Activation and Stabilization of Drugs by Supramolecular pK_a Shifts: Drug‐Delivery Applications Tailored for Cucurbiturils

Abstract

There is rapidly developing interest in the potential of macrocyclic host molecules to modify the effective pK a values of included guests. Following early reports of small pK a shifts of included guests in cyclodextrins (DpK a % 1) [1,2] and cucurbit[6]uril [3] (DpK a % 1), we have used cucurbit [7]uril (CB7, DpK a % 2-3) [4,5] and sulfonatocalixarenes (DpK a % 2) as additional hosts and proposed structure-reactivity relationships.

Spin Exchange Monitoring of the Strong Positive Homotropic Allosteric Binding of a Tetraradical by a Synthetic Receptor in Water

“…These three species were then considered for the DFT calculations. Because of the pK a shift effect of cucurbiturils (supramolecular charge stabilization), 41 Figure S8), the four TEMPO moieties tend to magnetically interact (folded conformations) with interspin distances in the range (8-13.8 Å) which is compatible with the EPR spectrum of 4T in water (Figure 1b). In the four most stable conformers of the 1:1 complex (supporting information Figure S9), three uncomplexed TEMPO moieties are placed relatively close (8.3-13.5 Å) while the last TEMPO is pushed away from the others once included in the CB[8] cavity (d > 17 Å except for the monoammonium form).…”

Determining Protease Substrate Selectivity and Inhibition by Label-Free Supramolecular Tandem Enzyme Assays

“…Cucurbit [7]uril (CB7, Figure 1) is a water-soluble macrocycle that has been investigated extensively in biological applications including drug delivery, [29][30][31][32][33] interactions with enzymes, 34,35 plasma membrane protein fishing, 36 and label-free enzyme assays. [22][23][24][25] The repeating glycoluril units produce a barrel-shaped container that has a hydrophobic cavity and negatively charged portals.…”

A photoinduced pH jump applied to drug release from cucurbit[7]uril

“…[5][6][7] Except for the extremely unlikely event that the drug itself would be photochromic, this greatly complicates the design of such systems, because both the drug and one isomeric form of the photoactive guest would need to show a high affinity to the macrocycle (''competitive approach''). Since numerous drug complexes of different macrocycles have already been characterised and are in fact partially being used, [8][9][10][11][12][13] a ''stimulus approach'' would be complementary, in which the photoactive component does not need to compete for the macrocycle, but rather causes an effect on the macrocycle-drug equilibrium through a relay mechanism or chemical output. In the working principle established herein, this is a photoinduced pH jump.…”

“…26,27 As a consequence of the increased affinity of CBs for cationic species, 28 they display a pronounced preference for binding the protonated forms of guests over their neutral forms. 8,29,30 Accordingly, host-guest binding of CBs is strongly pH-dependent and the differential binding manifests itself in complexationinduced pK a shifts. 18,30,31 Invariably, when basic guests are investigated, their affinity increases at low pH and decreases at high pH.…”