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

杂环氨基酸的 C-H 官能化方法在药物发现中的应用

• 批准号: 9320019
• 负责人: Lara Rebecca Malins
• 金额: $ 4.01万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320019
• 关键词: Address; Amino Acids; Area; Biological; Chemicals; Chemistry; Development; Disease; Drug Targeting; Generations; Goals; Histidine; Laboratories; Libraries; Light; Metals; Methodology; Methods; Nature; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plant Resins; Play; Preparation; Process; Proteins; Protocols documentation; Reaction; Research; Research Institute; Role; Salts; Side; Solid; Source; Specificity; Technology; Therapeutic; Variant; Vertebral column; Work; analog; base; combinatorial; cost; cost effective; drug development; drug discovery; human disease; innovation; non-Native; novel; novel therapeutics; peptide drug; peptidomimetics; polypeptide; prevent; public health relevance; rapid technique; small molecule; therapeutic development; therapy development; tryptophan analog; unnatural amino acids

 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.

 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结构和功能多样性的丰富来源。这种结构基序在药物发现中发挥着特别重要的作用，在许多用于治疗疾病的市售药物中具有特征。尽管具有生物学相关性，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目标。因此，拟议研究的目标是为非天然 α-氨基酸的合成提供一个强大的平台，重点关注杂环变体，并促进它们快速纳入治疗先导药物中。本研究的第一个具体目标是开发一种 C-H 功能化方法，用于从新型 α-氨基酸亚磺酸盐结构单元制备非天然氨基酸。金属亚磺酸盐是已知的烷基中间体的前体，能够参与杂芳族底物的高效且高产率的氧化C-H官能化。通过制备氨基酸亚磺酸盐衍生物的小工具箱，通过在氧化C-H官能化条件下与杂芳族底物进行程序反应，可以快速获得多样化的杂环氨基酸变体库。还将探讨亚磺酸盐衍生的烷基自由基中间体与各种自由基受体的反应，目的是 使用所提出的方法增强非天然氨基酸的多样性。 鉴于具有非天然结构基序的肽药物和肽模拟物的制药相关性不断增长，对将非天然氨基酸快速掺入肽药物先导化合物的新方法的需求很高。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具有潜在亚磺酸盐官能团的氨基酸，并使用固相肽合成（SPPS）将这些稳定的亚磺酸盐衍生物掺入目标肽中。构建肽主链后，可以暴露潜在的亚磺酸盐（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盐。因此，该方法将能够在后期引入结构多样性和复杂性，从而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过程，大大增加非天然氨基酸构件的可及性，并促进它们纳入新的治疗先导药物中。