Abstract

This dissertation primarily covers the impact of bulky <&alpha>,<&beta>-dehydroamino acids on the proteolytic stability and enhanced folding of <&beta>-hairpins. It partly describes the progress towards the total synthesis of yaku<'>amide A, a potent anticancer peptide with an IC50 value of 14 ng/mL against leukemia cells. Proteins and peptides are a very attractive source of potential medicinal agents as they can target various protein<&hyphen>“protein interactions that are implicated in several diseases and disorders. The global sales of peptide drugs in 2013 were estimated to be about $28 billion and are constantly rising at an appreciable rate. However, peptide drugs have a short plasma half-life because of their susceptibility to proteolysis. Multiple approaches have been discovered to overcome this shortcoming, but there is still an urgent need for better peptidomimetics to increase the stream of peptides entering the pharmaceutical market. Here, it has been demonstrated that the incorporation of a bulky <&alpha>,<&beta>-dehydroamino acid in the turn regions of <&beta>-hairpins can substantially increase their proteolytic stability and folding. Insertion of a dehydrovaline (ΔVal) residue at the i+1 position imparted ca. 7-fold increase in proteolytic resistance and ca. 15% increase in folding when compared to the parent peptide. Since the insertion of a bulky <&alpha>,<&beta>-dehydroamino acid into the turn regions of <&beta>-hairpins can promote proteolytic stability without perturbing the secondary structures, it is believed that this novel approach is very promising in stabilizing bioactive turn-containing peptides for therapeutic use.Yaku<'>amide A is a medium-sized peptide that contains several bulky dehydroamino acids, <&beta>-hydroxyamino acids and unique N- and C-termini. It has an unprecedented anticancer profile, and potent bioactivity, hence it was imperative to accomplish its total synthesis to elicit its unique mode of action and biological target. More efficient methods were developed to synthesize bulky dehydroamino acids and <&beta>-hydroxyamino acids. A regioselective base-free aminohydroxylation was developed for the synthesis of <&beta>-hydroxyamino acids. The major focus was the three-step synthesis of the N-terminal acyl group from a known compound by a one-pot indium-catalyzed cross-Claisen condensation/reduction and the synthesis of (2S,3R)-<&beta>-hydroxyisoleucine, and racemic <&beta>-hydroxyisoleucine, which are the precursors of E- and Z-dehydroisoleucine.

Degree

PhD

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

Date Submitted

2018-03-01

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd9760

Keywords

bulky <&alpha>, <&beta>-dehydroamino acids, <&beta>-hairpins, proteolytic stability, increased folding, aminohydroxylation, <&beta>-hydroxyamino acids, N-terminal acyl group

Language

english

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