Date of Award

2001

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Robert P. Hammer

Abstract

Peptides and peptide analogs are central to the understanding of biological and biochemical phenomena as well as in the development of new pharmaceutical agents. This research encompasses two classes of peptide mimetics: phosphonopeptides and short, amphipathic peptides rich in alpha,alpha-disubstituted amino acids (alphaalphaAA). The focus of the first part of the peptide analog project was on the preparation of sterically-hindered phosphonamide and thiophosphonamide dipeptides. Conditions were developed, based on our P(III) synthetic approach, for the preparation of the phosphonamide dipeptides, Cbz-CyhGly psi [P (O) (OpNb) NH] Trp-NH2 and Cbz-CyhGly psi [P (O) (OpNb) NH] Trp-OMe, which were previously unattainable by P(V) methods. The use of reduced phosphorus intermediates also allowed preparation of the related thiophosphonamides, Cbz-CyhGly psi [P (S) (OpNb) NH] Trp-NH2 and Cbz-CyhGly psi [P (S) (O pNb) NH] TrpOMe. With the P(III) synthetic strategy we started from an amine-protected H-phosphinate amino acid ester and activated, in the presence of 2 equivalents of pyridine, with dichlorotriphenylphosphorane to generate a phosphonochloridite, which was treated with a diisopropylethylamine to form a proposed, very reactive, oxazaphospholine. The oxazaphospholine was coupled to an amine nucleophile followed by oxidation or sulfurization. This method was also used to prepare several simpler phosphonamide and thiophosphonamide dipeptides and thiophosphonates. In the second part of this project a homologous series of 9-mer, alphaalphaAA-rich peptides (and their acetylated versions), which were designed to be amphipathic and 310-helical, were prepared using solid-phase synthetic techniques. The peptides were composed of 78% alphaalphaAAs (one 4-aminopiperidine-4-carboxylic acid (Api) and six aminoisobutyric acid (Aib)). The in situ coupling agent, PyAOP, was used in the synthesis. The use of Fmoc-Aib-Aib-OH in the syntheses caused a significant improvement in the coupling and overall yields of the peptides. However, the monomer Aib had to be incorporated, along with double coupling, for the first two Aibs in each peptide's sequence. The helix preference of each peptide in different solvent environments were investigated as well as each peptide's antimicrobial activity and cytotoxicity. Significant populations of both alpha- and 310-helices were observed for the non-acetylated peptides under the solvent conditions tested. The 3 10-helical, amphipathic design was observed best for the acetylated peptides. Most of the peptides exhibited modest activity against E. coli and no activity against S. aureus. The non-acetylated peptides (concentrations ≤100 muM) and the acetylated peptides (concentrations ≤200 muM) did not exhibit, based on a trypan blue stain procedure, any significant cytotoxicity to normal macrophages.

ISBN

9780493272887

Pages

143

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