Photochemical Release of Hydropersulfides

Abstract

Hydropersulfides (RSSH) have received significant interest in the field of redox biology because of their intriguing biochemical properties. However, because RSSH are inherently unstable, their study is challenging, and as a result, the details of their physiological roles remain ill-defined. Herein, we report strategies to release RSSH utilizing photoremovable protecting groups. RSSH protection with the well-established p-hydroxyphenacyl (pHP) photoprotecting group resulted in inefficient RSSH photorelease along with complex chemistry. Therefore, an alternative precursor was examined in which a self-immolative linker was inserted between the pHP group and RSSH, providing nearly quantitative RSSH release following photolysis at 365 nm. Inspired by these results, we also synthesized an analogous precursor derivatized with 7-diethylaminocoumarin (DEACM), a visible light-cleavable photoprotecting group. Photolysis of this precursor at 420 nm led to efficient RSSH release, and in vitro experiments demonstrated intracellular RSSH delivery in breast cancer MCF-7 cells.

In pursuit of feedback activation: New insights into redox-responsive hydropersulfide prodrug combating oxidative stress

“…Our group also designed RSSH prodrugs in response to RNS against paracetamol poisoning using the above-described scaffold [ 37 ]. The second scaffold contains acyl persulfide moieties that can undergo intramolecular acyl migration to release RSSH [ 40 , 41 , 44 ]. This class of prodrugs includes an alkylamine-substituted perthiocarbamate [ 44 ] or alkylsulfenyl thiocarbonate scaffold [ 41 ], which recently focused on pH-controlled spontaneous hydrolysis to achieve RSSH release.…”

“…However, RSSH can be regarded as a reactive metabolite, and therefore its efficient delivery is more preferably achieved through prodrug strategies. In recent years, an array of RSSH prodrugs (also known as RSSH donors or RSSH precursors) have emerged [ [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] ], exhibiting ideal therapeutic effects against pathological processes such as ferroptosis [ 11 , 14 ], ischemia-reperfusion [ 12 , 15 ], paracetamol poisoning [ 37 ], doxorubicin-induced cardiotoxicity [ 13 ] and postoperative pain [ 36 ]. Furthermore, RSSH prodrugs are proven superior to their counterparts, such as H 2 S donors, in terms of antioxidant activity [ 36 ].…”

“Stereoelectronic Deprotection of Nitrogen”: Recovering Nucleophilicity with a Conformational Change

“…28−32 Ureas are sometimes used as "energy sinks" whose formation can provide the thermodynamic driving force for a challenging transforma- tion. 33 Interestingly, NH 2 C(O)NH 2 , i.e., urea itself, can be both a reagent and an unorthodox polar solvent�similar in properties to DMF but much easier to remove due to its great solubility in water. 34 We became interested in learning how substitution can control the reactivity of nitrogen atoms in ureas.…”

“…In this context, ureas represent a very interesting cross-conjugated system. Not only are they nontrivial from the electronic point of view, but they are ubiquitous in medicinal chemistry − and organocatalysis. − Ureas are sometimes used as “energy sinks” whose formation can provide the thermodynamic driving force for a challenging transformation . Interestingly, NH 2 C­(O)­NH 2 , i.e., urea itself, can be both a reagent and an unorthodox polar solventsimilar in properties to DMF but much easier to remove due to its great solubility in water .…”