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Dynamic Covalent Michael Acceptors to Penetrate Cells: Thiol‐Mediated Uptake with Tetrel‐Centered Exchange Cascades, Assisted by Halogen‐Bonding Switches

Von Wiley-VCH zur Verfügung gestellt

Introduced as the first explicitly tetrel-centered cascade exchangers, Michael acceptors are shown to enable and inhibit thiol-mediated uptake, generate distinct patterns in heatmaps to decode uptake circuitry, integrate novel halogen-bonding switches, deliver proteins to the cytosol, and break, as dimers, records for uptake inhibition related to drug discovery.


Abstract

Chalcogen-centered cascade exchange chemistry is increasingly understood to account for thiol-mediated uptake, that is, the ability of reversibly thiol-reactive agents to penetrate cells. Here, reversible Michael acceptors are shown to enable and inhibit thiol-mediated uptake, including the cytosolic delivery of proteins. Dynamic cyano-cinnamate dimers rival the best chalcogen-centered inhibitors. Patterns generated in inhibition heatmaps reveal contributions from halogen-bonding switches that occur independent from the thyroid transporter MCT8. The uniqueness of these patterns supports that the entry of tetrel-centered exchangers into cells differs from chalcogen-centered systems. These results expand the chemical space of thiol-mediated uptake and support the existence of a universal exchange network to bring matter into cells, abiding to be decoded for drug delivery and drug discovery in the broadest sense.

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