The Theoretical Modeling, Design, and Synthesis of Key Structural Units for Novel Molecular Clamps and Pro-Apoptotic Alpha Helix Peptidomimetics

This dissertation presents the theory and practice of designing, synthesizing and using peptidomimetics to disrupt protein-protein interactions. Our general strategy is to design and synthesize peptidomimetics that will mimic peptide secondary structures (alpha-helices and beta-sheets). Chapter One is a theoretical examination of the feasibility of using beta-sheet mimics called molecular clamps to inhibit substrate-receptor interactions by blocking the substrate rather than the receptor or enzyme. Several natural and synthetic examples of this approach are given in support of this concept. We also present the results of a kinetic modeling study and a consideration of which types of systems would be the best candidates for a substrate-targeted inhibitor approach. Chapter Two relates a continuation of previous work in our lab to synthesize five novel beta-protected hydrazino amino acids. These hydrazines are essential precursors for synthesizing constrained beta-strand mimetics. We showed that we could selectively deprotect the alpha-nitrogen of the hydrazines, and we synthesized several novel examples of polar beta-protected hydrazino amino acids. Chapter Three discusses the design and synthesis of small-molecule and peptidomimetic MDM2 inhibitors, including our work on synthesizing a new class of alpha-helix mimics that have improved water solubility compared with previously reported examples of alpha-helix mimics. As with the constrained beta-strand mimics described in Chapter Two, the synthesis of novel hydrazino amino acid precursors is a key step in synthesizing our alpha-helix mimics. One isoleucine hydrazine derivative was synthesized, and progress was made toward synthesizing two other hydrazines from tryptophan. In addition, the synthesis of three potential small-molecule inhibitors of MDM2 is described. Chapter Four describes the use of the GLIDE program to design and evolve an alpha-helix mimic that will interact with the pro-apoptotic protein Bax. Progress toward the synthesis of this compound is also reported