A C-H Functionalization Approach to Heterocyclic Amino Acids for Application in Drug Discovery

 描述（由申请人提供）：非天然氨基酸为创新材料和肽模拟物的开发提供了丰富的结构和功能多样性来源。这种结构基序在药物发现中起着特别重要的作用，在许多用于治疗疾病的市售药物中具有特征。尽管它们具有生物学相关性，但非规范氨基酸（特别是杂环α-氨基酸变体）代表了合成上具有挑战性的靶标。因此，拟议研究的目标是为合成非天然α-氨基酸提供一个强大的平台，重点是杂环变体，并促进其快速纳入治疗线索。本研究的第一个具体目标是发展一种C-H功能化方法，用于从新型α-氨基酸亚磺酸酯结构单元制备非天然氨基酸。金属亚磺酸盐是能够参与杂芳族底物的有效和高产率的氧化C-H官能化的烷基自由基中间体的已知前体。通过制备氨基酸亚磺酸酯衍生物的小工具箱，通过在氧化C-H官能化条件下与杂芳族底物的程序化反应，将有可能快速获得杂环氨基酸变体的多样化文库。亚磺酸酯衍生的烷基自由基中间体与各种自由基受体的反应也将被探测，目的是 增强使用所提出的方法可获得的非天然氨基酸的多样性。 考虑到具有非天然结构基序的肽药物和肽模拟物的日益增长的药物相关性，高度需要用于将非天然氨基酸快速掺入肽药物先导物中的新方法。因此，拟议研究的第二个具体目标是开发一个平台，用于将非天然氨基酸有效地后期掺入治疗性肽靶标中。所提出的方法需要合成的氨基酸轴承潜在的亚磺酸酯功能和纳入这些稳定的亚磺酸酯衍生物到目标肽使用固相肽合成（SPPS）。在构建肽骨架之后，潜在的亚磺酸酯可以被揭开（在树脂上或在溶液中）以提供准备用于C-H官能化的氨基酸亚磺酸酯。因此，这种方法将能够在后期引入结构多样性和复杂性，促进肽药物类似物的快速制备，否则需要从头合成。因此，拟议的研究目标将加快药物开发的过程，大大增加非天然氨基酸结构单元的可及性，并促进其纳入新的治疗线索。

 DESCRIPTION (provided by applicant): Unnatural amino acids provide an abundantly rich source of structural and functional diversity for the development of innovative materials and peptide mimetics. Such structural motifs play a particularly crucial role in drug discovery, featuring in a number of commercially available pharmaceuticals for the treatment of diseases. Despite their biological relevance, non-canonical amino acids (particularly heterocyclic α-amino acid variants) represent synthetically challenging targets. The goal of the proposed research is therefore to provide a robust platform for the synthesis of unnatural α-amino acids, with a focus on heterocyclic variants, and to facilitate their rapid incorporation into therapeutic leads. The frst specific aim of this study is to develop a C-H functionalization approach for the preparation of unnatural amino acids from novel α-amino acid sulfinate building blocks. Metal sulfinate salts are known precursors to alkyl radical intermediates capable of participating in the efficient and high-yielding oxidative C-H functionalization of heteroaromatic substrates. By preparing a small toolbox of amino acid sulfinate derivatives, rapid access to a diverse library of heterocyclic amino acid variants will be possible through programmed reaction with heteroaromatic substrates under oxidative C-H functionalization conditions. Reaction of the sulfinate-derived alkyl radical intermediate with a variety of radical acceptors will also be probed, with the aim of enhancing the diversity of unnatural amino acids accessible using the proposed methodology. Given the growing pharmaceutical relevance of peptide drugs and peptidomimetics bearing non-native structural motifs, new methods for the rapid incorporation of unnatural amino acids into peptide drug leads are in high demand. As such, the second specific aim of the proposed research is to develop a platform for the efficient, late-stage incorporation of unnatural amino acids into therapeutic peptide targets. The proposed methodology entails the synthesis of amino acids bearing latent sulfinate functionalities and the incorporation of these stable sulfinate derivatives into target peptides using solid-phase peptide synthesis (SPPS). Following construction of the peptide backbone, the latent sulfinate may be unmasked (on-resin or in solution) to provide an amino acid sulfinate poised for C-H functionalization. This methodology will therefore enable the late-stage introduction of structural diversity and complexity, facilitatng the rapid preparation of peptide drug analogues, which would otherwise require de novo synthesis. The proposed research aims will therefore expedite the process of drug development, greatly increasing the accessibility of non-native amino acid building blocks and facilitating their incorporation into novel therapeutic leads.