Learning from Proteins and Drugs: Receptors That Mimic Biomedically Important Binding Motifs - Designing Receptors for the Next Generation of Biosensors - page 42

Table 2 Association constants for selected anions with compounds 17-21
K assoc (M 1 )inCD 3 CN
Host Bu 4 N + Cl Bu 4 N + NBr Bu 4 N + OTs Bu 4 N + NO 3

17 3,300(1,200) 450(50) 900(50) 160(20)

18 310(10) 50(3) 40(4) 20(1)

19 28 < 10 nd nd

20 26,000(2,300) 1,500(430) 34,000(3,500) 1,600(300)

21 10 nd nd

Errors in brackets are standard deviations of 2-3 replicate titrations. For compounds 19 and 21,
errors are estimated to be < 15% [ 56 ]

138

<

that the tetrazole-functionalized hosts encoded a non-Hofmeister preference for
sulfonate/sulfate type anions relative to chloride, showing that even a subtle
structural change (in this case, the angle of the N-H donors relative to each
other) can have large effects on binding selectivities.

3 Receptors That Mimic Natural Aromatic Cage Motifs

As with receptors inspired by common drug motifs, inspection of natural binding
motifs in proteins provides a multitude of lessons on molecular recognition. One
that has found particular resonance and utility in supramolecular chemistry is the
aromatic cage motif that is used throughout nature to bind tertiary and quaternary
ammonium cations. This motif is typically defined as a rigid cluster of 2-4 aromatic
amino acid side chains (Trp, Phe, Tyr) describing a central binding site [ 57 ].
Notable examples include the choline-binding proteins, which include acetylcho-
linesterase and the nicotinic acetylcholine receptor, and several gene regulation
proteins that recognize and bind to the “histone code” marks of dimethyllysine and
trimethyllysine side chains (see Fig. 2 )[ 58 ]. The latter are especially interesting,
because they have evolved in a competitive environment where they must reject
binding of proteins that are identical to their targets but are unmethylated at the
critical lysine side chain. Thus, their aromatic cages are the sole and unique hot
spots that are responsible for this biologically driven selectivity.
It is notable that, for tertiary and especially quaternary ammonium ions, nature
rarely employs a negatively charged molecular recognition element such as car-
boxylate or phosphate. This leads one to the idea that the cation-pi interaction and
possibly the hydrophobic effect are the key operators. A large set of synthetic
receptors have been used both to demonstrate that the cation-pi interaction is adept
at encoding the strong and selective binding of quaternary ammonium ions in water.
The variety of such structures is large, and this area has been extensively reviewed
[ 59 ]. Exemplary evidence is provided by data from a single family of macrocyclic
hosts invented by Dougherty (Fig. 12 ). Host 22, a synthetic aromatic cage
functionalized with polar solubilizing groups, demonstrated the ability to bind
ammonium ion guests such as 23 and 24 with high affinities in pure water.