Thesis
Enhanced iridium complexes for amino acid and peptide isotope labelling processes
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2020
- Thesis identifier
- T15724
- Person Identifier (Local)
- 201677572
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Over the last decade, the number of new chemical entities approved as drugs within thepharmaceutical industry has greatly increased. Although this may seem promising, theattrition rate remains obtusely high, posing a major issue for pharmaceutical drugdevelopment. In an attempt to combat these problems, metabolism studies are utilised muchearlier in the drug discovery process, to enable the identification of potential issues before acandidate is entered into expensive pre-clinical or clinical trials. The use of heavy isotopes tolabel drug candidates play a central role in metabolism studies and as such methods ofsynthesising these are incredibly useful. Hydrogen isotopes are often utilised for this purpose,and are often introduced via hydrogen isotope exchange (HIE).Iridium has adopted a central role in HIE processes, and a large library of iridium(I) catalystshave been developed within the Kerr group for the efficient ortho-labelling of a large array ofaromatic compounds. Iridium catalysed HIE utilises a directing group within a molecule,meaning a large range of functionality can be employed. The Kerr group have presented animpressive advancement within the area of HIE, with efficient catalysts under mildconditions and high levels of labelling, however, labelling of sp3-rich, and more biologicallyrelevant, molecules remains in its infancy.More and more peptides are emerging on the market as therapeutics, providing a ‘sweet’ spotbetween small molecules and large biologics. Therefore, it is imperative that such moleculescan also be istopically labelled to allow metabolism studies much like their small moleculecounterparts. In a similar vein, amino acids, the building blocks of peptide molecules, alsorepresent an important class of molecules to be labelled.This report describes development of a method to label amino acid and small peptidesubstrates under iridium(I) catalysis, with high incorporations observed under mildconditions. Isotopic labelling of peptides on solid resin support has been investigated in anattempt to combat the solubility issues associated with these HIE substrates. In addition,Density Functional Theory (DFT) studies have been utilised to design new Ir(I) catalysts,targeted for the labelling of more complex amino acid and peptide motifs, which are, to date,significantly more challenging.
- Advisor / supervisor
- Kerr, William
- Resource Type
- DOI
- Date Created
- 2020
- Former identifier
- 9912928589502996
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