Enhanced Iridium complexes for amino acid and peptide isotope labelling processes

Student thesis: Doctoral Thesis

Abstract

Over the last decade, the number of new chemical entities approved as drugs within the pharmaceutical industry has greatly increased. Although this may seem promising, the attrition rate remains obtusely high, posing a major issue for pharmaceutical drug development. In an attempt to combat these problems, metabolism studies are utilised much earlier in the drug discovery process, to enable the identification of potential issues before a candidate is entered into expensive pre-clinical or clinical trials. The use of heavy isotopes to label drug candidates play a central role in metabolism studies and as such methods of synthesising 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) catalysts have been developed within the Kerr group for the efficient ortho-labelling of a large array of aromatic 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 an impressive advancement within the area of HIE, with efficient catalysts under mild conditions and high levels of labelling, however, labelling of sp3-rich, and more biologically relevant, molecules remains in its infancy.More and more peptides are emerging on the market as therapeutics, providing a 'sweet' spot between small molecules and large biologics. Therefore, it is imperative that such molecules can also be istopically labelled to allow metabolism studies much like their small molecule counterparts. In a similar vein, amino acids, the building blocks of peptide molecules, also represent an important class of molecules to be labelled.This report describes development of a method to label amino acid and small peptide substrates under iridium(I) catalysis, with high incorporations observed under mild conditions. Isotopic labelling of peptides on solid resin support has been investigated in an attempt 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.
Date of Award27 Jul 2020
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council)
SupervisorWilliam Kerr (Supervisor) & Craig Jamieson (Supervisor)

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