Studies towards the synthesis and labelling of bioactive peptides

Rights statement
Awarding institution
  • University of Strathclyde.
Date of award
  • 2016
Thesis identifier
  • T15970
Qualification Level
Qualification Name
Department, School or Faculty
  • The photochemical synthesis of fluorescent pyrazoline adducts was investigated as a potential methodology for intracellular visualisation of cell permeable peptides. Alkene-tagged amino acids were reacted with 2,5-diaryl tetrazoles. These small tags were chosen as they would minimise alterations to the physicochemical properties when incorporated into peptides. The resulting pyrazoline adducts fluoresced at concentrations suitable for exploitation in cells; however, the addition of N-acetyl cysteine, a glutathione substitute, resulted in additional side reactions. A number of competition reactions and cell-based trials were conducted to determine the cause, and the methodology was determined to be unsuitable for intracellular peptide visualisation. From this work several interesting side reactions were identified and were investigated further. The photochemical irradiation of lone 2,5-diaryl tetrazoles was shown to provide access to a number of azoles including: 2,4,5-trisubstituted 1,2,3-triazoles; 1,3,5-pyrazolines; 1,3,5-pyrazoles; and 3,5-indazoles. Irradiation in the presence of carboxylic acids was shown to yield hydrazides. This latter reaction was determined to be selective over both alkene and alkyne labelling and could represent a novel means of derivatising functionalised carboxylic acids. Kallikrein 5 (KLK5) is a Trypsin-Like Serine Protease (TLSP) which is involved in the development of skin diseases such as atopic dermatitis. The cyclotheonamide (Ct) family of natural products has shown inhibitory activity against analogous TLSPs. Using previous learnings from literature syntheses of these macrocyclic peptides a flexible and efficient solid phase peptide synthesis (SPPS) has been developed. A number of protecting group strategies were investigated and the solid phase assembly of macrocyclic cyclotheonamide precursors has successfully been performed to enable SAR analysis with Trypsin-Like Serine Proteases (TLSPs) such as KLK5.
Advisor / supervisor
  • Harris, Robert
  • Jamieson, Craig
Resource Type
  • Previously held under moratorium in Chemistry department (GSK) from 27/4/18 until 24 August 2021.
  • The confidentiality statement on each page of this thesis DOES NOT apply