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首页> 外文期刊>Chemistry: A European journal >'Click-to-Chelate': Design and incorporation of triazole-containing metal-chelating systems into biomolecules of diagnostic and therapeutic interest
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'Click-to-Chelate': Design and incorporation of triazole-containing metal-chelating systems into biomolecules of diagnostic and therapeutic interest

机译：“点击螯合”：设计并将含三唑的金属螯合系统并入具有诊断和治疗意义的生物分子中

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The site-specific conjugation of metal chelating systems to biologically relevant molecules is an important contemporary topic in bioinorganic and bioorganometallic chemistry. In this work, we have used the Cu-I-catalyzed cycloaddition of azides and terminal alkynes to synthesise novel ligand systems, in which the 1,2,3-triazole is an integral part of the metal chelating system. A diverse set of bidentate alkyne building blocks with different aliphatic and aromatic backbones and various donor groups were prepared. The bidentate alkynes were reacted with benzyl azide in the presence of a catalytic amount of Cut to form tridentate model ligands. The chelators were reacted with [ReBr3(Co)(3)](2-) to form well-defined and stable complexes with different overall charges, structures and hydrophilicities. In all cases tridentate coordination of the ligands, including through N3 of the 1,2,3-triazole ring, was observed. The ligand systems could also be quantitatively radiolabelled with the precursor [Tc-99m (H2O)(3)(CO)(3)](+) at low ligand concentrations. Similarly the alkynes were reacted with an azido thymidine derivative to form a series of compounds, which could be radiolabelled in situ to form single products. Subsequent incubation of the neutral and cationic organometallic Tc-99m thymidine derivatives with human cytosolic thymidine kinase, a key enzyme in tumour proliferation, revealed that only the neutral compounds maintained substrate activity towards the enzyme. Bioconjugation, radiolabelling and enzymatic reactions were successfully performed in a matter of hours. Thus, click chemistry provides an elegant method for rapidly functionalising a biologically relevant molecule with a variety of efficient metal chelators suitable for (radio)labelling with the M(CO)(3) core (M= Tc-99m, Re), to offer new potential for technetium-99m in clinical and preclinical tracer development.
机译：金属螯合系统与生物学相关分子的位点特异性缀合是生物无机和生物有机金属化学中的重要当代课题。在这项工作中，我们已经使用了Cu-I催化的叠氮化物和末端炔烃的环加成反应来合成新的配体系统，其中1,2,3-三唑是金属螯合系统的组成部分。制备了一组具有不同脂族和芳族主链以及各种供体基团的二齿双炔结构单元。在催化量的Cut存在下，使二齿炔与苄基叠氮化物反应以形成三齿模型配体。螯合剂与[ReBr3（Co）（3）]（2-）反应，形成定义明确且稳定的配合物，具有不同的总电荷，结构和亲水性。在所有情况下，观察到配体的三齿配位，包括通过1,2,3-三唑环的N3。配体系统也可以在低配体浓度下用前体[Tc-99m（H2O）（3）（CO）（3）]（+）进行定量放射性标记。类似地，炔烃与叠氮胸腺嘧啶核苷衍生物反应形成一系列化合物，这些化合物可以在原位进行放射性标记以形成单一产物。随后将中性和阳离子有机金属Tc-99m胸腺嘧啶核苷衍生物与人胞质胸腺嘧啶核苷激酶（一种肿瘤增殖的关键酶）一起孵育，结果表明只有中性化合物才能维持对该酶的底物活性。生物缀合，放射性标记和酶促反应在数小时内成功完成。因此，点击化学提供了一种优雅的方法，可通过多种有效的金属螯合剂快速功能化生物学相关分子，这些螯合剂适用于以M（CO）（3）核（M = Tc-99m，Re）进行（放射性）标记，以提供net 99m在临床和临床前示踪剂开发方面的新潜力。

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