| Type of Document |
Dissertation |
| Author |
Wakefield, Bryan
|
| Author's Email Address |
bhw4@pitt.edu |
| URN |
etd-07192008-221135 |
| Title |
Synthetic Studies on (E)-Alkene Peptide Isosteres and Thiophene-containing Furanosteroids |
| Degree |
Doctor of Philosophy |
| Program |
Chemistry |
| School |
School of Arts and Sciences |
| Advisory Committee |
| Advisor Name |
Title |
| Peter Wipf |
Committee Chair |
| John Lazo |
Committee Member |
| Paul Floreancig |
Committee Member |
| Scott Nelson |
Committee Member |
|
| Keywords |
- peptide isosteres
- thio-halenaquinone
- halenaquinone
|
| Date of Defense |
2008-07-01 |
| Availability |
unrestricted |
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 然 against Pfnek-1 and an analog that had an IC90 ~3 然. Based on these results we designed and synthesized a simplified analog that showed an IC90 ~4 然. 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.
|
| Files |
| Filename |
Size |
Approximate Download Time
(Hours:Minutes:Seconds)
|
| 28.8 Modem |
56K Modem |
ISDN (64 Kb) |
ISDN (128 Kb) |
Higher-speed Access |
| |
Wakefield_Bryan_PHD_7_2008.pdf |
6.31 Mb |
00:29:12 |
00:15:01 |
00:13:08 |
00:06:34 |
00:00:33 |
|
