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. 2015 Jan 1;6(1):625-631.
doi: 10.1039/c4sc02090a. Epub 2014 Jul 31.

pH-dependent binding of guests in the cavity of a polyhedral coordination cage: reversible uptake and release of drug molecules

William Cullen  1 , Simon Turega  1 , Christopher A Hunter  1 , Michael D Ward  1
Affiliations

pH-dependent binding of guests in the cavity of a polyhedral coordination cage: reversible uptake and release of drug molecules

William Cullen et al. Chem Sci. .

Abstract

A range of organic molecules with acidic or basic groups exhibit strong pH-dependent binding inside the cavity of a polyhedral coordination cage. Guest binding in aqueous solution is dominated by a hydrophobic contribution which is compensated by stronger solvation when the guests become cationic (by protonation) or anionic (by deprotonation). The Parkinson's drug 1-amino-adamantane ('amantadine') binds with an association constant of 104 M-1 in the neutral form (pH greater than 11), but the stability of the complex is reduced by three orders of magnitude when the guest is protonated at lower pH. Monitoring the uptake of the guests into the cage cavity was facilitated by the large upfield shift for the 1H NMR signals of bound guests due to the paramagnetism of the host. Although the association constants are generally lower, guests of biological significance such as aspirin and nicotine show similar behaviour, with a substantial difference between neutral (strongly binding) and charged (weakly binding) forms, irrespective of the sign of the charged species. pH-dependent binding was observed for a range of guests with different functional groups (primary and tertiary amines, pyridine, imidazole and carboxylic acids), so that the pH-swing can be tuned anywhere in the range of 3.5-11. The structure of the adamantane-1-carboxylic acid complex was determined by X-ray crystallography: the oxygen atoms of the guest form CH···O hydrogen bonds with one of two equivalent pockets on the internal surface of the host. Reversible uptake and release of guests as a function of pH offers interesting possibilities in any application where controlled release of a molecule following an external stimulus is required.

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Figures

Fig. 1
Fig. 1. (a) Sketch of the cubic host cage showing the disposition of bridging ligands spanning each edge (R = CH2OH); (b) a space-filling view of the complete cage cation, showing the external O atoms of the hydroxyl groups in red (reproduced from ref. 16a).
Fig. 2
Fig. 2. Series of partial 1H NMR spectra recorded for a mixture of host cage H (0.2 mM) and 1-aminoadamantane in D2O (1.26 mM), at pH values from 3.82 (bottom) to 12.46 (top). Progressing upwards the spectra show how 1-aminoadamantane enters the cavity as it is converted from the protonated to the neutral form at higher pH values; the signals marked • in part (a) are from the host–guest complex. pH values (from bottom up) are 3.82, 7.61, 8.62, 9.42, 9.98, 10.54, 10.90, 11.68, 12.01, 12.46.
Fig. 3
Fig. 3. Graphical representation of data extracted from Fig. 2: (a) blue curve, chemical shift of one of the signals of 1-aminoadamantane as a function of pH; (b) red curve, occupancy of the cavity of H as a function of pH on the basis of 1H NMR signal integrals. The two curves mirror each other and intersect at the pK a of 1-aminoadamantane.
Fig. 4
Fig. 4. Series of partial 1H NMR spectra recorded for a mixture of host cage H and 1-adamantane-carboxylic acid in D2O (0.24 mM), at pH values from 2.31 (bottom) to 9.57 (top). Progressing upwards the spectra show how 1-adamantane-carboxylic acid is ejected from the cavity as it is converted from the neutral to the anionic form at higher pH values; the signals marked • in part (a) are from the host–guest complex. pH values (from bottom up) are 2.31, 4.79, 5.43, 6.34, 7.00, 8.02, 9.57.
Fig. 5
Fig. 5. Graphical representation of data extracted from Fig. 4: (a) blue curve, chemical shift of one of the signals of 1-adamantane-carboxylic acid as a function of pH; (b) red curve, occupancy of the cavity of H as a function of pH on the basis of 1H NMR integrals. The two curves mirror each other and intersect at the pK a of 1-adamantane-carboxylic acid.
Fig. 6
Fig. 6. Graphical summary of association constants for guests in neutral and charged states (see also Table 1).
Fig. 7
Fig. 7. Structure of the H·(1-adamantane-carboxylic acid) complex from crystallographic data, showing the cage (in wireframe) and the encapsulated guest (space-filling mode).
Fig. 8
Fig. 8. Close-up view from the crystal structure of the four closest contacts between the oxygen atoms of the guest and some of the naphthyl and methylene CH protons of the host in the binding pocket (see main text); the C···O distances lie in the range 2.68–2.86 Å.
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