Brown, Zachary Z
(2011)
Synthesis and Application of Functionalized Bis-Peptides Through Hindered Amide Bond Formation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
This work presents significant advances towards installing chemical functionality within bis-peptide scaffolds, an important milestone towards designer, functional macromolecules for our group. First was the discovery of acyl-transfer coupling, a new synthetic route to assemble extremely hindered peptide bonds which were not previously accessible through conventional means. A novel amino-anhydride intermediate and five-membered ring acyl-transfer mechanism is postulated and multiple supporting pieces of evidence are presented. Applying this chemistry to the bis-amino acid building blocks developed in our group, the first functionalized bis-peptides were created which are oligomeric, diketopiperazine-based peptidomimetics. The first application for this new class of macromolecules was to mimic the bound conformation of the p53 ƒÑ-helical domain to its binding partner hDM2. Further structure and function optimization and characterization of the compound¡¦s biological effects showed these bis-peptides to be potent inhibitors of this protein-protein interaction, be cell-permeable and elicit a surprising biological response with human liver cancer cells.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
30 January 2011 |
| Date Type: |
Completion |
| Defense Date: |
25 October 2010 |
| Approval Date: |
30 January 2011 |
| Submission Date: |
27 October 2010 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Amide Bond Formation; Bis-Peptides; Peptide Chemistry; Peptidomimietics |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-10272010-171526/, etd-10272010-171526 |
| Date Deposited: |
10 Nov 2011 20:03 |
| Last Modified: |
15 Nov 2016 13:50 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9524 |
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