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: 8458782
• 负责人: Alexander Michael Spokoyny
• 金额: $ 4.92万
• 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/8458782
• 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.

描述（由申请人提供）：生物缀合物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，这些连接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。有效的生物缀合策略的要求通常包括高水平的官能团耐受性、与水和环境友好溶剂的相容性以及有效的转化（在反应时间和产率方面）。Sharpless及其同事在2001年提出的“点击化学”原则，是生物缀合应用的理想候选者。令人惊讶的是，目前用于获得芳基叠氮化物、硫醇和异硫氰酸酯（其可用作“点击”生物缀合的前体）的合成方法局限于通常具有苛刻条件和低成本的合成策略。 低官能团耐受性。这项工作的最终目标是致力于开发有效的催化方法，用于将官能化芳基卤化物转化为可用于高度特异性生物缀合过程的分子。具体而言，我们将专注于催化C-N和C-S键的形成，使用高活性的第10族（Ni，Pd，Pt）的N-杂环卡宾（NHC）催化歧管。这些NHC配体将具有大的空间体积和半不稳定部分，这将加强单核，富电子的金属位点，对高催化活性至关重要。提出的催化功能化的范围将包括重要的功能基序，如叠氮化物，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一种有效的方案，用于后期引入高活性官能团， 通常使用的同源和异源双功能蛋白质交联剂、缀合荧光探针和其它生物正交试剂。

项目成果

Enzyme-catalyzed macrocyclization of long unprotected peptides.

• DOI: 10.1021/ol501609y
• 发表时间: 2014-07-18
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Zhang, Chi;Dai, Peng;Spokoyny, Alexander M.;Pentelute, Bradley L.
• 通讯作者: Pentelute, Bradley L.

Rapid flow-based peptide synthesis.

• DOI: 10.1002/cbic.201300796
• 发表时间: 2014-03-21
• 期刊: CHEMBIOCHEM
• 影响因子: 3.2
• 作者: Simon, Mark D.;Heider, Patrick L.;Adamo, Andrea;Vinogradov, Alexander A.;Mong, Surin K.;Li, Xiyuan;Berger, Tatiana;Policarpo, Rocco L.;Zhang, Chi;Zou, Yekui;Liao, Xiaoli;Spokoyny, Alexander M.;Jensen, Klavs F.;Pentelute, Bradley L.
• 通讯作者: Pentelute, Bradley L.