radical precursors, acrylamide peptide substrates, and resin. We go on to generate solid-phase alaninyl and homoalaninyl radicals from Asp and Glu side-chains utilizing the EDA complex to perform tandem photochemical reactions to synthesize hydrocarbon-stapled Atosiban and cyclo-RGDf. These results comprise the first solid-phase photochemical reactions on peptides and the first use of Asp and Glu as peptide radical precursors for making carbon-carbon bonds.

Notes:

Source: Dissertations Abstracts International, Volume: 84-08, Section: B.

Advisors: Chenoweth, David M.; Committee members: Molander, Gary A.; Petersson, E. James; Dmochowski, Ivan J.

Department: Chemistry.

Ph.D. University of Pennsylvania 2022.

Local Notes:

School code: 0175

ISBN:

9798374413083

Access Restriction:

Restricted for use by site license.

This item is not available from ProQuest Dissertations & Theses.