Tuning Chloride Binding, Encapsulation, and Transport by Peripheral Substitution of Pseudopeptidic Tripodal Small Cages

Authors

  • Inés Martí,

    1. Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, Avda. Sos Baynat, s/n, 12071 Castellón (Spain), Fax: (+34) 964728214
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  • Dr. Jenifer Rubio,

    1. Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, Avda. Sos Baynat, s/n, 12071 Castellón (Spain), Fax: (+34) 964728214
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  • Dr. Michael Bolte,

    1. Institut für Anorganische Chemie, J.-W.-Goethe-Universität, Max-von-Laue-Str.7, 60438 Frankfurt/Main (Germany)
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  • Prof. Dr. M. Isabel Burguete,

    1. Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, Avda. Sos Baynat, s/n, 12071 Castellón (Spain), Fax: (+34) 964728214
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  • Dr. Cristian Vicent,

    1. Serveis Centrals d'Instrumentació Científica, Universitat Jaume I, Avda. Sos Baynat, s/n, 12071 Castellón (Spain)
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  • Dr. Roberto Quesada,

    1. Departamento de Química, Facultad de Ciencias, Universidad de Burgos, 09001 Burgos (Spain)
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  • Dr. Ignacio Alfonso,

    Corresponding author
    1. Departamento de Química Biológica y Modelización Molecular, Instituto de Química Avanzada de Cataluña (IQAC-CSIC), Jordi Girona, 18-26, 08034 Barcelona (Spain), Fax: (+34) 932045904
    • Departamento de Química Biológica y Modelización Molecular, Instituto de Química Avanzada de Cataluña (IQAC-CSIC), Jordi Girona, 18-26, 08034 Barcelona (Spain), Fax: (+34) 932045904
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  • Prof. Dr. Santiago V. Luis

    Corresponding author
    1. Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, Avda. Sos Baynat, s/n, 12071 Castellón (Spain), Fax: (+34) 964728214
    • Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, Avda. Sos Baynat, s/n, 12071 Castellón (Spain), Fax: (+34) 964728214
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Abstract

A highly efficient synthesis of small pseudopeptidic cages from simple precursors has been achieved by the triple SN2 reaction between tripodal tris(amido amines) and several 1,3,5-tris(bromomethyl)benzene electrophiles. The success of the macrobicyclization strongly depends on the central triamine scaffold, which dictates the correct preorganization of the intermediates. The chloride binding properties of the protonated pseudopeptidic cages have been studied in the solid state (by X-ray diffraction) as well as in solution (by NMR spectroscopy and ESI-MS) and in the gas phase (by collision-induced dissociation (CID)-MS). The crystal structure of the HCl salts of several cages show a chloride partially or completely caged within the cavity of the macrobicycle. Both the amino acid side chain and the substitution at the aromatic tripodal ring have an effect on the chloride binding ability. The cages derived from the 1,3,5-benzene moiety show low affinity, whereas the triple substitution in the ring (either with Me or Et) increases the chloride binding by one order of magnitude. Besides, the cages derived from aliphatic amino acids display a stronger interaction than those derived from phenylalanine. The basis for the different mode of binding depending on the receptor structure is proposed according to the structural data (X-ray and NMR spectroscopy). Finally, the transport of the chloride anion through lipid bilayers has been studied for selected cages. Despite the important differences in the chloride binding, the transport properties are better correlated with the lipophilicity of the molecules. Therefore, the pseudopeptidic cages sharing the same binding motif for chloride rendered very different interaction and transport properties depending on the peripheral substitution.

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