Title page for ETD etd-0428103-180827

Document Type thesis

Author Name Nowak, Cheryl L

URN etd-0428103-180827

Title Design, Synthesis, and Evaluation of Bicyclic Peptides as Ammonium Ionophores

Degree MS

Department Chemistry & Biochemistry

Advisors
Dr. W. Grant McGimpsey, Advisor
Dr. James P. Dittami, Department Head

Keywords
solution 13C-NMR study
solid phase peptide synthesis
bicyclic peptides
ammonium ionophores
valinomycin
ion selective electrode

Date of Presentation/Defense 2003-04-30

Availability unrestricted

Abstract
A series of bicyclic peptides have been designed and synthesized to provide ammonium ion complexation sites via hydrogen bonding in a tetrahedral geometry. Molecular modeling dynamics and electrostatics studies indicate that target compounds 1d-6d may provide better selectivity for ammonium ions over potassium ions than the ammonium ionophore currently used for blood analysis applications, nonactin. Attempts to synthesize 1d, cyclo(L-Glu¹—D-Val²—L-Ala³—D-Lys⁴—D-Val⁵—L-Val⁶)-cyclo-(1ã-4å), were unsuccessful due to poor solubility of the synthetic intermediates. This led to the design of 2d-6d in which specific amino acid residues were chosen to provide higher solubility. Compound 2d, cyclo(L-Glu¹—D-Ala²—D-Ala³—L-Lys⁴—D-Ala⁵—L-Ala⁶)-cyclo-(1ã-4å), was successfully synthesized, but was also too insoluble for characterization or testing in an ion selective electrode (ISE) sensor format. Compound 6d, cyclo(L-Glu¹—D-Leu²—Aib³—L-Lys⁴—D-Leu⁵—D-Ala⁶)-cyclo-(1ã-4å), was successfully synthesized and characterized. When 6d was incorporated into an ISE sensor and tested as an ammonium ionophore, results indicated that the bicyclic peptide lacked solubility in the ISE membrane. A ¹³C-NMR study has been initiated in order to evaluate selectivity of 6d for ammonium over potassium and sodium cations in solution. Preliminary results with the potassium ionophore valinomycin as a control have been completed.

Files
cnowak.pdf

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Document Type	thesis
Author Name	Nowak, Cheryl L
URN	etd-0428103-180827
Title	Design, Synthesis, and Evaluation of Bicyclic Peptides as Ammonium Ionophores
Degree	MS
Department	Chemistry & Biochemistry
Advisors	Dr. W. Grant McGimpsey, Advisor Dr. James P. Dittami, Department Head
Keywords	solution 13C-NMR study solid phase peptide synthesis bicyclic peptides ammonium ionophores valinomycin ion selective electrode
Date of Presentation/Defense	2003-04-30
Availability	unrestricted
Abstract A series of bicyclic peptides have been designed and synthesized to provide ammonium ion complexation sites via hydrogen bonding in a tetrahedral geometry. Molecular modeling dynamics and electrostatics studies indicate that target compounds 1d-6d may provide better selectivity for ammonium ions over potassium ions than the ammonium ionophore currently used for blood analysis applications, nonactin. Attempts to synthesize 1d, cyclo(L-Glu¹—D-Val²—L-Ala³—D-Lys⁴—D-Val⁵—L-Val⁶)-cyclo-(1ã-4å), were unsuccessful due to poor solubility of the synthetic intermediates. This led to the design of 2d-6d in which specific amino acid residues were chosen to provide higher solubility. Compound 2d, cyclo(L-Glu¹—D-Ala²—D-Ala³—L-Lys⁴—D-Ala⁵—L-Ala⁶)-cyclo-(1ã-4å), was successfully synthesized, but was also too insoluble for characterization or testing in an ion selective electrode (ISE) sensor format. Compound 6d, cyclo(L-Glu¹—D-Leu²—Aib³—L-Lys⁴—D-Leu⁵—D-Ala⁶)-cyclo-(1ã-4å), was successfully synthesized and characterized. When 6d was incorporated into an ISE sensor and tested as an ammonium ionophore, results indicated that the bicyclic peptide lacked solubility in the ISE membrane. A ¹³C-NMR study has been initiated in order to evaluate selectivity of 6d for ammonium over potassium and sodium cations in solution. Preliminary results with the potassium ionophore valinomycin as a control have been completed.
Files	cnowak.pdf