Department of Chemistry , University of Pennsylvania , Philadelphia , Pennsylvania 19104 , United States.
J Am Chem Soc. 2018 Aug 1;140(30):9486-9493. doi: 10.1021/jacs.8b03738. Epub 2018 Jul 20.
Small-molecule fluorescent probes are powerful tools for chemical biology; however, despite the large number of probes available, there is still a need for a simple fluorogenic scaffold, which allows for the rational design of molecules with predictable photophysical properties and is amenable to concise synthesis for high-throughput screening. Here, we introduce a highly modular quinoline-based probe containing three strategic domains that can be easily engineered and optimized for various applications. Such domains are allotted for (1) compound polarization, (2) tuning of photophysical properties, and (3) structural diversity. We successfully synthesized our probes in two steps from commercially available starting materials in overall yields of up to 95%. Facile probe synthesis was permitted by regioselective palladium-catalyzed cross-coupling, which enables combinatorial development of structurally diverse quinoline-based fluorophores. We have further applied our probes to live-cell imaging, utilizing their unique two-stage fluorescence response to intracellular pH. These studies provide a full demonstration of our strategy in rational design and stream-lined probe discovery to reveal the diverse potential of quinoline-based fluorescent compounds.
小分子荧光探针是化学生物学的有力工具；然而，尽管已有大量的探针可供使用，但仍需要一个简单的荧光骨架，以便能够合理设计具有可预测光物理性质的分子，并且易于进行简洁的合成以进行高通量筛选。在这里，我们介绍了一种基于喹啉的高度模块化探针，其中包含三个战略域，可以轻松地进行工程设计和优化，以满足各种应用需求。这些域分别用于（1）化合物极化，（2）光物理性质的调节，以及（3）结构多样性。我们成功地从商业上可获得的起始原料出发，通过两步反应以高达 95%的总收率合成了我们的探针。通过区域选择性钯催化交叉偶联反应实现了探针的简便合成，这使得基于喹啉的荧光团的结构多样性能够进行组合开发。我们还进一步将我们的探针应用于活细胞成像，利用其独特的两步荧光响应来检测细胞内 pH 值。这些研究充分展示了我们在合理设计和简化探针发现方面的策略，揭示了基于喹啉的荧光化合物的多样化潜力。
