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

by Wakefield, Bryan

Abstract (Summary)
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.
Bibliographical Information:

Advisor:John Lazo; Paul Floreancig; Peter Wipf; Scott Nelson

School:University of Pittsburgh

School Location:USA - Pennsylvania

Source Type:Master's Thesis



Date of Publication:11/05/2008

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