Catalyst-free "click" reactions for the direct conjugation of metal complexes to bio(macro)molecules

用于金属配合物与生物（大）分子直接缀合的无催化剂“点击”反应

• 批准号: 246278426
• 负责人: Professor Dr. Ulrich Schatzschneider
• 金额: --
• 依托单位: Institut für Anorganische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/246278426?language=en
• 关键词: Catalyst; free; click; reactions; direct

The mild and site-selective modification of biomacromolecules like peptides and proteins with non-natural functional groups is a significant challenge due to the multitude of reactive groups these compounds present. At the same time, such hybrid systems offer great promise as tools to study fundamental biological processes and they might also find interesting applications in medical diagnosis and therapy. Bioorthogonal "click reactions" like the copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC) are now heavily utilized to introduce new functionalities to biomacromolecules. However, the application of the CuAAC and other coupling methods in living systems is hampered by the need for a potentially toxic transition metal catalyst.Therefore, it is the aim of the present project to develop novel mild and catalyst-free methods for the conjugation of functional metal complexes to peptides and proteins. However, in contrast to other very recent bioorthogonal coupling reactions like the strain-promoted azide-alkyne cycloaddition, our work will be specifically based on a metal-inherent reactivity. At the core of our strategy will be the direct reaction of substitutionally inert metal azides with alkyne-functionalized biomacromolecules in an "iClick reaction" to form a metal-triazolate linkage. Facile variation of the metal center and coligand sphere will allow us to tune the electronic and steric properties of the coupling partners to ensure fast reaction kinetics and introduce a wide variety of functionalities to probe biological systems.The hybrid metal complex-peptide bioconjugates prepared this way will then be studied for stability of the triazolate linkage in challenge experiments with common cellular constituents like amino acids, nucleotides, and biogenic thiols. While initial work will focus on the use of simple model peptides, their complexity will then subsequently be increased to larger carrier peptides of potential biological relevancy. Selected metal complex-peptide hybrids will be tested for their biological activity on human cancer cells.With an established set of metal reaction partners and coupling conditions at hand, this project will then take initials steps towards the modification of functional proteins using the "iClick" reactivity to introduce novel, metal-based functionality to these systems.

利用非天然官能团对生物大分子（如多肽和蛋白质）进行温和和选择性的修饰是一个重大挑战，因为这些化合物存在大量的活性基团。与此同时，这种混合系统作为研究基本生物过程的工具提供了巨大的希望，它们也可能在医学诊断和治疗中找到有趣的应用。像铜催化的1,3-偶极叠氮-炔环加成反应（CuAAC）这样的生物正交“点击反应”现在被大量用于向生物大分子引入新的功能。然而，由于需要一种潜在有毒的过渡金属催化剂，CuAAC和其他偶联方法在生命系统中的应用受到阻碍。因此，本项目的目标是开发新的温和和无催化剂的功能金属配合物与肽和蛋白质的偶联方法。然而，与其他最近的生物正交偶联反应（如菌株促进的叠氮化物-炔环加成反应）相比，我们的工作将专门基于金属固有的反应性。我们策略的核心将是取代惰性金属叠氮化物与炔功能化生物大分子在“iClick反应”中直接反应，形成金属-三唑酸酯连接。金属中心和共配体球体的简单变化将使我们能够调整耦合伙伴的电子和空间特性，以确保快速反应动力学，并引入各种功能来探测生物系统。以这种方式制备的杂化金属配合物-肽生物偶联物将在与常见细胞成分（如氨基酸、核苷酸和生物硫醇）的挑战实验中研究三唑酸键的稳定性。虽然最初的工作将集中在使用简单的模型肽，但其复杂性随后将增加到具有潜在生物学相关性的更大的载体肽。选定的金属配合物-肽复合物将测试其对人类癌细胞的生物活性。有了一组已建立的金属反应伙伴和耦合条件，该项目将采取初步步骤，利用“iClick”反应性对功能性蛋白质进行修饰，为这些系统引入新颖的金属功能。

项目成果

Sonogashira, CuAAC, and Oxime Ligations for the Synthesis of MnI Tricarbonyl PhotoCORM Peptide Conjugates

• DOI: 10.1002/ejic.201402123
• 发表时间: 2014-06
• 期刊: European Journal of Inorganic Chemistry
• 影响因子: 2.3
• 作者: S. Pai;K. Radacki;U. Schatzschneider

Catalyst-free room-temperature iClick reaction of molybdenum(ii) and tungsten(ii) azide complexes with electron-poor alkynes: structural preferences and kinetic studies.

叠氮钼(ii) 和钨(ii) 叠氮配合物与贫电子炔烃的无催化剂室温 iClick 反应：结构偏好和动力学研究

• DOI: 10.1039/c7dt03096g
• 发表时间: 2017
• 期刊: Dalton transactions
• 影响因子: 4
• 作者: P. Schmid;M. Maier;H. Pfeiffer;L. Henry;A. Belz;A. Friedrich;F. Schönfeld;K. Edkins;U. Schatzschneider
• 通讯作者: U. Schatzschneider

Electronic Influences on the Stability and Kinetics of Cp* Rhodium(III) Azide Complexes in the iClick Reaction with Electron‐Poor Alkynes

电子对贫电子炔烃 iClick 反应中 Cp* 铑 (III) 叠氮化物配合物稳定性和动力学的影响

• DOI: 10.1002/ejic.201700199
• 发表时间: 2017
• 期刊: European Journal of Inorganic Chemistry
• 影响因子: 2.3
• 作者: L. Hiersch;J. Mößeler;U. Schatzschneider
• 通讯作者: U. Schatzschneider