The design and synthesis of conformationally restricted and epoxide-based peptidomimetics
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
This thesis presents research into the design and synthesis of conformationally restricted and epoxide-based peptidomimetics. The introduction reviews the general topic of peptidomimetics, agents that either imitate or block the action of a peptide at the receptor level. The development of peptidomimetics is discussed and different types of peptidomimetics are surveyed. Chapter 1 presents the design and synthesis of conformationally restricted cis peptide bond mimics. The convenient preparation of dipeptide surrogates which contain a 1,2-pyrrole moiety, designed to mimic the cis peptide bond, is reported. Protection of the amino terminus, and chain extension, by coupling of an amino acid residue at the carboxyl terminus, are demonstrated. Chapter 2 presents the design, synthesis, and in vitro testing of a series of epoxide-based peptidomimetics, designed as inhibitors of the HIV Protease (HIV PR). Included are a series of pseudosymmetrical epoxides, designed to capitalise on the unique symmetry of the HIV PR. Unfortunately, these compounds were found to be inactive. However, a further series of epoxide-based compounds, inspired by the known inhibitor of the HIV PR, 1,2-epoxy-3-(p-nitrophenoxy)propane, displayed good inhibitory activity. Chapter 3 presents an investigation of the "Horner-Wadsworth-Emmons" (HWE) reaction, an extension of a synthesis presented in Chapter 2. The effect of the aldehyde reactant and of the phosphonate reagent on the stereochemical outcome of the HWE reaction is examined. The nature of the aldehyde substituent was found to influence the stereochemistry of the product. For example, conjugated aldehydes were found to favour the formation of the E olefin, while alpha-branched aldehydes favoured the Z olefin. Further, the nature of the phosphoryl ester was shown to have a significant influence on the stereochemistry of the product. Large alkyl groups were found to favour the formation of the E olefin, while electron withdrawing substituents strongly favoured the formation of the Z olefin.