Thesis

Development of new synthetic approaches in solid-phase peptide synthesis

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2024
Thesis identifier
  • T16934
Person Identifier (Local)
  • 201993957
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Chapter 1 of this thesis will focus on the development of a synthetic route to access dual-labelled peptides using bioorthogonal reacting pairs. Since its inception in 2003, bioorthogonal chemistry is a growing area of chemistry which has greatly aided in the studies of biomolecules. We have developed a route which could facilitate the selective and sequential labelling of biomolecules through means of leveraging chemistry highlighted in literature. We have employed two orthogonal reacting pairs, nitrile imines with carboxylic acids and azides with aromatic ynamines, Figure 1. [Figure reproduced in thesis text] Nitrile imines are highly reactive 1,3-dipoles which can be accessed in situ through the photolytic degradation of 2,5-diaryl tetrazoles. Given their inherent dipole, they can undergo 1,3-dipolar cycloadditions as expected, however, through competition experimental studies we have shown that NIs will preferentially react with carboxylicacids when exposed to a dipolarophile, such as an aromatic ynamine. Aromatic ynamines have been shown to provide high selectivity in CuAAC over aliphatic alkynes. We have shown that both of these processes can occur orthogonally to one another and can be applied to a biomolecule setting, Scheme 1. [Figure reproduced in thesis text] Chapter 2 of this report will shift the focus onto the solvents used to synthesise peptides. Typically, the solvent of choice employed in SPPS is N,N’-dimethylformamide (DMF) which is highly toxic as it is teratogenic and with that, restrictions around its sale and manufacture are being tightened as of December 2023. Therefore, the requirement to identify a robust replacement for this crucial process is of the utmost importance. We report the development of an interactive solvent selection guide for SPPS andconduct studies examining solvents ability to swell resins in addition to solubilising amino acids and coupling reagents which identified cyclopentanone as a potential candidate to replace DMF, and when applied to SPPS, we were successful in synthesising a pentapeptide with good crude purity.
Advisor / supervisor
  • Jamieson, Craig
Resource Type
DOI
Date Created
  • 2023
Funder

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file details File 2024-05-21 Embargo