Controlled Sulfane Sulfur Delivery via Allyl Disulfide Rearrangement-Mediated Thiosulfoxide Formation.

Protein S-persulfidation is a key post-translational modification in redox signaling. In this process, hydropersulfides (RSSH) and hydrogen persulfide (H2S2) act as regulatory sulfane sulfur species, transferring their electrophilic sulfane sulfur (S0) atoms to protein thiols (P-SH) to form protein persulfides (P-SSH). Due to the high reactivity and instability of RSSH/H2S2, controllable donors are essential chemical tools for inducing protein S-persulfidation. Existing donors are primarily disulfide-based; however, this structural feature leads to a major limitation, as disulfide-based donors are known to undergo unavoidable disulfide exchange reactions with cellular thiols (e.g., glutathione (GSH), cysteine (Cys)) and subsequently lose their ability to release the desired RSSH/H2S2. In this work, we proposed that thiosulfoxides [R-S(═S)-R'] could serve as equivalents of RSSH/H2S2 for protein S-persulfidation and that controlled thiosulfoxide formation is an alternative way for the design of RSSH/H2S2 donors. To prove the hypothesis, we studied spontaneous [2,3]-sigmatropic allyl disulfide rearrangements with a variety of allyl disulfide substrates. We identified structural elements that promote the rearrangement to form thiosulfoxide adducts and demonstrated that the resulting transient thiosulfoxide intermediates were effective S0 transfer agents. Based on this discovery, we developed stable allyl disulfide reagents (such as 3i) that could be selectively activated by cellular thiols via the inevitable disulfide exchange, followed by a [2,3]-sigmatropic rearrangement cascade to induce protein S-persulfidation. Our results present a conceptually new way to deliver reactive sulfane sulfur species in biological systems.