Small-molecule fluorescent probes are indispensable tools for chemical biology. However, despite the large number of probes available, there is still a need for a simple fluorogenic scaffold that 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, with 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. The diverse potential of our probes is demonstrated by a unique two-state fluorescence response to intracellular pH in live cell imaging and by a significant turn-on fluorescence response upon click ligation. These studies provide a full demonstration of our strategy in rational design and stream-lined probe discovery to reveal the potential of quinoline-based fluorescent compounds.

Highly tunable quinoline-based fluorescent small molecule scaffold for live cell imaging

256th National Meeting (2018)

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