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Modular Assembly Using Sequential Palladium Coupling Gives Easy Access to the SMoC Class of Cellular Transporters

Authors

  • Anne-Sophie Rebstock Dr.,

    1. Biological and Medicinal Chemistry Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT (UK)
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    • These authors contributed equally to this work.

  • Cristina Visintin Dr.,

    1. Biological and Medicinal Chemistry Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT (UK)
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    • These authors contributed equally to this work.

  • Elisabetta Leo Dr.,

    1. Cancer Research UK Chromosomal Replication Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT (UK)
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    • These authors contributed equally to this work.

  • Cristina Garcia Posada,

    1. Biological and Medicinal Chemistry Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT (UK)
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  • Sarah R. Kingsbury Dr.,

    1. Cancer Research UK Chromosomal Replication Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT (UK)
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  • Gareth H. Williams Prof.,

    1. Cancer Research UK Chromosomal Replication Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT (UK)
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  • Kai Stoeber Dr.,

    1. Cancer Research UK Chromosomal Replication Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT (UK)
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  • David L. Selwood Dr.

    1. Biological and Medicinal Chemistry Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT (UK)
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Abstract

The transducing ability of the third helix of transcription factor homeodomains is effectively mimicked by a biphenyl system displaying guanidine groups. The biphenyl class of small molecule carriers (SMoCs) can carry biomolecules into a wide variety of cell types. A “combinatorial” approach to the synthesis of SMoCs is described using sequential Pd0 coupling chemistry to assemble the molecules from highly functionalized building blocks. SMoCs coupled to the DNA licensing repressor protein geminin can inhibit DNA replication in vitro. We conducted a structure–activity investigation utilizing a range of SMoC–geminin conjugates and demonstrate that both electrostatic and structural features are important for efficient uptake and functional activity. The best analogue was more efficient than either (Arg)4 or (Arg)8 linked to geminin. Effective inhibition of DNA synthesis was achieved in fibroblasts and osteosarcoma cell lines.

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