Intramolecular Thiol‐Promoted Decomposition of Cysteine Ester (ITPDC): A General Platform for Controllable Release of Reactive Sulfur Species

Endogenously generated reactive sulfur species (RSS) play critical roles in various physiological processes. RSS donors can enhance our understanding of RSS chemical biology and open new avenues for treating RSS-associated diseases. Nevertheless, general strategies for the controllable release of distinct RSS remain lacking. Herein, we present the first general platform for controllable release of RSS with sulfur oxidation states ranging from -2 to +4, based on the intramolecular thiol-promoted decomposition of cysteine ester (ITPDC). We first rationally designed ITPDC-based hydrogen sulfide (H₂S) donors that avoid electrophilic byproducts and exhibit high H₂S release efficiencies (>50%). Mechanistic investigations and density functional theory calculations elucidated the detailed pathways of pH-controllable H₂S release from ITPDC, and computational studies also predicted other H₂S-related RSS release from the ITPDC-based motifs. Importantly, we developed a series of ITPDC-based donors capable of releasing various RSS, including persulfide, hydrogen persulfide, sulfenic acid, sulfinic acid, and sulfur dioxide (SO₂). Moreover, fluorescent imaging demonstrated the successful cellular delivery of H₂S, persulfide, and SO₂ from these donors, and the ITPDC-based motif was employed to create a light-triggered donor. We anticipate that these innovative chemistries will provide valuable tools for studying sulfur biology and for developing new RSS donors and bio-orthogonal cleavage techniques.