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Sidechain Engineering in Cell‐Penetrating Poly(disulfide)s
Author(s) -
Morelli Paola,
Matile Stefan
Publication year - 2017
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.201600370
Subject(s) - chemistry , counterion , fluorophore , azide , reagent , combinatorial chemistry , covalent bond , cytosol , disulfide bond , phosphonium , polymer chemistry , biophysics , organic chemistry , ion , biochemistry , fluorescence , enzyme , physics , quantum mechanics , biology
Cell‐penetrating poly(disulfide)s ( CPD s) have been introduced recently to explore new ways to enter into cells. In this report, we disclose a general method to covalently modify the sidechains of CPD s. Compatibility of copper‐catalyzed alkyne‐azide cycloaddition (Cu AAC ) with the addition of either strained cyclic disulfides of varied ring tension or increasing numbers of guanidinium and phosphonium cations is demonstrated. Reloading CPD s with disulfide ring tension results in an at least 20‐fold increase in activity with preserved sensitivity toward inhibition with the Ellman 's reagent. The cumulation of permanent positive charges by sidechain engineering affords Ellman ‐insensitive CPD s with similarly increased activity. Co‐localization experiments indicate that the CPD s reach endosomes, cytosol and nucleus, depending on their nature and their concentration. Supported by pertinent controls, these trends confirm that CPD s operate with combination of counterion‐ and thiol‐mediated uptake, and that the balance between the two can be rationally controlled. For the most active CPD s, uptake can be observed at substrate (fluorophore) concentrations as low as 5 n m .