Dynamic Phosphorus: Thiolate Exchange Cascades with Higher Phosphorothioates

In this study, we introduce phosphorus, a pnictogen, as an exchange center for dynamic covalent chemistry. Cascade exchange of neutral phosphorotri- and -tetrathioates with thiolates is demonstrated in organic solvents, aqueous micellar systems, and in living cells. Exchange rates increase with the pH value, electrophilicity of the exchange center, and nucleophilicity of the exchangers. Molecular walking of the dynamic phosphorus center along Hammett gradients is simulated by the sequential addition of thiolate exchangers. Compared to phosphorotrithioates, tetrathioates are better electrophiles with higher exchange rates. Dynamic phosphorotri- and -tetrathioates are non-toxic to HeLa Kyoto cells and participate in the dynamic networks that account for thiol-mediated uptake into living cells. Inspired by cell-penetrating disulfides and oligonucleotide phosphorothioates, dynamic covalent cascade exchange chemistry centered on phosphorus has been achieved using neutral higher phosphorotri- and -tetrathioates. They walk along Hammett gradients of thiolate exchangers in triton X-100 micelles, exchange with cysteine and glutathione in neutral water, and protect from thiol-mediated uptake into living cells.image

Automated summary

In this study, phosphorus is introduced as an exchange center for dynamic covalent chemistry. The cascade exchange of phosphorotri- and -tetrathioates with thiolates is demonstrated in different systems. The exchange rates are influenced by factors such as pH value, electrophilicity of the exchange center, and nucleophilicity of the exchangers. The dynamic phosphorotri- and -tetrathioates are non-toxic and participate in thiol-mediated uptake into living cells.