Design and syntheses of peptidomimetic building blocks and bioactive molecules

Somatostatin is one of the most important regulatory peptides in human metabolism. It has a broad range of bioactivity including inhibition of growth hormone, insulin and glucagon. The actions of somatostatin are mediated by specific membrane-bound receptors. In recent years, five somatostatin receptor subtypes (sst1-5) have been cloned from various species. They belong to the super family of G-protein coupled receptors. Development of subtype selective somatostatin analogs not only facilitates studies on the biological functions of individual somatostatin receptor subtypes, but also has important clinical applications.;In our laboratories, we employ an interdisciplinary approach to study somatostatin and its analogs. We design and synthesize novel peptidomimetic building blocks, templates, scaffolds and incorporate them into novel somatostatin structures. Biophysical study is then undertaken in our laboratories. At the same time, the biological assays are carried out in our collaborators' laboratories. Based on this information, we can establish the structure-activity relationships.;This dissertation focuses on the synthetic aspect of our interdisciplinary approach. Based on extensive studies of structure-activity relationships and the information obtained from modeling of somatostatin receptor-ligand complexes, a family of somatostatin analogs was designed and synthesized. The binding affinities of these compounds to sst1-5 confirmed our design rationale. To the best of our knowledge, one of these analogs is by far the most sst5-selective compound.;We also developed methods to synthesize peptidomimetics of cystine, namely the lanthionines, which have greater metabolic stability and a more constrained structure than the disulfide counterparts. We therefore incorporated these building blocks into two important bioactive molecules, an anti-tumor agent and a cell adhesion modulator.;In another area of our studies, we employed 1,4-benzodiazepine as the scaffold to develop nonpeptide somatostatin analogs. We anticipate the pharmacophores attached to benzodiazepines are able to reduce the flexibility of native peptide and maintain the proper side chain orientation required for somatostatin activity.;In an effort to study racemization during peptide synthesis, a protocol has been developed in our laboratories to measure intrinsic rates of racemization employing the separation and quantitative analysis of N-protected amino acids derivatives by chiral HPLC. In this dissertation, we will describe the evaluation of a new coupling reagent, 3-(diethoxyphosphoryloxy)-1,2,3-benzotrazin-4(3H)-one (DEPBT), using this protocol.