Metal Catalyzed CN and CS Bond Forming Reactions for Bioconjugation Targets

金属催化生物共轭靶标的 CN 和 CS 键形成反应

• 批准号: 8309581
• 负责人: Alexander Michael Spokoyny
• 金额: $ 4.71万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309581
• 关键词: Attention; Azides; Benign; Binding; Biological; Carbon; Chemistry; Conjugating Agent; Development; Disease; Electrons; Ensure; Environment; Fluorescent Probes; Goals; Halogens; Homo; Isothiocyanates; Life; Ligands; Ligation; Metals; Methodology; Methods; Mononuclear; Nitrogen; Pharmacologic Substance; Process; Production; Protocols documentation; Reaction; Reaction Time; Reagent; Research; Research Personnel; Route; Site; Solvents; Source; Staging; Sulfhydryl Compounds; Sulfur; Water; Work; aryl halide; base; carbene; catalyst; cellular imaging; design; dimer; functional group; protein crosslink; protein protein interaction; small molecule

DESCRIPTION (provided by applicant): Researchers in the field of bioconjugate chemistry have long needed well-defined ligation strategies that can be rationally and effectively used for orthogonal and selective binding of specific small molecule and biological targets under a wide range of conditions. Requirements for efficient bioconjugation strategies generally include high levels of functional group tolerance, compatibility with water and environmentally benign solvents, and efficient conversions (in terms of reaction times and yields). Reactions that adhere to the principles of "click chemistry," introduced by Sharpless and co-workers in 2001, are ideal candidates for bioconjugation applications. Surprisingly, current synthetic methodologies for accessing the aryl azides, thiols and isothyocyanates, which can be used as precursors for "click" bioconjugation are limited to synthetic strategies that generally have harsh conditions and low functional group tolerance. The ultimate goal of this work is devoted to the development of efficient catalytic methodologies for the conversion of functionalized aryl halides to molecules useful for highly specific bioconjugation processes. Specifically, we will focus on catalytic C-N and C-S bond formations using the highly active Group 10 (Ni, Pd, Pt) based N-heterocyclic carbene (NHC) catalytic manifold. These NHC ligands will feature large steric bulk and hemilabile moieties, which will enforce a mononuclear, electron-rich metal site, crucial for high catalytic activity. The scope of the proposed catalytic functionalizations will include important functional motifs, such as azides, thiols, and isothiocyanates. Successful establishment of the reactive intermediates and optimized conditions for the catalytic reaction cycle will enable us to develop an efficient protocol for late-stage introduction of highly-active functional groups within commonly used homo- and hetero-bifunctional protein crosslinking agents, conjugating fluorescent probes, and other bioorthogonal reagents. PUBLIC HEALTH RELEVANCE: Development of new functional targets for bioconjugation will further our understanding in protein-protein interactions and live cell imaging, which is crucial t the development of new methods for disease treatments. The proposed methodology will also impact facile production of new building blocks for pharmaceuticals, containing nitrogen- and sulfur-based building blocks via more practical and safe routes.

描述(申请人提供)：生物结合化学领域的研究人员长期以来一直需要定义明确的连接策略，这些策略可以在广泛的条件下合理有效地用于特定小分子和生物靶标的正交和选择性结合。有效的生物偶联策略的要求通常包括高水平的官能团耐受性、与水和环境友好的溶剂的兼容性以及高效的转化(就反应时间和产率而言)。符合2001年夏普莱斯和他的同事提出的“点击化学”原理的反应是生物偶联应用的理想候选者。令人惊讶的是，目前用于获得芳基叠氮化合物、硫醇和异硫氰酸酯的合成方法，可以用作生物偶联的前体，仅限于通常具有苛刻条件和 官能团耐受性低。这项工作的最终目标是开发高效的催化方法，将功能化的芳基卤化物转化为对高度特定的生物结合过程有用的分子。具体地说，我们将专注于使用高活性第10族(Ni，Pd，Pt)基氮杂环卡宾催化歧管催化C-N和C-S键的形成。这些NHC配体将具有大的空间体积和半易变的部分，这将加强一个单核，富含电子的金属中心，这对高催化活性至关重要。建议的催化功能化的范围将包括重要的功能基元，如叠氮化合物、硫醇和异硫氰酸酯。活性中间体的成功建立和催化反应循环的优化条件将使我们能够开发出一种高效的方案，用于在 常用的同、异双功能蛋白交联剂、共轭荧光探针和其他生物正交剂。 公共卫生相关性：生物偶联新功能靶点的开发将加深我们对蛋白质-蛋白质相互作用和活细胞成像的理解，这对开发新的疾病治疗方法至关重要。拟议的方法还将影响通过更实用和安全的路线生产包含氮和硫基构建块的药品新构建块的简便性。