Wakefield, Bryan
(2008)
Synthetic Studies on (E)-Alkene Peptide Isosteres and Thiophene-containing Furanosteroids.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Peptide isosteres are important tools for the understanding of peptide function and for the development of drugs. (E)-Alkene peptide isosteres are particularly useful due to their close geometric match of the amide bond structure. We developed a method for the generation of a small library of (E)-alkene peptide isosteres on solid support via cuprate mediated SN2′ ring opening of allylic BUS-aziridines. We also studied the selectivity for the opening of these aziridines in the solution phase.Halenaquinone is a marine natural product that was first isolated in 1983 from the Pacific sponge Xestosongia exigua. We realized the synthesis of a thiophene-containing analog, thio-halenaquinone. The key steps include an alkynyl ketone-benzocylcobutane Diels-Alder reaction to construct the naphthalene subunit, a Heck cyclization to form the quaternary carbon, and a ring closing metathesis to install the final ring. This compound showed an IC90 ~5 µM against Pfnek-1 and an analog that had an IC90 ~3 µM. Based on these results we designed and synthesized a simplified analog that showed an IC90 ~4 µM. This compound was selected to move on to animal testing and the synthesis was optimized for the preparation of and 200 mg of the lead structure.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Wakefield, Bryan | bhw4@pitt.edu | BHW4 | |
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| ETD Committee: |
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| Date: |
5 November 2008 |
| Date Type: |
Completion |
| Defense Date: |
1 July 2008 |
| Approval Date: |
5 November 2008 |
| Submission Date: |
19 July 2008 |
| 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: |
halenaquinone; peptide isosteres; thio-halenaquinone |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-07192008-221135/, etd-07192008-221135 |
| Date Deposited: |
10 Nov 2011 19:52 |
| Last Modified: |
15 Nov 2016 13:46 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/8450 |
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