Ammonia Thio-alpha-oxy Acids And Polar Side Chains Of ¦Á-the Ammonia Oxy Acid Oligomer Synthesis, Conformation And Its Preliminary Application

Peptidomimetics are molecules that mimic the functions of peptides and proteins but have better biostability and bioavailability than natural peptides and proteins. As a new class of peptidomimetic foldamers, a-aminoxy acids and their oligomers display a series of novel, well-defined secondary structures such as turns, sheets and helices. In this thesis, syntheses and conformational features of several new members of aminoxy peptide family have been described. The main results are summarized below:By substituting the oxygen atom of carbonyl group with sulfur atom in regular amides and/or aminoxy amides, we have developed two new types of building blocks for peptidomimetics. The change of regular amide to thioamide led to N(C=S)-O turn formation based on an NHi+2…O=Ci intramolecular eight-membered-ring hydrogen bond, with the side chain anti to the N-O bond. When sulfur atom was introduced into aminoxy amide, the thioimidic acid was found to be the predominant tautomeric form. The auto-oxidation of thioimidic acid resulted in disulfide-bridged dimers, which are C2 symmetric and adopt a loop conformation induced by disulfide bond and an NHi+1…O-Ni intramolecular hydrogen bond.Conformational studies ofα-aminoxy peptides with functionalized side chains were carried out in both non-polar and protic solvents such as methanol and aqueous solutions. 1H NMR, X-ray and FT-IR spectroscopic studies confirmed the presence of the eight-membered-ring intramolecular hydrogen bonds (the N-O turns) in non-polar solvents as well as in methanol. CD studies indicated that a substantial degree of helical content was retained in methanol and acidic aqueous buffers. The introduction of functionalized side chains inα-aminoxy peptides provides opportunities for designing biologically active peptides.Helix D of the large extracellular loop of CD81 is important to the entry of hepatitis C virus (HCV). Since peptides ofα-aminoxy acids and of alternating L-α-amino acids and D-α-aminoxy acids can adopt the 1.88 helix and 7/8 helix respectively, we have designed and synthesized these two kinds of aminoxy oligomers to mimic the structure of Helix D with a long-term goal of developing HCV entry inhibitors.