Inorganic click reactions in the inner metal coordination sphere as a quick access to combinatorial metal complex synthesis and luminescent probes (iClick^2)

受有机化学中点击反应的巨大成功的启发，如2022年诺贝尔化学奖对Bertozzi，Meldal和Sharpless的强调，以及我们在过去几年中收集的关于iClick(无机点击)反应范围的重要结构-反应性关系，直接在金属中心的内部配位球中进行金属络合物修饰，该项目旨在沿着三条线将iClick反应的边界推向生物学应用：在第一个工作包中，将制备新的炔类和金属叠氮配合物作为活细胞中的反应性发光探针，具有方便的生物连接选项，以专门针对细胞目标结构。特别是，通过适当的分子设计，炔烃的反应性将得到调节，以确保快速的iClick反应伴随着低细胞毒性。在该项目的第二部分，将开发快速访问大化学空间的组合iClick反应的新方法。这将允许筛选合适的亲偶极分子，从而产生具有良好光物理性能的iClick Triazolato产品，并提供能够针对不同细胞靶点的广泛的生物偶联物面板。将开发快速“基于活性”筛选的自动化方案，其中仅在准备规模上合成这些络合物，以供在简单读出中显示出有前景的性能的进一步研究。最后，将对以前工作包中确定的系统的光物理性质进行全面表征，然后将其传递到活细胞中对在细胞毒性筛选中显示低活性的化合物的显微镜研究。

Inspired by the great success of click reactions in organic chemistry, as highlighted by the 2022 Nobel Prize in Chemistry to Bertozzi, Meldal, and Sharpless, and the significant structure-reactivity relationships we have gathered in the last years on the scope of iClick (inorganic click) reactions for metal complex modification directly in the inner coordination sphere of a metal center, this project aims to push the boundaries of the iClick reaction towards applications in biology along three lines: In a first work package, new alkynes and metal azido complexes as reactive luminescent probes in living cells with facile options for bioconjugation will be prepared to specifically address cellular target structures. In particular, by proper molecular design, the alkyne reactivity will be tuned to ensure fast iClick reactions go along with low cytotoxicity. In the second part of the project, new methods for combinatorial iClick reactions to quickly access a large chemical space will be developed. This will allow to screen for suitable dipolarophiles that give rise to iClick triazolato products with favorable photophysical properties and provide access to a broad panel of bioconjugates that are able to address different cellular targets. Automated protocols for quick "activity-based" screening will be developed in which only those complexes are synthesized on a preparative scale for further investigations that show promising properties in simple read-outs. Finally, the systems identified in the previous work packages will be comprehensively characterized for their photophysical properties and then passed on to microscopy studies in living cells for compounds that show low activity in cytotoxicity screening.