I. Studies Towards the Synthesis of Manassantins A and B and Analogues II. Efforts Towards a FRET-Based Assay to Characterize Palmitoylation of Src Kinases III. Synthesis of Oxepanes via Organocatalytic Oxa-Michael Reactions

Abstract

This dissertation focuses on three main projects that include aspects of natural product synthesis, synthetic methodology, as well as the development of a small molecular probe for the study of protein palmitoylation. This first project introduces studies towards the synthesis of manassantins A and B which are potent inhibitors of hypoxia-inducible factor 1 (HIF-1). In addition, the preparation of manassantin A analogues is described along with preliminary structure-activity relationship (SAR) studies providing further insight into the structural requirements for HIF-1 inhibitory activity. The second project describes efforts towards the development of a fluorescence resonance energy transfer (FRET)-based assay system to characterize the palmitoylation of oncogenic Src family kinases. The initial work on this project involves the synthesis of a modified lipopeptide mimicking the critical N-terminus sequence of Src signaling proteins required for activation. Lastly, the third project focuses on the development of an asymmetric organocatalytic method to synthesize 2,7-cis- and 2,7-trans oxepanes as well as its application to the preparation of a simple cyclic ether. Ultimately, the goal of this work would be to extend this methodology to the preparation of complex, biologically active cyclic ethers.