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Synthesis and Application of Functionalized Bis-Peptides Through Hindered Amide Bond Formation

Brown, Zachary Z (2011) Synthesis and Application of Functionalized Bis-Peptides Through Hindered Amide Bond Formation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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Status: Unpublished
CreatorsEmailPitt UsernameORCID
Brown, Zachary
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee CoChairSchafmeister,
Committee CoChairFloreancig, Paulflorean@pitt.eduFLOREAN
Committee MemberWaldeck, Davedave@pitt.eduDAVE
Committee MemberChapman, Tobytchapman@pitt.eduTCHAPMAN
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:, etd-10272010-171526
Date Deposited: 10 Nov 2011 20:03
Last Modified: 15 Nov 2016 13:50


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