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

受到有机化学中点击反应的巨大成功的启发，正如2022年诺贝尔化学奖授予Bertozzi，Meldal和Sharpless所强调的那样，以及我们在过去几年中收集的关于iClick范围的重要结构-反应性关系直接在金属中心的内配位层中进行金属络合物改性的（无机点击）反应，该项目的目标是沿着沿着三条路线将iClick反应的边界推向生物学应用：在第一个工作包中，将制备新的炔和金属叠氮基络合物作为活细胞中的反应性发光探针，具有生物缀合的简易选择，以特异性地处理细胞靶结构。特别地，通过适当的分子设计，将调节炔反应性以确保快速iClick反应沿着低细胞毒性。在该项目的第二部分，将开发用于组合iClick反应的新方法，以快速访问大型化学空间。这将允许筛选合适的亲偶极试剂，其产生具有有利生物物理性质的iClick三唑合产物，并提供获得能够解决不同细胞靶标的广泛生物缀合物的途径。将开发用于快速"基于活性"筛选的自动化方案，其中仅在制备规模上合成那些复合物，以用于在简单读出中显示有希望的性质的进一步研究。最后，在以前的工作包中确定的系统将全面表征其生物物理特性，然后传递到活细胞中的显微镜研究，用于在细胞毒性筛选中显示低活性的化合物。

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.