Synthesis of Novel Amino Acids and 310- And Alpha-Helical Alpha, Alpha-Disubstituted Amino Acid Rich Antimicrobial Peptides
Date of Award
Amphipathic peptides rich in α, α-disubstituted amino acids (ααAAs) were synthesized and examined for antimicrobial activity and helix preference in various solvent systems. Also, a series of polar, ααAAs were synthesized for incorporation into helical peptides and a red-shifted tryptophan analog was synthesized as a fluorescent probe.
A series of short, amphipathic, 310- and α-helical peptides containing 50 to 80 percent ααAAs was synthesized. Various combinations of 1-aminocyclohexane-lcarboxylic acid, α-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, ααAAs 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 α-amino was protected with 9-fluorenylmethyloxycarbonyl to yield the desired amino acid.
An amphipathic a-helical peptide, an amphipathic 310-helical peptide, and an amphipathic 3io-helical peptide containing two salt-bridges were studied for their helix preference via circular dichroism in organic and aqueous-organic solvent mixtures. The a-helical peptide displayed the designed structure in all solvents studied. Both 310-helical peptides exhibited a transition from a 310-helix to an α-helix as the percent water is increased.
N^α -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.
Yokum, Thomas Scott, "Synthesis of Novel Amino Acids and 310- And Alpha-Helical Alpha, Alpha-Disubstituted Amino Acid Rich Antimicrobial Peptides" (1998). LSU Historical Dissertations and Theses. 8385.