Time‐Gated Detection of Cystathionine γ‐Lyase Activity and Inhibition with a Selective, Luminogenic Hydrogen Sulfide Sensor

Herein, we report the design, synthesis, and characterization of a lanthanideIII complex‐based probe for the time‐gated luminescence detection of hydrogen sulfide (H2S) in aqueous media. The probe's unique sensing mechanism relies on the selective reduction of azide to amine by sulfide, followed by intramolecular cyclization to form a quinolinone. The quinolinone is a sensitizer that absorbs near‐UV light and transfers excitation energy to coordinated TbIII or EuIII ions to trigger a strong “turn‐on” luminescence response with ms‐scale lifetimes characteristic of lanthanide complexes. Using this probe, we developed a robust, high throughput screening (HTS) assay for detecting H2S generated by cystathionine γ‐lyase (CSE), one of the main producers of H2S in mammalian cells. In a 240‐compound screen to identify potential CSE inhibitors, the EuIII analogue of the sensor showed a low false‐positive rate and high Z′‐factor (>0.7). Time‐gated sensing: An emissive lanthanide probe LLPS‐LnIII was developed that gives a strong turn‐on response to hydrogen sulfide. H2S reduces an aryl azide moiety to trigger an intramolecular cyclization to form a quinolinone that efficiently sensitizes long‐lifetime TbIII or EuIII luminescence (see figure). Time‐gated detection permits sensitive, high‐throughput screening for inhibition of H2S‐producing cystathionine γ‐lyase.