Published on Web 11/24/2005
Oligomeric Cholates: Amphiphilic Foldamers with
Nanometer-Sized Hydrophilic Cavities
Yan Zhao* and Zhenqi Zhong
Contribution from the Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011-3111
Abstract: The hydroxyl at the C-3 of cholic acid was converted to an amino group, and the resulting amino-
functionalized 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.
opposite directions.4,5 It has a curvature toward the hydrophilic
face as a result of the cis-fused A,B rings of the steroid
Introduction
Conformational control in biomolecules such as polypeptides
is at the heart of biology. The binding and catalytic functions
of many protein receptors and enzymes are regulated through
backbone. We hypothesized that combination of these two
features would make cholic acid a suitable monomer for
foldamer synthesis. The contrafacial hydrophilic and hydro-
phobic faces allow the utilization of solvophobic interactions
in conformational control; the curvature of the backbone creates
an intrinsic preference for oligomeric cholates to adopt folded
conformations. Another distinguishing feature of cholic acid is
its size. The distance between the carboxyl tail and the hydroxyl
group at C-3 is about 1.4 nm. Therefore, oligomers with just a
few repeating units would reach several nanometers in dimen-
sion. A large monomer unit will not only improve the synthetic
efficiency dramatically, but also provide a strong solvophobic
driving force in the conformational control, as the strength of
1
their controlled conformational changes. Biological systems rely
on these conformationally responsive molecules to sense and
react to constantly fluctuating environmental conditions. As
chemists, however, we have difficulty controlling the conforma-
tions of even small-medium-sized molecules. With an emerging
recognition for the importance of conformational control in
synthetic molecules, chemists have directed significant efforts
in recent years to foldamers, or synthetic molecules with
2
biomolecule-like, compact, ordered conformations. It is an-
ticipated that advancement in foldamer chemistry may not only
shed new light on the folding and function of biomolecules but
also allow the design of biomolecule-like, stimuli-responsive
materials based on abiotic backbones.
(
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3
1
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J. AM. CHEM. SOC. 2005, 127, 17894-17901
10.1021/ja056151p CCC: $30.25 © 2005 American Chemical Society