School of Pharmacy, The University of Nottingham, University Park, NG72RD, Nottingham, UK.
School of Computing, Engineering and Physical Sciences, University of the West of Scotland, PA12BE, Paisley, UK.
Chemistry. 2020 Mar 9;26(14):3173-3180. doi: 10.1002/chem.201905634. Epub 2020 Feb 21.
Development of novel bioimaging materials that exhibit organelle specific accumulation continues to be at the forefront of research interests and efforts. Among the various subcellular organelles, mitochondria, which are found in the cytoplasm of eukaryotic cells, are of particular interest in relation to their vital function. To date, most molecular probes that target mitochondria utilise delocalised lipophilic cations such as triphenylphosphonium and pyridinium. However, the use of such charged motifs is known to be detrimental to the working function of the mitochondrial transmembrane potential and there remains a strong case for development of neutral mitochondrial fluorescent probes. Herein, we demonstrate for the first time the exploitation of diketopyrrolopyrrole-based chemistries for the realisation of a neutral fluorescent probe that exhibits organelle specific accumulation within the mitochondria at the nanomolar level. The synthesised probe, which bears a neutral triphenylphosphine oxide moiety, exhibits a large Stokes shift and high fluorescence quantum yield in water, both highly sought-after properties in the development of bioimaging agents. In vitro studies reveal no interference with cell metabolism when tested for the human MCF7 breast cancer cell and nanomolar subcellular organelle colocalisation with commercially available mitochondrial staining agent Mitotracker Red. In light of its novelty, neutral structure and the preferential accumulation at nanomolar concentrations we anticipate this work to be of significant interest for the increasingly larger community devoted to the realisation of neutral mitochondrial selective systems and more widely to those engaged in the rational development of superior organic architectures in the biological field.
新型生物成像材料的开发，这些材料表现出细胞器特异性积累，一直是研究兴趣和努力的前沿。在各种亚细胞细胞器中，线粒体存在于真核细胞的细胞质中，与它们的重要功能有关，因此特别受到关注。迄今为止，大多数靶向线粒体的分子探针利用非定域亲脂性阳离子，如三苯基膦和吡啶鎓。然而，已知使用这种带电基序会对线粒体跨膜电位的工作功能造成损害，因此强烈需要开发中性线粒体荧光探针。在此，我们首次展示了基于二酮吡咯并吡咯的化学物质在实现中性荧光探针方面的应用，该探针在纳摩尔水平下在细胞器特异性积累方面表现出细胞器特异性积累。所合成的探针带有中性三苯基氧膦部分，在水中具有大的斯托克斯位移和高荧光量子产率，这是生物成像剂开发中非常需要的特性。体外研究表明，当用于人 MCF7 乳腺癌细胞时，不会干扰细胞代谢，并且与市售的线粒体染色剂 Mitotracker Red 纳米级亚细胞器共定位。鉴于其新颖性、中性结构以及在纳摩尔浓度下的优先积累，我们预计这项工作将对越来越多致力于实现中性线粒体选择性系统的研究人员以及更广泛地对那些从事生物领域中优越有机结构的合理开发的人员具有重要意义。
