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 Award | 27 Jul 2020 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Sponsors | EPSRC (Engineering and Physical Sciences Research Council) |
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| Supervisor | William Kerr (Supervisor) & Craig Jamieson (Supervisor) |
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