Phthalimide-based sulfur transfer reagents for the preparation of biologically relevant trisulfides

Reactive sulfur species (RSS) are a class of biological sulfur compounds that play significant roles in various physiological processes. Among these, trisulfides (RSSSR) have been recognized for their unique biological activities such as antioxidation. However, there is still a lack of suitable methods for the preparation of biothiol and protein trisulfides that will enable a better understanding of trisulfide's roles in RSS biology. In this study, we developed and analyzed the use of phthalimide-based disulfide reagents to generate trisulfides from thiols found abundantly in physiologically relevant environments. This approach was tested on both small molecule and larger protein thiols. The results demonstrated that this method provides access to both biothiol- and protein-based trisulfides and may facilitate further exploration of the functions of trisulfides in biological systems.