Enhanced Iridium Complexes for Elevated Substrate Applicability in Isotope Labelling Processes

复杂的3H和2h标记肽和蛋白质的制备是目前对现有同位素标记方法的主要挑战。随着制药公司越来越多地将生物制剂作为新药，对3H和2h标记的肽和蛋白质的生物检测开发以及体外和体内代谢研究的需求显著增加。传统上，这些标记肽是通过钯催化的氚气体还原碘酪氨酸或脱氢亮氨酸的类似物制备的。然而，这些方法有两个主要缺点。首先，需要前体肽或蛋白质的合成，这在实践中具有挑战性且成本高。其次，前体肽一旦得到，可能含有与还原条件不相容的氨基酸，往往导致反应失败。在本研究项目中，将开发一套铱(I)催化剂来促进sp3 C-H键交换，初步采用简单-氨基酸作为底物来指导催化剂的开发。在对氨基酸进行这些广泛的研究之后，这项工作将扩展到肽和蛋白质的标记。计划将活性催化剂应用于多肽和蛋白质的氚标记，这对支持工业合作伙伴的生物制剂管道有直接的兴趣。

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.