Dynamic Phosphorus: Thiolate Exchange Cascades with Higher Phosphorothioates

Abstract

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 pH, electrophilicity of the exchange center and nucleophilicity of the exchangers. Molecular walking of the dynamic phosphorus 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.

Inclusive Pattern Generation Protocols to Decode Thiol-Mediated Uptake

“…Ellman’s reagent DTNB (5,5′-dithio-bis­(2-nitrobenzoic acid)) is the established, yet poorly performing standard thiol-reactive inhibitor in biology, ,,,, proposed long ago to inhibit cellular entry of HIV by inhibiting PDIs on the cell surface. , To probe for cytosolic delivery by TMU early on, millimolar DTNB concentrations were needed, that is, 3 orders of magnitude above the best inhibitors in the CAX collection. Not yet ready for consideration in this study were other privileged or emerging CAXs like tetrel-centered thiolactones and thioesters, higher phosphorothioates with exchange cascades centered on dynamic covalent phosphorus, cyclic diselenides, , and the popular cell-penetrating poly­(disulfide)­s, , mentioned here only to highlight the dimensions of the CAX universe waiting to be explored.…”

“…1,36 To probe for cytosolic delivery by TMU early on, millimolar DTNB concentrations were needed, 71 that is, 3 orders of magnitude above the best inhibitors in the CAX collection. Not yet ready for consideration in this study were other privileged or emerging CAXs like tetrel-centered thiolactones and thioesters, 31 higher phosphorothioates with exchange cascades centered on dynamic covalent phosphorus, 72 cyclic diselenides, 73,74 and the popular cell-penetrating poly(disulfide)s, 1,4 mentioned here only to highlight the dimensions of the CAX universe waiting to be explored. 43 O, 22 and P−W 38 and parts of J, K, 37,53 and M 42 If not commercially available, TMU inhibitors were prepared as previously reported (Figure 2).…”