Selenenylsulfide Bond as a General Scaffold for Constructing Thiol Probes with Enhanced Response Rate

Abstract

Leveraging disulfide (−S–S−) or diselenide (−Se–Se−) units as triggers in the design of small-molecule fluorescent probes for detecting intracellular reductive species has demonstrated high efficacy. However, selenenylsulfides, which exhibit reactivity between diselenides and disulfides, remain relatively unexplored. In this work, we compare the efficiency of −S–S–, seleno-sulfur (−Se–S−), and sulfur–selenium (−S–Se−) structural units in constructing thiol probes, disclose the scaffold of −Se–S– as a versatile recognition site for thiols, and successfully apply this unit to design a near-infrared (NIR) probe, ASC-SeS. The mechanism reveals that breaking the −Se–S– bond leads to a selenolate, which undergoes faster cyclization than the corresponding thiolate that is from the cleavage of the −S–S– or −S–Se– bond. Conjugation of this trigger unit with multiple NIR fluorophores validates the general applicability of linear selenenylsulfides in accelerating the response rate to thiols. By harnessing the superior thiol responsiveness of ASC-SeS, we employ this probe in live cells and in vivo, and elucidate a severe depletion of thiols in the drug-induced liver injury (DILI).