Title page for ETD etd-0407103-120733

Type of Document Dissertation
Author Oguz, Umut
Author's Email Address uoguz1@lsu.edu
URN etd-0407103-120733
Title Design and Synthesis of Constrained Dipeptide Units for Use as Beta-Sheet Promoters
Degree Doctor of Philosophy (Ph.D.)
Department Chemistry
Advisory Committee
Advisor Name Title
Mark L. McLaughlin Committee Chair
Paul S. Russo Committee Member
Robert P. Hammer Committee Member
Robin L. McCarley Committee Member
Frederick M. Enright Dean's Representative
  • aza-dipeptide
  • hydrazine
  • constrained
  • dipeptide unit
Date of Defense 2003-03-18
Availability unrestricted
The study of factors promoting beta-sheet formation has recently gained interest due to the suspected involvement of beta-sheets in brain degenerative diseases such as Alzheimer's disease (AD), Creutzfeldt-Jacob disease (CJD) and bovine spongiform encephalopathy. Understanding beta-sheet formation and the factors that stabilize beta-sheet structure may serve as a basis for future drug design. The extended structure of a beta-sheet can be stabilized by constrained amino acid analogs that are pre-organized to adopt the extended conformation. In this dissertation using innovative synthetic organic chemistry methods, two dipeptide units are designed and synthesized that are constrained to form the extended conformation and mimic the hydrogen-bonding and side chain interactions that natural beta-sheets form along one edge of the individual peptide strands. DiPeptideUnit (DPU) 45 and Aza-DiPeptide unit (ADP) 46 are designed to have increasing levels of constraint in order to directly measure the relative beta-sheet forming propensity of the constrained dipeptides when incorporated into selected positions of a prototypical, "semi-stable" beta-hairpin peptide.

An improved synthesis of DPU(Gly, Xxx) 45 from D-glutamic acid is reported. Previously described syntheses of lactam-constrained dipeptide amino acids involve lengthy and expensive procedures to obtain an aldehyde intermediate. The key to the synthesis of the DPU(Gly, Xxx) 45 is the convenient synthesis of an alpha-amino acid semialdehyde in high yields. When DPU(Gly, Leu) 47b is incorporated into an analogous peptide it stabilizes the beta-sheet secondary structure according to CD measurements and this stabilizing effect is higher when more DPU residues are incorporated.

A very efficient way of synthesizing ADP(Gly, Phe) 46 is also reported. The key intermediate in this synthesis is a protected alpha-hydrazino ester derivative that is synthesized from alpha-amino esters using inexpensive reagents and in excellent overall yields. The key reaction step in the synthesis is the very effective coupling of a D-aspartic acid derivative with the N-alpha of the alpha-hydrazino ester by symmetrical anhydride method.

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