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Tuning Chloride Binding, Encapsulation, and Transport by Peripheral Substitution of Pseudopeptidic Tripodal Small Cages
Author(s) -
Martí Inés,
Rubio Jenifer,
Bolte Michael,
Burguete M. Isabel,
Vicent Cristian,
Quesada Roberto,
Alfonso Ignacio,
Luis Santiago V.
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201202182
Subject(s) - chemistry , moiety , protonation , chloride , electrophilic substitution , nuclear magnetic resonance spectroscopy , crystallography , molecule , stereochemistry , medicinal chemistry , ion , organic chemistry
A highly efficient synthesis of small pseudopeptidic cages from simple precursors has been achieved by the triple S N 2 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.