Date of Award

2000

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Mark L. McLaughlin

Abstract

A series of amphipathic peptides rich in alpha,alpha-disubstituted amino acids (alphaalphaAA's) was synthesized and studied for antimicrobial activity and helix preferences in various solvent systems. In addition, a constrained lactam dipeptide amino acid was synthesized and incorporated into a peptide to examine beta-sheet dimer formation. Several short, amphipathic, 310- and alpha-helical peptides containing 80% alphaalphaAA's were synthesized using various combinations of 1-aminocyclohexane-1-carboxylic acid, alpha-aminoisobutyric acid, and 4-aminopiperidine-4-carboxylic acid. The peptides showed direct antimicrobial activity against E. coli and S. aureus. In addition, several of the peptides showed in vivo and in vitro activity against Brucella abortus and Mycobacterium chelonei. Studies were done with a strain of B. abortus expressing a green fluorescent protein to show the peptides selectively destroyed infected macrophages. The series of amphipathic 310- and alpha-helical peptides were also studied, using circular dichroism spectroscopy, for their helix preference in organic and aqueous-organic solvent systems. The alpha-helical peptides showed the expected spectra in all solvents used. One designed 3 10-helical peptide exhibited a transition from a 310-helix to an alpha-helix as the water content was increased. The other designed 310-helical peptide exhibited a spectrum indicative of an alpha-helix in all solvents tested, presumably due to steric interactions of the amino acid side-chains. A constrained lactam dipeptide amino acid, 3-(R)-N '-[(9H-fluoren-9-ylmethoxy)carbonyl]-amino-1-[1-(S)-methylethyledianoic acid]-2-piperidinone, was synthesized from D-glutamic acid and incorporated into a peptide. The starting material was esterified with allyl alcohol and the alpha-nitrogen was doubly protected with Boc protecting groups. Selective DIBAL reduction of the side-chain ester yielded the semi-aldehyde. Reductive amination with valine followed by removal of the remaining allyl ester and intramolecular amide bond formation yielded the fully protected constrained lactam dipeptide amino acid. Treatment with TFA and introduction of the Fmoc protecting group resulted in the amino acid ready for peptide coupling. A peptide using the constrained amino acid was synthesized and studied for beta-sheet dimer formation.

ISBN

9780599990685

Pages

137

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