Enhanced Iridium Complexes for Elevated Substrate Applicability in Isotope Labelling Processes

The preparation of complex 3H- and 2H-labelled peptides and proteins is currently a major challenge for existing isotope labelling methodology. The demand for 3H- and 2H-labelled peptides and proteins for biological assay development, and in vitro and in vivo metabolism studies have significantly increased as pharmaceutical companies increasingly target biologics as new medicines. Traditionally, these labelled peptides are prepared via a palladium-catalysed tritium gas reduction of iodotyrosine- or dehydroleucine-containing analogues. These methods, however, suffer from two main drawbacks. Firstly, precursor peptide or protein synthesis is required, which can be practically challenging and cost intensive. Secondly, once the precursor peptide has been obtained, it may contain amino acids that are not compatible with the reduction conditions, which often leads to reaction failure.

In this research project, a suite of iridium(I) catalysts will be developed to promote sp3 C-H bond exchange, initially using simple -amino acids as substrates to guide catalyst development. Following these extensive studies on amino acids, the work will be extended to the labelling of peptides and proteins. It is planned to apply active catalysts to the tritium labelling of peptides and proteins that are of direct interest in supporting the industrial collaborator's biologics pipeline.