Enhanced Iridium Complexes for Elevated Substrate Applicability in Isotope Labelling Processes

增强型铱配合物可提高同位素标记过程中的底物适用性

• 批准号: 1810958
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1810958
• 关键词: Enhanced; Iridium; Complexes; Elevated; Substrate

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.

制备复杂的3 H-和2 H-标记的肽和蛋白质目前是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，用于生物测定开发以及体外和体内代谢研究的3 H和2 H标记肽和蛋白质的需求显着增加。传统上，这些标记的肽是通过钯催化的氚气还原碘酪氨酸或脱氢亮氨酸的类似物制备的。然而，这些方法具有两个主要缺点。首先，需要前体肽或蛋白质合成，这在实践中可能具有挑战性并且成本高。第二，一旦获得前体肽，它可能含有与还原条件不相容的氨基酸，这常常导致反应失败。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，最初使用简单的-氨基酸作为底物来指导催化剂的开发。在这些对氨基酸的广泛研究之后，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肽和蛋白质的氚标记，这些肽和蛋白质对支持工业合作者的生物制剂管道有直接利益。

项目成果

Synthesis of [3 H] and [14 C]Genipin.

• DOI: 10.1002/jlcr.3832
• 发表时间: 2020-02
• 期刊: Journal of labelled compounds & radiopharmaceuticals
• 影响因子: 1.8
• 作者: A. Queen;D. Hesk;D. Lindsay;W. Kerr;K. Rehder;T. Fennell;W. Mascarella;D. Zhong;S. Runyon