Peptide synthesis and characterization: Part 1. Synthesis and characterization of cyclic pseudopeptide analogs of endothelin antagonist BQ-123. Part 2. Comparative study of mild cleavage techniques for solid-phase synthesis of penta-, tetra-, and tri-peptides.

摘要

This dissertation describes the design and synthesis of cyclic pseudopeptide analogs of the endothelin receptor antagonist BQ-123. Four analogs were synthesized with the reduced amide isostere, psi[CH2NH], inserted into the cyclic peptide. Analog I was synthesized with the psi[CH 2NH] in the hydrogen bond donating position of the gamma turn. In Analog II, the reduced amide was placedin the hydrogen bond accepting position of the beta turn. Analog III included reduced amide isostere substitution away from the hydrogen bond in the beta turn. Analog IV replaced the amide in the hydrogen bond donating position of the beta turn.; Conformational studies were conducted using 1D and 2D NMR techniques. Analog I was capable of attaining a "loosely" held beta turn similar to that of the parent while Analog II was found to maintain a "loosely" held gamma turn similar to BQ-123. In Analog IV the presence of reverse turns could not be confirmed. Analog III could not be evaluated for reverse turns due to multiple conformations existing in solution. These results demonstrate that reverse turns can tolerate the substitution of the psi[CH2NH] isostere.; All four analogs were evaluated to determine effectiveness as an ETA receptor antagonist. Analog I was active as an endothelin antagonist. However, Analog I was less active than the parent compound BQ-123. Analogs II, III, and IV were not active as endothelin antagonists.; This dissertation also describes systematic comparison of traditional anhydrous HF, Phase Transfer Catalysis, and Ammonium Formate-Catalytic Transfer Hydrogenolysis for effectiveness of peptide removal. Acetylated tri-, tetra-, and pentapeptides were synthesized on identical chloromethylated polystyrene resin. Each peptide contained a 14C labeled alanine. The quantities of product from the cleavages were determined by the amount of radioactivity present using a scintillation counter.; In all cases the HF was the most effective. However, PTC results were consistent and produced acceptable yields. AF-CTH consistently produced significantly lower yields than HF and PTC. However, the percent of effectiveness, of AF-CTH greatly increased with the acetylated pentapeptide. The results presented in this work suggest that peptide length and hydrophobicity could influence the effectiveness of AF-CTH.