Synthesis of Novel Amino Acids and 3(10)-And Alpha-Helical Alpha, Alpha-Disubstituted Amino Acid Rich Antimicrobial Peptides.

Date of Award

1998

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Mark L. McLaughlin

Abstract

Amphipathic peptides rich in $\alpha ,\alpha$-disubstituted amino acids ($\alpha\alpha$AAs) were synthesized and examined for antimicrobial activity and helix preference in various solvent systems. Also, a series of polar, $\alpha\alpha$AAs were synthesized for incorporation into helical peptides and a red-shifted tryptophan analog was synthesized as a fluorescent probe. A series of short, amphipathic, 3$\sb{10}$- and $\alpha$-helical peptides containing 50 to 80 percent $\alpha\alpha$AAs was synthesized. Various combinations of 1-aminocyclohexane-1-carboxylic acid, $\alpha$-aminoisobutyric acid, and 4-aminopiperidine-4-carboxylic acid were incorporated using preformed acid fluorides. In vitro testing revealed that most of these peptides show direct antibacterial activity against E. coli and S. aureus while none exhibited direct activity against B. abortus. However, many of the peptides significantly reduced B. abortus loads in chronically infected BALB/c mice. A series of orthogonally protected, polar, $\alpha\alpha$AAs was synthesized. A variety of amines were introduced onto 1,4-cyclohexanedione monoethylene ketal via reductive amination. Ketal removal and amino protection with tert-butyloxycarbonyl was followed by hydantoin formation via a Bucherer-Bergs reaction. The hydantoin was activated and then hydrolyzed using mild base and the resulting $\alpha$-amino was protected with 9-fluorenylmethyloxycarbonyl to yield the desired amino acid. An amphipathic $\alpha$-helical peptide, an amphipathic 3$\sb{10}$-helical peptide, and an amphipathic 3$\sb{10}$-helical peptide containing two salt-bridges were studied for their helix preference via circular dichroism in organic and aqueous-organic solvent mixtures. The $\alpha$-helical peptide displayed the designed structure in all solvents studied. Both 3$\sb{10}$-helical peptides exhibited a transition from a 3$\sb{10}$-helix to an $\alpha$-helix as the percent water is increased. $N\sp{\alpha}$-Boc-benz (f) tryptophan, a red-shifted tryptophan analog, was synthesized in seven steps from 3-bromo-2-aminonaphthalene. Alkylation of the starting material, anionic cyclization, hydantoin formation, hydantoin activation, indoline deprotection, and dehydrogenation yielded the activated hydantoin of benz (f) tryptophan. Mild hydrolysis of the hydantoin gave the tert-butyloxycarbonyl protected amino acid. The work presented focuses on synthesis of helical peptides for antimicrobial and structural studies and amino acids for the synthesis and characterization of these peptides.

ISBN

9780591905069

Pages

202

DOI

10.31390/gradschool_disstheses.91

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