The design and synthesis of peptidomimetics of pharmacological interest

This dissertation focuses on the design and synthesis of conformationally constrained peptidomimetics and their incorporation in the synthesis of bioactive molecules.; In an effort to study the role of conformations in binding selectivity, we introduce a rigid {dollar}beta{dollar}-turn peptidomimetic template into an RGD containing peptide. The template is intended to limit the conformational flexibility of the intervening peptide sequence and to replace stable peptide secondary structures with organic surrogates. This peptidomimetic exhibits selective binding to the {dollar}rmalphasb{lcub}v{rcub}betasb3{dollar} receptor which has been recognized as a potentially important pharmaceutical target involved in neovascularization and in angiogenesis.; We describe the synthesis of peptidomimetic analogs of the immunosupressant FK506. These peptidomimetics were developed around the {dollar}alpha{dollar}-keto homoprolyl amide moiety, as this element appears to be a critical binding determinant. We anticipated that this group would serve as an anchor point to an attached peptide mimicking the region of FK506 that is involved in the receptor recognition. These peptidomimetics of FK506 exhibit weak binding to FKPB.; In another research area, we examine analogs of somatostatin related to the cyclic hexapeptide, c(Pro-Phe-D-Trp-Lys-Thr-Phe). We present a novel approach utilizing {dollar}beta{dollar}-methyl chiral substitutions to constrain the peptoid side chain conformation and to restrict the overall conformations of the somatostatin analogs. In an in vivo study, these peptoid somatostatin analogs selectively inhibit the release of growth hormone but have no effect on the inhibition of insulin.; A novel route to the development of nonpeptide peptidomimetics involves the design of new scaffolds, with the retention of peptide-like side chains. A highly constrained tricyclic molecule has been synthesized to mimic a {dollar}beta{dollar}-turn, a secondary structural feature found in many bioactive peptides and proteins. This scaffold for pharmacophoric arrays can replace the more flexible backbone found in naturally-occurring biomolecules while maintaining the proper side chain orientation required for bioactivity.; Our design and synthesis of peptidomimetics and nonpeptide structures have led to new building blocks, efficient synthetic methods, and important structure-activity relationships. From such studies it will be possible to obtain new bioactive molecules.