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Synthetic Studies on (E)-Alkene Peptide Isosteres and Thiophene-containing Furanosteroids

Wakefield, Bryan (2008) Synthetic Studies on (E)-Alkene Peptide Isosteres and Thiophene-containing Furanosteroids. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Wakefield, Bryanbhw4@pitt.eduBHW4
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWipf, Peterpwipf@pitt.eduPWIPF
Committee MemberLazo, Johnlazo@pitt.eduLAZO
Committee MemberFloreancig, Paulflorean@pitt.eduFLOREAN
Committee MemberNelson, Scottsgnelson@pitt.eduSGNELSON
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:, etd-07192008-221135
Date Deposited: 10 Nov 2011 19:52
Last Modified: 15 Nov 2016 13:46


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