The hydroxyl at the C-3 of cholic acid was converted to an amino group, and the resulting aminofunctionalized cholic acid was used as a monomer to prepare amide-linked oligomeric cholates. These cholate oligomers fold into helical structures with nanometer-sized hydrophilic internal cavities in solvent mixtures consisting of mostly nonpolar solvents such as carbon tetrachloride or ethyl acetate/hexane and 2−5% of a polar solvent such as methanol or DMSO. The conformations of the foldamers were studied by UV, fluorescence, fluorescence quenching, and fluorescence resonance energy transfer. The nature of the polar/ nonpolar solvents and their miscibility strongly influenced the folding reaction. Folding was cooperative, as evidenced by the sigmoidal curves in solvent denaturation experiments. The folded conformers became more stable with an increase in the chain length. The folding/unfolding equilibrium was highly sensitive toward the amount of polar solvent. One percent variation in the solvent composition could change the folding free energies by 0.5−1.4 kcal/mol. Disciplines Chemistry CommentsReprinted (adapted) Abstract:The hydroxyl at the C-3 of cholic acid was converted to an amino group, and the resulting aminofunctionalized cholic acid was used as a monomer to prepare amide-linked oligomeric cholates. These cholate oligomers fold into helical structures with nanometer-sized hydrophilic internal cavities in solvent mixtures consisting of mostly nonpolar solvents such as carbon tetrachloride or ethyl acetate/hexane and 2-5% of a polar solvent such as methanol or DMSO. The conformations of the foldamers were studied by UV, fluorescence, fluorescence quenching, and fluorescence resonance energy transfer. The nature of the polar/nonpolar solvents and their miscibility strongly influenced the folding reaction. Folding was cooperative, as evidenced by the sigmoidal curves in solvent denaturation experiments. The folded conformers became more stable with an increase in the chain length. The folding/unfolding equilibrium was highly sensitive toward the amount of polar solvent. One percent variation in the solvent composition could change the folding free energies by 0.5-1.4 kcal/mol.

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A hybrid foldamer constructed from six cholate units and two methionines was labeled with a DANSYL (DNS) group. The foldamer was solubilized by surfactant micelles to allow its usage as a fluorescent sensor for mercury ions present in the micromolar range in aqueous solutions. Its sensitivity was largely independent of the concentration of nonionic surfactants but was strongly influenced by both the nature and the concentration of ionic surfactants. Disciplines Chemistry CommentsReprinted (adapted) with permission from Organic Letters 8 (2006) ABSTRACTA hybrid foldamer constructed from six cholate units and two methionines was labeled with a DANSYL (DNS) group. The foldamer was solubilized by surfactant micelles to allow its usage as a fluorescent sensor for mercury ions present in the micromolar range in aqueous solutions. Its sensitivity was largely independent of the concentration of nonionic surfactants but was strongly influenced by both the nature and the concentration of ionic surfactants.

The conformations of three cholate foldamers and one molecular basket were studied by fluorescence and NMR spectroscopy. In nonpolar solvents (e.g., hexane/ethyl acetate or ethyl acetate) mixed with a small amount of a polar solvent (e.g., alcohol or DMSO), the cholate oligomer folded into a helix with the hydrophilic faces of the cholates turned inward. Folding created a hydrophilic nanocavity preferentially solvated by the entrapped polar solvent concentrated from the bulk. This microphase separation of the polar solvent was critical to the folding process. Folding was favored by larger-sized polar solvent molecules, as fewer such molecules could occupy and solvate the nanocavity, thus requiring a smaller extent of phase separation during folding. Folding was also favored by smaller/acyclic nonpolar solvent molecules, probably because they could avoid contact with the OH/NH groups within the nanocavity better than larger/cyclic nonpolar solvent molecules. Disciplines Chemistry CommentsReprinted (adapted) Abstract: The conformations of three cholate foldamers and one molecular basket were studied by fluorescence and NMR spectroscopy. In nonpolar solvents (e.g., hexane/ethyl acetate or ethyl acetate) mixed with a small amount of a polar solvent (e.g., alcohol or DMSO), the cholate oligomer folded into a helix with the hydrophilic faces of the cholates turned inward. Folding created a hydrophilic nanocavity preferentially solvated by the entrapped polar solvent concentrated from the bulk. This microphase separation of the polar solvent was critical to the folding process. Folding was favored by larger-sized polar solvent molecules, as fewer such molecules could occupy and solvate the nanocavity, thus requiring a smaller extent of phase separation during folding. Folding was also favored by smaller/acyclic nonpolar solvent molecules, probably because they could avoid contact with the OH/NH groups within the nanocavity better than larger/cyclic nonpolar solvent molecules.

Glutamate-functionalized oligocholate foldamers bound Zn(OAc)(2), guanidine, and even amine compounds with surprisingly high affinities. The conformational change of the hosts during binding was crucial to the enhanced binding affinity. The strongest cooperativity between the conformation and guest-binding occurred when the hosts were unfolded but near the folding-unfolding transition. These results suggest that high binding affinity in molecular recognition may be more easily obtained from large hosts capable of strong cooperative conformational changes instead of those with rigid, preorganized structures.

Amphiphilic molecular baskets were obtained by attaching facially amphiphilic cholate groups to a covalent scaffold (calix[4]arene or 1,3,5-2,4,6-hexasubstituted benzene). In a solvent mixture consisting of mostly a nonpolar solvent (i.e., CCl4) and a polar solvent (i.e., DMSO), the hydrophilic faces of cholates turned inward to form a reversed-micelle-like conformer whose stability was strongly influenced by the number of the cholates and the topology of the scaffold. Preferential solvation of the hydrophilic faces of cholates within the molecule by the polar solvent was cooperative and gave the fundamental driving force to the conformational change. The reversed-micelle-like conformer was most stable in structures that allowed multiple cholates to form a microenvironment that could efficiently enrich the polar solvent molecules from the bulk solvent mixture. Disciplines Chemistry CommentsReprinted (adapted) Amphiphilic molecular baskets were obtained by attaching facially amphiphilic cholate groups to a covalent scaffold (calix[4]arene or 1,3,5-2,4,6-hexasubstituted benzene). In a solvent mixture consisting of mostly a nonpolar solvent (i.e., CCl 4 ) and a polar solvent (i.e., DMSO), the hydrophilic faces of cholates turned inward to form a reversed-micelle-like conformer whose stability was strongly influenced by the number of the cholates and the topology of the scaffold. Preferential solvation of the hydrophilic faces of cholates within the molecule by the polar solvent was cooperative and gave the fundamental driving force to the conformational change. The reversed-micelle-like conformer was most stable in structures that allowed multiple cholates to form a microenvironment that could efficiently enrich the polar solvent molecules from the bulk solvent mixture.

A hybrid foldamer containing six cholate units and two glutamic acids was labeled with two pyrenyl groups at the chain ends. Folding was particularly favorable in the presence of zinc(II), as shown by the enhanced emission of the pyrene excimer. The sensitivity of the detection depended on the relative population of the folded and unfolded conformers, being highest when about 90% of the foldamer was in the unfolded state.

Fluorescence resonance energy transfer (FRET) occurred readily in a cholate hexamer labeled with a naphthyl donor and a dansyl acceptor at the chain ends when the hexamer was solubilized by sodium dodecyl sulfate (SDS) micelles in water. Independence of the energy transfer efficiency over 1−70 mM SDS suggested that the energy transfer resulted from the folding of the hexamer instead of its intermolecular aggregation within the micelle. Upon addition of sodium chloride to the solution, energy transfer became less efficient, indicating unfolding of the oligocholate. In contrast, the oligocholate stayed folded in the micelle of nonionic Brij 30, in the presence or absence of NaCl. These results suggested that the oligocholate preferred to fold within the small spherical SDS micelles but unfold when the preference for spherical over rodlike micelles was not strong enough to overcome the tendency for the oligocholate to unfold. Disciplines Chemistry CommentsReprinted (adapted) Fluorescence resonance energy transfer (FRET) occurred readily in a cholate hexamer labeled with a naphthyl donor and a dansyl acceptor at the chain ends when the hexamer was solubilized by sodium dodecyl sulfate (SDS) micelles in water. Independence of the energy transfer efficiency over 1-70 mM SDS suggested that the energy transfer resulted from the folding of the hexamer instead of its intermolecular aggregation within the micelle. Upon addition of sodium chloride to the solution, energy transfer became less efficient, indicating unfolding of the oligocholate. In contrast, the oligocholate stayed folded in the micelle of nonionic Brij 30, in the presence or absence of NaCl. These results suggested that the oligocholate preferred to fold within the small spherical SDS micelles but unfold when the preference for spherical over rodlike micelles was not strong enough to overcome the tendency for the oligocholate to unfold.