Towards the synthesis of a protein β-turn mimetic based on the opioid pentapeptide leu-enkephalin

Strowes, Derek (2012) Towards the synthesis of a protein β-turn mimetic based on the opioid pentapeptide leu-enkephalin. PhD thesis, University of Glasgow.

Abstract

Synthetic targets that mimic key structural and conformational features in proteins are of intense scientific interest. These structures can reproduce the biological activity of their naturally occurring counterparts, while improving their properties in vivo. This project focuses on the synthesis of beta-turn mimetic structures, based on the opioid pentapeptide leu‑enkephalin. More specifically, the target mimetics in this project are based on the enkephalin derivative, leu‑enkephalinamide.

Leu-enkephalin is conformationally very flexible, giving it the ability to bind to different opioid receptors. This results not only in the physiological relief of pain, but also in various potential side effects such as miosis or physical dependency. Natural peptide structures also have limited suitability for drug applications because of their poor transport properties and their tendency to undergo proteolytic degradation. The synthesis of macrocyclic mimetics can overcome these problems and give a conformationally rigid molecule that exhibits a desired biological activity.

This thesis will discuss some published examples of beta-turn mimetic structures that have been designed and synthesised by research groups working in this field. The examples that are shown have been chosen to illustrate some of the work that has taken place in this area over recent years. Advances in the synthesis of ynamides and other ynamine analogues is also discussed, due to the importance of this type of chemistry in the research project.
Efforts towards the synthesis of several 10-membered macrocycles are described herein. The target structures are model compounds that are designed to explore varied chemical approaches towards such ring systems. This thesis will discuss the synthesis of several linear precursors to the proposed macrocycles and efforts to cyclise these structures to form the desired targets.

The targets that were synthesized employed varied approaches to the key cyclisation reaction. Initially, a metal-mediated coupling approach to an ynamide target was chosen. This was subsequently refined by including a proline residue in the linear precursor to bring the reacting groups into closer proximity. Finally, several approaches were investigated to close an alkyne bonded macrocycle by coupling the amide functionality at the opposite side of the ring.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: organic synthesis, peptide mimetics
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Clark, Prof. J. Stephen
• Date of Award: 2012
• Depositing User: Mr Derek Strowes
• Unique ID: glathesis:2012-3792
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 21 Dec 2012 11:23
• Last Modified: 21 Dec 2012 11:30
• URI: https://theses.gla.ac.uk/id/eprint/3792