The synthesis of pyrrolinone-peptide hybrid MHC class II ligands, and an effective method for the synthesis of pyrrolinones bearing functionalized amino acid sidechains

The design of biologically active non-peptide peptidomimetics is an important goal, since many potentially therapeutic peptides display unfavorable pharmacokinetic properties. These properties, including rapid in vivo degradation, poor transport properties, and rapid excretion, have mostly prevented the use of peptides as medicinal agents. Research in the Smith/Hirschmann group toward the development of non-peptide peptidomimetics has resulted in the design and synthesis of β-strand mimics based on the 3,5,5-pyrrolin-4-one scaffold.* This thesis focuses on expanding the utility of the pyrrolinone scaffold through several projects. Thus, chapter 2 describes the successful design and synthesis of two pyrrolinone-peptide hybrid ligands for the non-enzymatic MHC class II HLA-DR1 protein. One of these hybrid ligands (90) was found to bind to the MHC class II protein with similar affinity as both a native peptide and a control peptide. This result, combined with earlier studies involving pyrrolinone-based inhibitors of renin and HIV-1 protease, indicates that the pyrrolinone scaffold can be used to construct high affinity ligands for a variety of protein targets.* Chapter 3 of this thesis focuses on the problem of incorporating functionalized amino acid sidechains onto the pyrrolinone scaffold. To this end, a unified strategy based on the asymmetric alkylation of a ‘common’ oxazolidinone (160) was developed. This tactic was used to construct pyrrolinones bearing sidechains corresponding to tyrosine, serine, lysine, and tryptophan. Additionally, methods to incorporate other amino acid sidechains (excluding glycine and proline) have been proposed. These methods will significantly enhance the utility of the pyrrolinone scaffold by providing access to a wide variety of pyrrolinone-based compounds.* Chapter 4 of this thesis describes studies directed toward the synthesis of a prospective pyrrolinone-based somatostatin mimic embodying a turned backbone conformation (222). This compound employs a series of pyrrolinones bearing sidechains with alternating D and L stereochemistry; molecular modeling predicts close correspondence with the known structure of the Merck peptidal somatostatin mimic L-363,301. Successful completion of this project will provide important insights into backbone conformations available to the pyrrolinone scaffold.* *Please refer to dissertation for diagrams